基于纳米胶束的Micelleplex输送小干扰RNA用于癌症治疗
|
摘要
癌症是危害人类生命健康的重大疾病之一,放疗和化疗均存在不可忽略的副作用,基于小干扰RNA (siRNA)的核酸类药物为癌症的治疗带来了新的可能。选取合适的靶基因,将针对该基因的siRNA导入肿瘤细胞中,下调其表达,可以安全有效地抑制肿瘤生长。另一方面,由于并不是所有看似“完美”的靶基因都能够通过siRNA直接沉默,当直接干扰其表达存在障碍时,可以绕开目的基因,对其合成致死相关基因进行干扰,在不损伤正常细胞的前提下,达到治疗效果。
本论文发展基于纳米胶束的micelleplex载药系统,输运siRNA治疗癌症,探索siRNA药物抗肿瘤治疗方案。在前一部分,论文利用官能化的聚乙二醇单甲醚-聚己内酯-聚磷酸酯三嵌段共聚物(mPEG-b-PCL-b-PPEEA)形成的胶束纳米颗粒,制备micelleplex,携载针对酸性神经酰胺酶的siAC,经系统给药后,将siAC输送至荷瘤小鼠的肿瘤细胞中,显著抑制了乳腺肿瘤的生长,为乳腺癌的治疗提供了新方法。在论文的后一部分,在KRAS突变的非小细胞肺癌肿瘤模型中,绕开了难以直接靶向的KRAS基因,利用KRAS与CDK4基因之间的合成致死效应,使用携载有针对CDK4siRNA (siCDK4)的混合胶束颗粒对荷瘤小鼠进行治疗。结果显示,携载有siCDK4的micelleplex对KRAS突变的肿瘤生长有显著抑制效果,而对正常细胞或KRAS野生型肿瘤的生长影响不明显,从而提供了可用于KRAS突变肿瘤的治疗方案。同时,研究结果提示,基于合成致死效应的RNA干扰治疗手段,不仅可有效杀伤目标肿瘤细胞,而且对正常组织和细胞不造成明显影响。
本论文的主要研究内容和结论如下：
(1)构建了基于mPEG-b-PCL-b-PPEEA三嵌段两亲性阳离子聚合物的micelleplex,可有效携载siRNA进入乳腺癌细胞BT474中,并在细胞内有效释放siRNA,沉默目的基因表达。当该micelleplex携载针对酸性神经酰胺酶基因的siAC进入BT474细胞后,诱发肿瘤细胞凋亡。在体内研究中,通过系统给药,给原位接种BT474乳腺癌的小鼠注射携载siAC的micelleplex,显著抑制肿瘤生长,研究结果进一步显示上述micelleplex输送siAC,有效抑制了酸性神经酰胺酶在肿瘤的表达。此研究证实了基于RNA干扰的micelleplex用于乳腺癌治疗的有效性和可行性。
(2)利用两种嵌段共聚物PCL29-b-PPEEA21和PCL40-b-PEG45制备了混合胶束纳米颗粒,并进一步制备了携载siRNA的micelleplex。研究应用合成致死原理,研究了一种针对KRAS基因突变的肿瘤治疗方案。由于CDK4基因与KRAS基因之间存在合成致死效应,在KRAS基因突变的非小细胞肺癌细胞(NSCLC)中抑制CDK4基因表达可导致肿瘤细胞的凋亡。在体外研究中,我们利用混合胶束纳米颗粒制备的micelleplex携载siCDK4,转染KRAS突变的NSCLC细胞及KRAS野生型的细胞,发现CDK4的表达均被下调。然而,随着CDK4表达的下降,仅KRAS突变的NSCLC细胞增殖受到抑制,KRAS野生型的NSCLC细胞以及正常人肝细胞的生长增殖均影响不明显。同时,构建了小鼠的KRAS突变型以及KRAS野生型的NSCLC细胞皮下植入肿瘤模型,通过尾静脉注射携载有siCDK4的micelleplex进行治疗,发现仅KRAS突变的肿瘤生长被有效抑制,KRAS野生型的肿瘤生长则没有受到显著影响,证实该治疗方案的特异性、高效性和安全性,为开发siRNA药物提供了新的策略。
Cancer remains the leading cause of death in the world after heart and infectious diseases. Radiotherapy and chemotherapy are two of the major treatment modalities for cancer, which are accompanied by inevitable side effects. Thus, identifying therapeutics that will kill cancer cells and do not harm patients is the bottleneck, which lies with our inability. Based on the fact that nanoparticulate siRNA delivery system has shown great promise for cancer therapy, the suitable drug target and nanocarrier can be chosen for efficient gene downregulation and tumor growth inhibition. On the other hand, the therapeutics based on RNAi are not omnipotent and a lot of drug targets still undruggable. With a more complete understanding of the complex and extensive network of effectors and regulators, secondary dependencies on genes that are themselves not oncogenes but could lead to vulnerabilities caused by the target genes mutation state can also be developed to provide more efficient and safe therapeutic opportunities.
This dissertation aims to exploit safe and efficient treatment against cancer based on siRNA delivery system with micelleplex. The main content and conclusions of this dissertation are summarized as below:
1. One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcriptin vivo. In this part, we have developed a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. The triblock copolymer, mPEG-b-PCL-b-PPEEA, can self-assemble into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of60nm and a zeta potential of approximately48mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplexsiAC significantly inhibited tumor growth in a BT474xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy.
2. The KRAS mutation is present in approximately20%of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in NSCLC and confers resistance to standard anticancer treatment drugs, including EGFR tyrosine kinase inhibitors. In this part, we have exploited a new therapeutic strategy based on the synthetic lethal interaction between CDK4downregulation and the KRAS mutation to deliver micellar nanoparticles containing siRNA targeting CDK4(MNPsiCDK4) for treatment in NSCLC harboring the oncogenic KRAS mutation. Following MNPSiCDK4administration, CDK4expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLC. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4significantly inhibited tumor growth in an A549NSCLC xenograft murine model, with depressed expression of CDK4and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4delivery in KRAS mutant NSCLC via a synthetic lethal interaction between KRAS and CDK4. These investigations are promising in terms of exploiting a new therapeutic strategy that is effective and safe in KRAS mutant NSCLC.
本论文发展基于纳米胶束的micelleplex载药系统,输运siRNA治疗癌症,探索siRNA药物抗肿瘤治疗方案。在前一部分,论文利用官能化的聚乙二醇单甲醚-聚己内酯-聚磷酸酯三嵌段共聚物(mPEG-b-PCL-b-PPEEA)形成的胶束纳米颗粒,制备micelleplex,携载针对酸性神经酰胺酶的siAC,经系统给药后,将siAC输送至荷瘤小鼠的肿瘤细胞中,显著抑制了乳腺肿瘤的生长,为乳腺癌的治疗提供了新方法。在论文的后一部分,在KRAS突变的非小细胞肺癌肿瘤模型中,绕开了难以直接靶向的KRAS基因,利用KRAS与CDK4基因之间的合成致死效应,使用携载有针对CDK4siRNA (siCDK4)的混合胶束颗粒对荷瘤小鼠进行治疗。结果显示,携载有siCDK4的micelleplex对KRAS突变的肿瘤生长有显著抑制效果,而对正常细胞或KRAS野生型肿瘤的生长影响不明显,从而提供了可用于KRAS突变肿瘤的治疗方案。同时,研究结果提示,基于合成致死效应的RNA干扰治疗手段,不仅可有效杀伤目标肿瘤细胞,而且对正常组织和细胞不造成明显影响。
本论文的主要研究内容和结论如下：
(1)构建了基于mPEG-b-PCL-b-PPEEA三嵌段两亲性阳离子聚合物的micelleplex,可有效携载siRNA进入乳腺癌细胞BT474中,并在细胞内有效释放siRNA,沉默目的基因表达。当该micelleplex携载针对酸性神经酰胺酶基因的siAC进入BT474细胞后,诱发肿瘤细胞凋亡。在体内研究中,通过系统给药,给原位接种BT474乳腺癌的小鼠注射携载siAC的micelleplex,显著抑制肿瘤生长,研究结果进一步显示上述micelleplex输送siAC,有效抑制了酸性神经酰胺酶在肿瘤的表达。此研究证实了基于RNA干扰的micelleplex用于乳腺癌治疗的有效性和可行性。
(2)利用两种嵌段共聚物PCL29-b-PPEEA21和PCL40-b-PEG45制备了混合胶束纳米颗粒,并进一步制备了携载siRNA的micelleplex。研究应用合成致死原理,研究了一种针对KRAS基因突变的肿瘤治疗方案。由于CDK4基因与KRAS基因之间存在合成致死效应,在KRAS基因突变的非小细胞肺癌细胞(NSCLC)中抑制CDK4基因表达可导致肿瘤细胞的凋亡。在体外研究中,我们利用混合胶束纳米颗粒制备的micelleplex携载siCDK4,转染KRAS突变的NSCLC细胞及KRAS野生型的细胞,发现CDK4的表达均被下调。然而,随着CDK4表达的下降,仅KRAS突变的NSCLC细胞增殖受到抑制,KRAS野生型的NSCLC细胞以及正常人肝细胞的生长增殖均影响不明显。同时,构建了小鼠的KRAS突变型以及KRAS野生型的NSCLC细胞皮下植入肿瘤模型,通过尾静脉注射携载有siCDK4的micelleplex进行治疗,发现仅KRAS突变的肿瘤生长被有效抑制,KRAS野生型的肿瘤生长则没有受到显著影响,证实该治疗方案的特异性、高效性和安全性,为开发siRNA药物提供了新的策略。
Cancer remains the leading cause of death in the world after heart and infectious diseases. Radiotherapy and chemotherapy are two of the major treatment modalities for cancer, which are accompanied by inevitable side effects. Thus, identifying therapeutics that will kill cancer cells and do not harm patients is the bottleneck, which lies with our inability. Based on the fact that nanoparticulate siRNA delivery system has shown great promise for cancer therapy, the suitable drug target and nanocarrier can be chosen for efficient gene downregulation and tumor growth inhibition. On the other hand, the therapeutics based on RNAi are not omnipotent and a lot of drug targets still undruggable. With a more complete understanding of the complex and extensive network of effectors and regulators, secondary dependencies on genes that are themselves not oncogenes but could lead to vulnerabilities caused by the target genes mutation state can also be developed to provide more efficient and safe therapeutic opportunities.
This dissertation aims to exploit safe and efficient treatment against cancer based on siRNA delivery system with micelleplex. The main content and conclusions of this dissertation are summarized as below:
1. One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcriptin vivo. In this part, we have developed a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. The triblock copolymer, mPEG-b-PCL-b-PPEEA, can self-assemble into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of60nm and a zeta potential of approximately48mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplexsiAC significantly inhibited tumor growth in a BT474xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy.
2. The KRAS mutation is present in approximately20%of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in NSCLC and confers resistance to standard anticancer treatment drugs, including EGFR tyrosine kinase inhibitors. In this part, we have exploited a new therapeutic strategy based on the synthetic lethal interaction between CDK4downregulation and the KRAS mutation to deliver micellar nanoparticles containing siRNA targeting CDK4(MNPsiCDK4) for treatment in NSCLC harboring the oncogenic KRAS mutation. Following MNPSiCDK4administration, CDK4expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLC. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4significantly inhibited tumor growth in an A549NSCLC xenograft murine model, with depressed expression of CDK4and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4delivery in KRAS mutant NSCLC via a synthetic lethal interaction between KRAS and CDK4. These investigations are promising in terms of exploiting a new therapeutic strategy that is effective and safe in KRAS mutant NSCLC.
引文
[1]SIEGEL R, DESANTIS C, VIRGO K, et al. Cancer treatment and survivorship statistics,2012 [J]. Ca-Cancer J Clin,2012,62(4):220-41.
[2]SIEGEL R, NAISHADHAM D, JEMAL A. Cancer statistics,2012 [J]. Ca-Cancer J Clin,2012, 62(1):10-29.
[3]ZHU L, PICKLE L W, GHOSH K, et al. Predicting US-and state-level cancer counts for the current calendar year [J]. Cancer-Am Cancer Soc,2012,118(4):1100-9.
[4]JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics [J]. Ca-Cancer J Clin,2011, 61(2):69-90.
[5]BRAY F, JEMAL A, GREY N, et al. Global cancer transitions according to the human development Index (2008-2030):a population-based study [J]. Lancet Oncol,2012,13(8): 790-801.
[6]赫捷、陈万青.2012中国肿瘤登记年报[M].军事医学科学出版社,2012.
[7]SINGER C F, TEA M K, PRISTAUZ G, et al. Guideline for the Prevention and early detection of breast and ovarian cancer in high-risk patients, especially in women from HBOC (Hereditary Breast and Ovarian Cancer) families [J]. Wien Klin Wochenschr,2012,124(19-20):735-41.
[8]PHUNG Y, WANG Z H, AKSAMIT I, et al. Guideline-based treatment utilization, treatment time, and cost of chemotherapy for metastatic colon cancer patients treated in US community oncology practices from 2005 to 2009 [J]. J Clin Oncol,2012,30(15):
[9]PACINIF, CASTAGNA M G, BRILLIL, et al. Thyroid cancer:ESMO clinical practice guidelines for diagnosis, treatment and follow-up [J]. Ann Oncol,2012,23(110-9.
[10]THERASSE P, ARBUCK S G, EISENHAUER E A, et al. New guidelines to evaluate the response to treatment in solid Tumors [J]. J Natl Cancer I,2000,92(3):205-16.
[11]ENGELMAN J A. Targeting PI3K signalling in cancer:opportunities, challenges and limitations [J]. Nat Rev Cancer,2009,9(8):550-62.
[12]YU H, PARDOLL D, JOVE R. STATs in cancer inflammation and immunity:a leading role for STAT3 [J]. Nat Rev Cancer,2009,9(11):798-809.
[13]DESGROSELLIER J S, CHERESH D A. Integrins in cancer:biological implications and therapeutic opportunities [J]. Nat Rev Cancer,2010,10(1):9-22.
[14]LUO J, SOLIMINI N L, ELLEDGE S J. Principles of cancer therapy:Oncogene and non-oncogene addiction [J]. Cell,2009,136(5):823-37.
[15]LAPENNA S, GIORDANO A. Cell cycle kinases as therapeutic targets for cancer [J]. Nat Rev Drug Discov,2009,8(7):547-66.
[16]SCOTT A M, WOLCHOK J D, OLD L J. Antibody therapy of cancer [J]. Nat Rev Cancer,2012, 12(4):278-87.
[17]ZHANG J M, YANG P L, GRAY N S. Targeting cancer with small molecule kinase inhibitors [J]. Nat Rev Cancer,2009,9(1):28-39.
[18]GARZON R, MARCUCCI G, CROCE C M. Targeting microRNAs in cancer:rationale, strategies and challenges [J]. Nat Rev Drug Discov,2010,9(10):775-89.
[19]OPALINSKA J B, GEWIRTZ A M. Nucleic-acid therapeutics:Basic principles and recent applications [J]. Nat Rev Drug Discov,2002,1(7):503-14.
[20]GUTIERREZ A A, LEMOINE N R, SIKORA K. Gene-therapy for Cancer [J]. Lancet,1992, 339(8795):715-21.
[21]Leading Anti-Cancer Drugs and Associated Market 2012-2022 [M/OL].2012.
[22]MARIOTTO A B, YABROFF K R, SHAO Y W, et al. Projections of the Cost of Cancer Care in the United States:2010-2020 [J]. J Natl Cancer I,2011,103(2):117-28.
[23]TABARA H, GRISHOK A, MELLO C C. RNAi in C-elegans:Soaking in the genome sequence [J]. Science,1998,282(5388):430-1.
[24]SONG E W, LEE S K, WANG J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis [J]. Nat Med,2003,9(3):347-51.
[25]KIM D H, ROSSI J J. Strategies for silencing human disease using RNA interference [J]. Nat Rev Genet,2007,8(3):173-84.
[26]KLEINMAN M E, YAMADA K, TAKEDA A, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 [J]. Nature,2008,452(7187):591-U1.
[27]JACQUE J M, TRIQUES K, STEVENSON M. Modulation of HIV-1 replication by RNA interference [J]. Nature,2002,418(6896):435-8.
[28]ELBASHIR S M, LENDECKEL W, TUSCHL T. RNA interference is mediated by 21-and 22-nucleotide RNAs [J]. Gene Dev,2001,15(2):188-200.
[29]YU J Y, DERUITER S L, TURNER D L. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells [J]. P Natl Acad Sci USA,2002,99(9):6047-52.
[30]GAVRILOV K, SALTZMAN W M. Therapeutic siRNA:Principles, challenges,and strategies [J]. Adv Drug Deliver Rev,2007,59(2):75-86.
[31]HARBORTH J, ELBASHIR S M, BECHERT K, et al. RNAi based gene silencing in mammalian tissue culture cells:a key procedure fur functional gone analysis [J]. Mol Biol Cell,2001, 12(520a-la.
[32]HANNON G J, ROSSI J J. Unlocking the potential of the human genome with RNA interference [J]. Nature,2004,431(7006):371-8.
[33]ASHIHARA E, KAWATA E, MAEKAWA T. Future prospect of RNA interference for cancer therapies [J]. Curr Drug Targets,2010,11(3):345-60.
[34]LEUNG R K M, WHITTAKER P A. RNA interference:From gene silencing to gene-specific therapeutics [J]. Pharmacol Therapeut,2005,107(2):222-39.
[35]DE FOUGEROLLES A, VORNLOCHER H P, MARAGANORE J, et al. Interfering with disease: a progress report on siRNA-based therapeutics [J]. Nat Rev Drug Discov,2007,6(6):443-53.
[36]BURNETT J C, ROSSI J J, TIEMANN K. Current progress of siRNA/shRNA therapeutics in clinical trials [J]. Biotechnol J,2011,6(9):1130-46.
[37]NGUYEN T A, FRUEHAUF J H. Transkingdom RNA interference (tkRNAi):a novel method,to induce therapeutic gene silencing [J]. Meth Mol Biol,2009,514(27-34.
[38]XIANG S, KEATES A C, FRUEHAUF J, et al. In vitro and in vivo gene silencing by TransKingdom RNAi (tkRNAi) [J]. Meth Mol Biol,2009,487(147-60.
[39]REAGAN-SHAW S, AHMAD N. Silencing of polo-like kinase (Plk) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer [J]. Faseb J,2005,19(1):611-3.
[40]VAISHNAW A K, CERVANTES A, ALSINA M, et al. RNAi in humans:phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement [J]. Nucleic Acid Ther,2011,21 (5):A44.
[41]VAISHNAW A K, GOLLOB J, GAMBA-VITALO C, et al. A status report on RNAi therapeutics [J]. Silence,2010,1(1):14.
[42]KOLDEHOFF M, STECKEL N K, BEELEN D W, et al. Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukaemia [J]. Clin Exp Med,2007,7(2):47-55.
[43]SANTEL A, ALEKU M, RODER N, et al. AtuO27 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models [J]. Clin Cancer Res,2010,16(22):5469-80.
[44]DAVIS M E, ZUCKERMAN J E, CHOI C H J, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles [J]. Nature,2010,464(7291): 1067-U140.
[45]RIEDMANN E M. Gradalis cancer vaccine FANG prolongs survival In advanced stage cancer patients [J]. Hum Vacc Immunother,2012,8(4):417-.
[46]GHISOLIM, LENARSKY C, WEINTHAL J, et al. Phase I study of the "Triad" autologous (Fang (Tm)) vaccine incorporating bifunctional shrnafurin and Gmcsf transgene expression in advanced Ewing's sarcoma:Preliminary data in pediatrics patients [J]. Pediatr Blood Cancer,2013,60(S73).
[47]DANNULL J, LESHER D T, HOLZKNECHT R, et al. Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity [J]. Blood,2007,110(13): 4341-50.
[48]GUO P X, COBAN O, SNEAD N M, et al. Engineering RNA for Targeted siRNA Delivery and Medical Application [J]. Adv Drug Deliver Rev,2010,62(6):650-66.
[49]WHITEHEAD K A, LANGER R, ANDERSON D G. Knocking down barriers:advances in siRNA delivery [J]. Nat Rev Drug Discov,2009,8(2):129-38.
[50]AAGAARD L, ROSSI J J. RNAi therapeutics:Principles, prospects and challenges [J]. Adv Drug Deliver Rev,2007,59(2-3):75-86.
[51]CHO W G, ALBUQUERQUE R J C, KLEINMAN M E, et al. Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth [J]. P Natl Acad Sci USA,2009, 106(17):7137-42.
[52]DEJNEKA N S, WAN S H, BOND O S, et al. Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes [J]. Mol Vis,2008,14(116-19):997-1005.
[53]KOLDEHOFF M, BEELEN D W, EHMAAGACLI A H. Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukemia. [J]. Blood,2007,110(11):217b-b.
[54]SAMUEL-ABRAHAM S, LEONARD J N. Staying on message:design principles for controlling nonspecific responses to siRNA [J]. Febs J,2010,277(23):4828-36.
[55]JUDGE A D, BOLA G, LEE A C H, et al. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo [J]. Mol Ther,2006,13(3):494-505.
[56]JACKSON A L, BURCHARD J, LEAKE D, et al. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing [J]. Rna,2006,12(7):1197-205.
[57]OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Nanomedicine based approaches for the delivery of siRNA in cancer [J]. J Intern Med,2010,267(1):44-53.
[58]PEER D, LIEBERMAN J. Special delivery:Targeted therapy with small RNAs [J]. Gene Ther, 2011,18(12):1127-33.
[59]WANG A Z, LANGER R, FAROKHZAD O C. Nanoparticle delivery of cancer drugs [J]. Annu Rev Med,2012,63(185-98.
[60]SHEKHAR C. Lean and Mean:Nanoparticle-based delivery improves performance of cancer drugs [J]. Chem Biol,2009,16(4):349-50.
[61]DE FOUGEROLLES A R. Delivery vehicles for small interfering RNA in vivo [J]. Hum Gene Ther,2008,19(2):125-32.
[62]MA X W, ZHAO Y L, LIANG X J. Theranostic nanoparticles engineered for clinic and pharmaceutics [J]. Accounts Chem Res,2011,44(10):1114-22.
[63]FENSKE D B, CULLIS P R. Liposomal nanomedicines [J]. Expert Opin Drug Del,2008,5(1): 25-44.
[64]ELOUAHABI A, RUYSSCHAERT J M. Formation and intracellular trafficking of lipoplexes and polyplexes [J]. Mol Ther,2005,11(3):336-47.
[65]WU S Y, MCMILLAN N A J. Lipidic systems for in vivo siRNA delivery [J]. Aaps J,2009,11(4): 639-52.
[66]LANDEN C N, CHAVEZ-REYES A, BUCANA C, et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery [J]. Cancer Res,2005,65(15): 6910-8.
[67]HALDER J, KAMAT A A, LANDEN C N, et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy [J]. Clin Cancer Res,2006,12(16):4916-24.
[68]OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Nanomedicine based approaches for the delivery of siRNA in cancer [J]. J Intern Med,2010,267(1):44-53.
[69]KOSTARELOS K, EMFIETZOGLOU D, PAPAKOSTAS A, et al. Binding and interstitial penetration of liposomes within avascular tumor spheroids [J]. Int J Cancer,2004,112(4):713-21.
[70]DOKKA S, TOLEDO D, SHI X Q et al. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes [J]. Pharm Res,2000,17(5):521-5.
[71]SPAGNOU S, MILLER A D, KELLER M. Lipidic carriers of siRNA:Differences in the formulation, cellular uptake, and delivery with plasmid DNA [J]. Biochemistry-Us,2004,43(42): 13348-56.
[72]LV H T, ZHANG S B, WANG B, et al. Toxicity of cationic lipids and cationic polymers in gene delivery [J]. J Control Release,2006,114(1):100-9.
[73]UNER M, YENER G Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives [J]. Int J Nanomed,2007,2(3):289-300.
[74]SANTEL A, ALEKU M, KEIL O, et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy [J]. Gene Ther,2006,13(18): 1360-70.
[75]SANTEL A, ALEKU M, KEIL O, et al. A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium [J]. Gene Ther,2006,13(16):1222-34.
[76]ALEKU M, SCHULZ P, KEIL O, et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression [J]. Cancer Res,2008,68(23):9788-98.
[77]BROWER V. RNA interference advances to early-stage clinical trials [J]. J Natl Cancer I,2010, 102(19):1459-61.
[78]ALABI C, VEGAS A, ANDERSON D. Attacking the genome:emerging siRNA nanocarriers from concept to clinic [J]. Curr Opin Pharmacol,2012,12(4):427-33.
[79]JIN J, BAE K H, YANG H, et al. In vivo specific delivery of c-met siRNA to glioblastoma using cationic solid lipid nanoparticles [J]. Bioconjugate Chem,2011,22(12):2568-72.
[80]ZIMMERMANN T S, LEE A C H, AKINC A, et al. RNAi-mediated gene silencing in non-human primates [J]. Nature,2006,441(7089):111-4.
[81]JUDGE A D, ROBBINS M, TAVAKOLI I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice [J]. J Clin Invest,2009,119(3):661-73.
[82]EGUSQUIAGUIRRE S P, IGARTUA M, HERNANDEZ R M, et al. Nanoparticle delivery systems for cancer therapy:Advances in clinical and preclinical research [J]. Clin Transl Oncol, 2012,14(2):83-93.
[83]WANG Y, LI Z G, HAN Y, et al. Nanoparticle-based delivery system for application of siRNA in vivo [J]. Curr Drug Metab,2010,11(2):182-96.
[84]YUAN X D, NAGUIB S, WU Z Q. Recent advances of siRNA delivery by nanoparticles [J]. Expert Opin Drug Del,2011,8(4):521-36.
[85]DAVIS M E, BREWSTER M E. Cyclodextrin-based pharmaceutics:Past, present and future [J]. Nat Rev Drug Discov,2004,3(12):1023-35.
[86]HU-LIESKOVAN S, HEIDEL J D, BARTLETT D W, et al. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma [J]. Cancer Res,2005,65(19):8984-92.
[87]HOWARD K A, RAHBEK U L, LIU X D, et al. RNA interference in vitro and in vivo using a chitosan/siRNA nanoparticle system [J]. Mol Ther,2006,14(4):476-84.
[88]LIU X D, HOWARD K A, DONG M D, et al. The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing [J]. Biomaterials,2007,28(6): 1280-8.
[89]JEAN M, SMAOUI F, LAVERTU M, et al. Chitosan-plasmid nanoparticle formulations for IM and SC delivery of recombinant FGF-2 and PDGF-BB or generation of antibodies [J]. Gene Ther, 2009,16(9):1097-110.
[90]KATAS H, ALPAR H O. Development and characterisation of chitosan nanoparticles for siRNA delivery [J]. J Control Release,2006,115(2):216-25.
[91]MERKEL O M, BEYERLE A, BECKMANN B M, et al. Polymer-related off-target effects in non-viral siRNA delivery [J]. Biomaterials,2011,32(9):2388-98.
[92]MOGHIMI S M, SYMONDS P, MURRAY J C, et al. A two-stage poly(ethylenimine)-mediated cytotoxicity:Implications for gene transfer/therapy [J]. Mol Ther,2005,11(6):990-5.
[93]HUNTER A C, MOGHIMI S M. Cationic carriers of genetic material and cell death:A mitochondrial tale [J]. Bba-Bioenergetics,2010,1797(6-7):1203-9.
[94]WOODROW K A, CU Y, BOOTH C J, et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA [J]. Nat Mater,2009,8(6): 526-33.
[95]SINGHA K, NAMGUNG R, KIM W J. Polymers in Small-Interfering RNA Delivery [J]. Nucleic Acid Ther,2011,21(3):133-47.
[96]WU Z W, CHDEN C T, LIU C Y, et al. Recent progress in copolymer-mediated siRNA delivery [J]. J Drug Target,2012,20(7):551-60.
[97]KESHARWANI P, TEKADE R K, GAJBHIYE V, et al. Cancer targeting potential of some ligand-anchored polypropylene imine) dendrimers:a comparison [J]. Nanomed-Nanotechnol, 2011,7(3):295-304.
[98]LEE J H, CHA K E, KIM M S, et al. Nanosized polyamidoamine (PAMAM) dendrimer-induced apoptosis mediated by mitochondrial dysfunction [J]. Toxicol Lett,2009,190(2):202-7.
[99]TARATULA O, GARBUZENKO O B, KIRKPATRICK P, et al. Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery [J]. J Control Release,2009, 140(3):284-93.
[100]AGRAWAL A, MIN D H, SINGH N, et al. Functional delivery of siRNA in mice using dendriworms [J]. Acs Nano,2009,3(9):2495-504.
[101]JEONG J H, MOK H, OH Y K, et al. siRNA conjugate delivery systems [J]. Bioconjugate Chem, 2009,20(1):5-14.
[102]ROZEMA D B, LEWIS D L, WAKEFIELD D H, et al. Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes [J]. P Natl Acad Sci USA,2007,104(32):12982-7.
[103]MUDD S R, TRUBETSKOY V S, BLOKHIN A V, et al. Hybrid PET/CT for noninvasive pharmacokinetic evaluation of dynamic PolyConjugates, a synthetic siRNA delivery system [J]. Bioconjug Chem,2010,21(7):1183-9.
[104]LIU P X, CHENG H L, ROBERTS T M, et al. Targeting the phosphoinositide 3-kinase pathway in cancer [J]. Nat Rev Drug Discov,2009,8(8):627-44.
[105]BOLLAG G, HIRTH P, TSAI J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma [J]. Nature,2010,467(7315):596-9.
[106]ROBERTS P J, DER C J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer [J]. Oncogene,2007,26(22):3291-310.
[107]STREBHARDT K, ULLRICH A. Opinion-Targeting polo-like kinase 1 for cancer therapy [J]. Nat Rev Cancer,2006,6(4):321-30.
[108]MALUMBRES M, BARBACID M. Cell cycle, CDKs and cancer:a changing paradigm [J]. Nat Rev Cancer,2009,9(3):153-66.
[109]HARTWELL L H, KASTAN M B. Cell-cycle control and cancer [J]. Science,1994,266(5192): 1821-8.
[110]VERDINE G L, WALENSKY L D. The challenge of drugging undruggable targets in cancer: Lessons learned from targeting BCL-2 family members [J]. Clin Cancer Res,2007,13(24): 7264-70.
[111]YANO J, HKABAYASHI K, NAKAGAWA S, et al. Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer [J]. Clin Cancer Res,2004,10(22): 7721-6.
[112]ZEIDAN Y H, JENKINS R W, KORMAN J B, et al. Molecular targeting of acid ceramidase: Implications to cancer therapy [J]. Curr Drug Targets,2008,9(8):653-61.
[113]HUWILER A, ZANGEMEISTER-WITTKE U. Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy [J]. Crit Rev Oncol Hemat,2007, 63(2):150-9.
[114]MORALES A, PARIS R, VILLANUEVA A, et al. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo [J]. Oncogene,2007,26(6):905-16.
[115]CARMELIET P, JAIN R K. Molecular mechanisms and clinical applications of angiogenesis [J]. Nature,2011,473(7347):298-307.
[116]HU M, POLYAK K. Microenvironmental regulation of cancer development [J]. Curr Opin Genet Dev,2008,18(1):27-34.
[117]REDDY A, KAELIN W G. Using cancer genetics to guide the selection of anticancer drug targets [J]. Curr Opin Pharmacol,2002,2(4):366-73.
[118]KAELIN W G. Choosing anticancer drug targets in the postgenomic era [J]. J Clin Invest,1999, 104(11):1503-6.
[119]KAELIN W G The concept of synthetic lethality in the context of anticancer therapy [J]. Nat Rev Cancer,2005,5(9):689-98.
[120]YOUNG A, LYONS J, MILLER A L, et al. Ras Signaling and Therapies [J]. Adv Cancer Res, 2009,102(1-17.
[121]LUO J, EMANUELE M J, LI D N, et al. A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene [J]. Cell,2009,137(5):835-48.
[122]KARNOUB A E, WEINBERG R A. Ras oncogenes:split personalities [J]. Nat Rev Mol Cell Bio, 2008,9(7):517-31.
[123]MIZUARAI S, KOTANI H. Synthetic lethal interactions for the development of cancer therapeutics:biological and methodological advancements [J]. Hum Genet,2010,128(6):567-75.
[124]CHAN D A, GIACCIA A J. Harnessing synthetic lethal interactions in anticancer drug discovery [J]. Nat Rev Drug Discov,2011,10(5):351-64.
[125]QIU L Y, BAE Y H. Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs [J]. Biomaterials,2007,28(28):4132-42.
[126]SHUAI X T, MERDAN T, UNGER F, et al. Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG:Synthesis, characterization, and potential as efficient nonviral gene delivery vectors [J]. Macromolecules,2003,36(15):5751-9.
[127]WANG Y, GAO S J, YE W H, et al. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer [J]. Nat Mater,2006,5(10):791-6.
[128]WANG Y, WANG L S, GOH S H, et al. Synthesis and characterization of cationic micelles self-assembled from a biodegradable copolymer for gene delivery [J]. Biomacromolecules,2007, 8(3):1028-37.
[129]WANG Y, KE C Y, BEH C W, et al. The self-assembly of biodegradable cationic polymer micelles as vectors for gene transfection [J]. Biomaterials,2007,28(35):5358-68.
[130]ZHU C H, JUNG S, LUO S B, et al. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers [J]. Biomaterials,2010,31(8):2408-16.
[131]SEGURA T, HUBBELL J A. Synthesis and in vitro characterization of an ABC triblock copolymer for siRNA delivery [J]. Bioconjugate Chem,2007,18(3):736-45.
[132]XIONG X B, ULUDAG H, LAVASANIFAR A. Biodegradable amphiphilic polyethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery [J]. Biomaterials,2009,30(2):242-53.
[133]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[134]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic Iriblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials,2011,32(11):3124-33.
[135]SUN T M, DU J Z, YAO Y D, et al. Simultaneous delivery of siRNA and paclitaxel via a "Two-in-One" micelleplex promotes synergistic tumor suppression [J]. ACS Nano,2011,5(2): 1483-94.
[136]WANG H X, XIONG M H, WANG Y C, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. J Control Release,2013,166(2):106-14.
[137]LIU X Q, XIONG M H, SHU X T, et al. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth [J]. Mol Pharm,2012,9(10):2863-74.
[1]LANDTHALER M, YALCIN A, TUSCHL T. The human DiGeorge syndrome critical region gene 8 and its D-melanogaster homolog are required for miRNA biogenesis [J]. Curr Biol,2004,14(23): 2162-7.
[2]MCCAFFREY A P, NAKAI H, PANDEY K, et al. Inhibition of hepatitis B virus by RNA interference in mice [J]. Mol Ther,2003,7(5):S312-S3.
[3]JACQUE J M, TRIQUES K, STEVENSON M. Modulation of HIV-1 replication by RNA interference [J]. Nature,2002,418(6896):435-8.
[4]STEVENSON M. Therapeutic potential of RNA interference [J]. New Engl J Med,2004,351(17): 1772-7.
[5]KIM D H, ROSSI J J. Strategies for silencing human disease using RNA interference [J]. Nat Rev Genet,2007,8(3):173-84.
[6]HANNON G J, ROSSI J J. Unlocking the potential of the human genome with RNA interference [J]. Nature,2004,431(7006):371-8.
[7]MICHIENZI A, CASTANOTTO D, LEE N, et al. RNA-mediated inhibition of HIV in a gene therapy setting [J]. Ann Ny Acad Sci,2003,1002(1):63-71.
[8]RAOUL C, ABBAS-TERKI T, BENSADOUN J C, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS [J]. Nat Med,2005,11(4):423-8.
[9]MINAKUCHI Y, TAKESHITA F, KOSAKA N, et al. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo [J]. Nucleic Acids Res, 2004,32(13):
[10]MEDAROVA Z, PHAM W, FARRAR C, et al. In vivo imaging of siRNA delivery and silencing in tumors [J]. Nat Med,2007,13(3):372-7.
[11]SONG E W, ZHU P C, LEE S K, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors [J]. Nat Biotechnol,2005,23(6):709-17.
[12]DYKXHOORN D M, LIEBERMAN J. Running interference:Prospects and obstacles to using small interfering RNAs as small molecule drugs [J]. Annu Rev Biomed Eng,2006,8(377-402.
[13]DE FOUGEROLLES A, VORNLOCHER H P, MARAGANORE J, et al. Interfering with disease: A progress report on siRNA-based therapeutics [J]. Nat Rev Drug Discov,2007,6(6):443-53.
[14]JULIANO R, BAUMAN J, KANG H, et al. Biological barriers to therapy with antisense and siRNA oligonucleotides [J]. Mol Pharmaceut,2009,6(3):686-95.
[15]CASTANOTTO D, ROSSI J J. The promises and pitfalls of RNA-interference-based therapeutics [J]. Nature,2009,457(7228):426-33.
[16]BARTLETT D W, SU H, HILDEBRANDT I J, et al. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging [J].P Natl Acad Sci USA,2007,104(39):15549-54.
[17]AKINC A, ZUMBUEHL A, GOLDBERG M, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics [J]. Nat Biotechnol,2008,26(5):561-9.
[18]KUMAR P, WU H Q, MCBRIDE J L, et al. Transvascular delivery of small interfering RNA to the central nervous system [J]. Nature,2007,448(7149):39-43.
[19]ZHANG S B, ZHAO B, JIANG H M, et al. Cationic lipids and polymers mediated vectors for delivery of siRNA [J]. J Control Release,2007,123(1):1-10.
[20]GAO K, HUANG L. Nonviral methods for siRNA delivery [J]. Mol Pharmaceut,2009,6(3): 651-8.
[21]DAVIS M E. The First Targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle:From concept to clinic [J]. Mol Pharmaceut,2009,6(3):659-68.
[22]ALSHAMSAN A, HADDADI A, INCANI V, et al. Formulation and delivery of siRNA by oleic acid and stearic acid modified polyethylenimine [J]. Mol Pharmaceut,2009,6(1):121-33.
[23]KUMAR P, BAN H S, KIM S S, et al. T cell-specific siRNA delivery suppresses HTV-1 infection in humanized mice [J]. Cell,2008,134(4):577-86.
[24]ROTHDIENER M, MULLER D, CASTRO P G, et al. Targeted delivery of siRNA to CD33-positive tumor cells with liposomal carrier systems [J]. J Control Release,2010,144(2): 251-8.
[25]LI S D, HUANG L. Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells [J]. Mol Pharmaceut,2006,3(5):579-88.
[26]QIU L Y, BAE Y H. Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs [J]. Biomaterials,2007,28(28):4132-42.
[27]SHUAI X T, MERDAN T, UNGER F, et al. Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG:Synthesis, characterization, and potential as efficient nonviral gene delivery vectors [J]. Macromolecules,2003,36(15):5751-9.
[28]WANG Y, GAO S J, YE W H, et al. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer [J]. Nat Mater,2006,5(10):791-6.
[29]WANG Y, WANG L S, GOH S H, et al. Synthesis and characterization of cationic micelles self-assembled from a biodegradable copolymer for gene delivery [J]. Biomacromolecules,2007, 8(3):1028-37.
[30]WANG Y, KE C Y, BEH C W, et al. The self-assembly of biodegradable cationic polymer micelles as vectors for gene transfection [J]. Biomaterials,2007,28(35):5358-68.
[31]ZHU C H, JUNG S, LUO S B, et al. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers [J]. Biomaterials,2010,31(8):2408-16.
[32]SEGURA T, HUBBELL J A. Synthesis and in vitro characterization of an ABC triblock copolymer for siRNA delivery [J]. Bioconjugate Chem,2007,18(3):736-45.
[33]XIONG X B, ULUDAG H, LAVASANIFAR A. Biodegradable amphiphilic polyethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery [J]. Biomaterials,2009,30(2):242-53.
[34]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[35]SAAD A F, MEACHAM W D, BAI A, et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy [J]. Cancer Biol Ther,2007,6(9):1455-60.
[36]ZEIDAN Y H, JENKINS R W, KORMAN J B, et al. Molecular targeting of acid ceramidase: Implications to cancer therapy [J]. Curr Drug Targets,2008,9(8):653-61.
[37]KOLESNICK R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway [J]. J Clin Invest,2002,110(1):3-8.
[38]HUWILER A, ZANGEMEISTER-WITTKE U. Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy [J]. Crit Rev Oncol Hemat,2007, 63(2):150-9.
[39]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials, 2011,32(11):3124-33.
[40]MORALES A, PARIS R, VILLANUEVA A, et al. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo [J]. Oncogene,2007,26(6):905-16.
[41]SELZNER M, BIELAWSKA A, MORSE M A, et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer [J]. Cancer Res,2001,61(3):1233-40.
[42]COHEN G M, SUN X M, SNOWDEN R T, et al. Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation [J]. Biochem J,1992,286(331-4.
[43]ORMEROD M G, PAUL F, CHEETHAM M, et al. Discrimination of apoptotic thymocytes by forward light scatter [J]. Cytometry,1995,21(3):300-4.
[44]LI P, NIJHAWAN D, BUDIHARDJO I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade [J]. Cell,1997,91(4):479-89.
[45]CHENG E H Y A, WEI M C, WEILER S, et al. BCL-2, BCL-X-L sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis [J]. Mol Cell,2001,8(3): 705-11.
[46]GROSS A, YIN X M, WANG K, et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-X-L prevents this release but not tumor necrosis factor-Rl/Fas death [J]. J Biol Chem,1999,274(2):1156-63.
[47]CARDONE M, ROY N, STENNICKE H, et al. Regulation of cell death protease caspase-9 by Akt-mediated protein phosphorylation. [J]. Mol Biol Cell,1998,9(246a-a.
[48]REINERS J J, CARUSO J A, MATHIEU P, et al. Release of cytochrome c and activation of pro-caspase-9 following lysosomal photodamage involves bid cleavage [J]. Cell Death Differ, 2002,9(9):934-44.
[49]HU Y M, BENEDICT M A, WU D Y, et al. Bcl-X-L interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation [J]. P Natl Acad Sci USA,1998,95(8):4386-91.
[50]KRAJEWSKI S, KRAJEWSKA M, ELLERBY L M, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia [J]. P Natl Acad Sci USA,1999, 96(10):5752-7.
[51]RENN M, POECK H, MAIHOEFER C, et al.5'-triphosphate-siRNA:Turning gene silencing and RIG-I activation against melanoma [J]. Exp Dermatol,2009,18(3):315-.
[52]JUDGE A D, SOOD V, SHAW J R, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA [J]. Nat Biotechnol,2005,23(4):457-62.
[53]MARQUES J T, WILLIAMS B R G. Activation of the mammalian immune system by siRNAs [J]. Nat Biotechnol,2005,23(11):1399-405.
[1]FERLAY J, SHIN H R, BRAY F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 [J]. Int J Cancer,2010,127(12):2893-917.
[2]JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics [J]. Ca-Cancer J Clin,2011, 61(2):69-90.
[3]TRAVIS W D, BRAMBILLA E, NOGUCHI M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma [J]. J Thorac Oncol,2011,6(2):244-85.
[4]GOVINDAN R, PAGE N, MORGENSZTERN D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years:Analysis of the surveillance, epidemiologic, and end results database [J]. J Clin Oncol,2006,24(28):4539-44.
[5]SIEGEL R, NAISHADHAM D, JEMAL A. Cancer statistics,2012 [J]. Ca-Cancer J Clin,2012, 62(1):10-29.
[6]KELLAND L. The resurgence of platinum-based cancer chemotherapy [J]. Nat Rev Cancer,2007, 7(8):573-84.
[7]SCHILLER J H, HARRINGTON D, BELANI C P, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer [J]. New Engl J Med,2002,346(2):92-8.
[8]SHEPHERD F A, PEREIRA J R, CIULEANU T, et al. Erlotinib in previously treated non-small-cell lung cancer [J]. New Engl J Med,2005,353(2):123-32.
[9]SOMERFEELD M R, IHDE D C, PFISTER D G, et al. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer [J]. J Clin Oncol,1997,15(8):2996-3018.
[10]PAZ-ARES L. Beyond first-line NSCLC therapy:Chemotherapy or erlotinib? [J]. Lancet Oncol, 2012,13(3):225-7.
[11]PAO W, MILLER V, ZAKOWSKI M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib [J]. P Natl Acad Sci USA,2004,101(36):13306-11.
[12]MURPHY M, STORDAL B. Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer:A systematic review [J]. Drug Resist Update,2011,14(3):177-90.
[13]COUDERT B, CIULEANU T, PARK K, et al. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy [J]. Ann Oncol,2012,23(2):388-94.
[14]COHEN M H, JOHNSON J R, CHEN Y F, et al. FDA drug approval summary:Erlotinib (Tarceva (R)) tablets [J]. Oncologist,2005,10(7):461-6.
[15]SORDELLA R, BELL D W, HABER D A, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways [J]. Science,2004,305(5687):1163-7.
[16]GAZDAR A F. Activating and resistance mutations of EGFR in non-small-cell lung cancer:role in clinical response to EGFR tyrosine kinase inhibitors [J]. Oncogene,2009,28(S24-S31.
[17]GUHA U, CHAERKADY R, MARIMUTHU A, et al. Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS [J]. P Natl Acad Sci USA,2008,105(37):14112-7.
[18]MASSARELLI E, VARELLA-GARCIA M, TANG X M, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer [J]. Clin Cancer Res,2007,13(10):2890-6.
[19]YOUNG A, LYONS J, MILLER A L, et al. Ras Signaling and Therapies [J]. Adv Cancer Res, 2009,102(1-17.
[20]LUO J, EMANUELE M J, LI D N, et al. A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene [J]. Cell,2009,137(5):835-48.
[21]KARNOUB A E, WEINBERG R A. Ras oncogenes:split personalities [J]. Nat Rev Mol Cell Bio, 2008,9(7):517-31.
[22]ENGELMAN J A, CHEN L, TAN X H, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PK3CA H1047R murine lung cancers [J]. Nat Med,2008,14(12): 1351-6.
[23]SOLIMINI N L, LUO J, ELLEDGE S J. Non-oncogene addiction and the stress phenotype of cancer cells [J]. Cell,2007,130(6):986-8.
[24]HARTWELL L H, SZANKASI P, ROBERTS C J, et al. Integrating genetic approaches into the discovery of anticancer drugs [J]. Science,1997,278(5340):1064-8.
[25]KAELIN W G. The concept of synthetic lethality in the context of anticancer therapy [J]. Nat Rev Cancer,2005,5(9):689-98.
[26]LUO B, CHEUNG H W, SUBRAMANIAN A, et al. Highly parallel identification of essential genes in cancer cells [J]. P Natl Acad Sci USA,2008,105(51):20380-5.
[27]SCHOLL C, FROHLING S, DUNN I F, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells [J]. Cell,2009,137(5):821-34.
[28]BARBIE D A, TAMAYO P, BOEHM J S, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J]. Nature,2009,462(7269):108-U22.
[29]WANG Y, NGO V N, MARANI M, et al. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells [J]. Oncogene,2010,29(33): 4658-70.
[30]PUYOL M, MARTIN A, DUBUS P, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma [J]. Cancer Cell,2010, 18(1):63-73.
[31]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[32]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials, 2011,32(11):3124-33.
[33]JACKMAN D M, MILLER V A, CIOFFREDI L A, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-Small cell lung cancer patients:Results of an online tumor registry of clinical trials [J]. Clin Cancer Res,2009, 15(16):5267-73.
[34]RAPONI M, WINKLER H, DRACOPOLI N C. KRAS mutations predict response to EGFR inhibitors [J]. Curr Opin Pharmacol,2008,8(4):413-8.
[35]TORRANCE C J, AGRAWAL V, VOGELSTEIN B, et al. Use of isogenic human cancer cells for high-throughput screening and drug discovery [J]. Nat Biotechnol,2001,19(10):940-5.
[36]DOLMA S, LESSNICK S L, HAHN W C, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells [J]. Cancer Cell, 2003,3(3):285-96.
[37]SIMONS A, DAFNIN, DOTAN I, et al. Establishment of a chemical synthetic lethality screen in cultured human cells [J]. Genome Res,2001,11(2):266-73.
[38]WANG H X, XIONG M H, WANG Y C, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. J Control Release,2013,166(2):106-14.
[39]LIU X Q, XIONG M H, SHU X T, et al. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth [J]. Mol Pharm,2012,9(10):2863-74.
[2]SIEGEL R, NAISHADHAM D, JEMAL A. Cancer statistics,2012 [J]. Ca-Cancer J Clin,2012, 62(1):10-29.
[3]ZHU L, PICKLE L W, GHOSH K, et al. Predicting US-and state-level cancer counts for the current calendar year [J]. Cancer-Am Cancer Soc,2012,118(4):1100-9.
[4]JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics [J]. Ca-Cancer J Clin,2011, 61(2):69-90.
[5]BRAY F, JEMAL A, GREY N, et al. Global cancer transitions according to the human development Index (2008-2030):a population-based study [J]. Lancet Oncol,2012,13(8): 790-801.
[6]赫捷、陈万青.2012中国肿瘤登记年报[M].军事医学科学出版社,2012.
[7]SINGER C F, TEA M K, PRISTAUZ G, et al. Guideline for the Prevention and early detection of breast and ovarian cancer in high-risk patients, especially in women from HBOC (Hereditary Breast and Ovarian Cancer) families [J]. Wien Klin Wochenschr,2012,124(19-20):735-41.
[8]PHUNG Y, WANG Z H, AKSAMIT I, et al. Guideline-based treatment utilization, treatment time, and cost of chemotherapy for metastatic colon cancer patients treated in US community oncology practices from 2005 to 2009 [J]. J Clin Oncol,2012,30(15):
[9]PACINIF, CASTAGNA M G, BRILLIL, et al. Thyroid cancer:ESMO clinical practice guidelines for diagnosis, treatment and follow-up [J]. Ann Oncol,2012,23(110-9.
[10]THERASSE P, ARBUCK S G, EISENHAUER E A, et al. New guidelines to evaluate the response to treatment in solid Tumors [J]. J Natl Cancer I,2000,92(3):205-16.
[11]ENGELMAN J A. Targeting PI3K signalling in cancer:opportunities, challenges and limitations [J]. Nat Rev Cancer,2009,9(8):550-62.
[12]YU H, PARDOLL D, JOVE R. STATs in cancer inflammation and immunity:a leading role for STAT3 [J]. Nat Rev Cancer,2009,9(11):798-809.
[13]DESGROSELLIER J S, CHERESH D A. Integrins in cancer:biological implications and therapeutic opportunities [J]. Nat Rev Cancer,2010,10(1):9-22.
[14]LUO J, SOLIMINI N L, ELLEDGE S J. Principles of cancer therapy:Oncogene and non-oncogene addiction [J]. Cell,2009,136(5):823-37.
[15]LAPENNA S, GIORDANO A. Cell cycle kinases as therapeutic targets for cancer [J]. Nat Rev Drug Discov,2009,8(7):547-66.
[16]SCOTT A M, WOLCHOK J D, OLD L J. Antibody therapy of cancer [J]. Nat Rev Cancer,2012, 12(4):278-87.
[17]ZHANG J M, YANG P L, GRAY N S. Targeting cancer with small molecule kinase inhibitors [J]. Nat Rev Cancer,2009,9(1):28-39.
[18]GARZON R, MARCUCCI G, CROCE C M. Targeting microRNAs in cancer:rationale, strategies and challenges [J]. Nat Rev Drug Discov,2010,9(10):775-89.
[19]OPALINSKA J B, GEWIRTZ A M. Nucleic-acid therapeutics:Basic principles and recent applications [J]. Nat Rev Drug Discov,2002,1(7):503-14.
[20]GUTIERREZ A A, LEMOINE N R, SIKORA K. Gene-therapy for Cancer [J]. Lancet,1992, 339(8795):715-21.
[21]Leading Anti-Cancer Drugs and Associated Market 2012-2022 [M/OL].2012.
[22]MARIOTTO A B, YABROFF K R, SHAO Y W, et al. Projections of the Cost of Cancer Care in the United States:2010-2020 [J]. J Natl Cancer I,2011,103(2):117-28.
[23]TABARA H, GRISHOK A, MELLO C C. RNAi in C-elegans:Soaking in the genome sequence [J]. Science,1998,282(5388):430-1.
[24]SONG E W, LEE S K, WANG J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis [J]. Nat Med,2003,9(3):347-51.
[25]KIM D H, ROSSI J J. Strategies for silencing human disease using RNA interference [J]. Nat Rev Genet,2007,8(3):173-84.
[26]KLEINMAN M E, YAMADA K, TAKEDA A, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 [J]. Nature,2008,452(7187):591-U1.
[27]JACQUE J M, TRIQUES K, STEVENSON M. Modulation of HIV-1 replication by RNA interference [J]. Nature,2002,418(6896):435-8.
[28]ELBASHIR S M, LENDECKEL W, TUSCHL T. RNA interference is mediated by 21-and 22-nucleotide RNAs [J]. Gene Dev,2001,15(2):188-200.
[29]YU J Y, DERUITER S L, TURNER D L. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells [J]. P Natl Acad Sci USA,2002,99(9):6047-52.
[30]GAVRILOV K, SALTZMAN W M. Therapeutic siRNA:Principles, challenges,and strategies [J]. Adv Drug Deliver Rev,2007,59(2):75-86.
[31]HARBORTH J, ELBASHIR S M, BECHERT K, et al. RNAi based gene silencing in mammalian tissue culture cells:a key procedure fur functional gone analysis [J]. Mol Biol Cell,2001, 12(520a-la.
[32]HANNON G J, ROSSI J J. Unlocking the potential of the human genome with RNA interference [J]. Nature,2004,431(7006):371-8.
[33]ASHIHARA E, KAWATA E, MAEKAWA T. Future prospect of RNA interference for cancer therapies [J]. Curr Drug Targets,2010,11(3):345-60.
[34]LEUNG R K M, WHITTAKER P A. RNA interference:From gene silencing to gene-specific therapeutics [J]. Pharmacol Therapeut,2005,107(2):222-39.
[35]DE FOUGEROLLES A, VORNLOCHER H P, MARAGANORE J, et al. Interfering with disease: a progress report on siRNA-based therapeutics [J]. Nat Rev Drug Discov,2007,6(6):443-53.
[36]BURNETT J C, ROSSI J J, TIEMANN K. Current progress of siRNA/shRNA therapeutics in clinical trials [J]. Biotechnol J,2011,6(9):1130-46.
[37]NGUYEN T A, FRUEHAUF J H. Transkingdom RNA interference (tkRNAi):a novel method,to induce therapeutic gene silencing [J]. Meth Mol Biol,2009,514(27-34.
[38]XIANG S, KEATES A C, FRUEHAUF J, et al. In vitro and in vivo gene silencing by TransKingdom RNAi (tkRNAi) [J]. Meth Mol Biol,2009,487(147-60.
[39]REAGAN-SHAW S, AHMAD N. Silencing of polo-like kinase (Plk) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer [J]. Faseb J,2005,19(1):611-3.
[40]VAISHNAW A K, CERVANTES A, ALSINA M, et al. RNAi in humans:phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement [J]. Nucleic Acid Ther,2011,21 (5):A44.
[41]VAISHNAW A K, GOLLOB J, GAMBA-VITALO C, et al. A status report on RNAi therapeutics [J]. Silence,2010,1(1):14.
[42]KOLDEHOFF M, STECKEL N K, BEELEN D W, et al. Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukaemia [J]. Clin Exp Med,2007,7(2):47-55.
[43]SANTEL A, ALEKU M, RODER N, et al. AtuO27 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models [J]. Clin Cancer Res,2010,16(22):5469-80.
[44]DAVIS M E, ZUCKERMAN J E, CHOI C H J, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles [J]. Nature,2010,464(7291): 1067-U140.
[45]RIEDMANN E M. Gradalis cancer vaccine FANG prolongs survival In advanced stage cancer patients [J]. Hum Vacc Immunother,2012,8(4):417-.
[46]GHISOLIM, LENARSKY C, WEINTHAL J, et al. Phase I study of the "Triad" autologous (Fang (Tm)) vaccine incorporating bifunctional shrnafurin and Gmcsf transgene expression in advanced Ewing's sarcoma:Preliminary data in pediatrics patients [J]. Pediatr Blood Cancer,2013,60(S73).
[47]DANNULL J, LESHER D T, HOLZKNECHT R, et al. Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity [J]. Blood,2007,110(13): 4341-50.
[48]GUO P X, COBAN O, SNEAD N M, et al. Engineering RNA for Targeted siRNA Delivery and Medical Application [J]. Adv Drug Deliver Rev,2010,62(6):650-66.
[49]WHITEHEAD K A, LANGER R, ANDERSON D G. Knocking down barriers:advances in siRNA delivery [J]. Nat Rev Drug Discov,2009,8(2):129-38.
[50]AAGAARD L, ROSSI J J. RNAi therapeutics:Principles, prospects and challenges [J]. Adv Drug Deliver Rev,2007,59(2-3):75-86.
[51]CHO W G, ALBUQUERQUE R J C, KLEINMAN M E, et al. Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth [J]. P Natl Acad Sci USA,2009, 106(17):7137-42.
[52]DEJNEKA N S, WAN S H, BOND O S, et al. Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes [J]. Mol Vis,2008,14(116-19):997-1005.
[53]KOLDEHOFF M, BEELEN D W, EHMAAGACLI A H. Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukemia. [J]. Blood,2007,110(11):217b-b.
[54]SAMUEL-ABRAHAM S, LEONARD J N. Staying on message:design principles for controlling nonspecific responses to siRNA [J]. Febs J,2010,277(23):4828-36.
[55]JUDGE A D, BOLA G, LEE A C H, et al. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo [J]. Mol Ther,2006,13(3):494-505.
[56]JACKSON A L, BURCHARD J, LEAKE D, et al. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing [J]. Rna,2006,12(7):1197-205.
[57]OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Nanomedicine based approaches for the delivery of siRNA in cancer [J]. J Intern Med,2010,267(1):44-53.
[58]PEER D, LIEBERMAN J. Special delivery:Targeted therapy with small RNAs [J]. Gene Ther, 2011,18(12):1127-33.
[59]WANG A Z, LANGER R, FAROKHZAD O C. Nanoparticle delivery of cancer drugs [J]. Annu Rev Med,2012,63(185-98.
[60]SHEKHAR C. Lean and Mean:Nanoparticle-based delivery improves performance of cancer drugs [J]. Chem Biol,2009,16(4):349-50.
[61]DE FOUGEROLLES A R. Delivery vehicles for small interfering RNA in vivo [J]. Hum Gene Ther,2008,19(2):125-32.
[62]MA X W, ZHAO Y L, LIANG X J. Theranostic nanoparticles engineered for clinic and pharmaceutics [J]. Accounts Chem Res,2011,44(10):1114-22.
[63]FENSKE D B, CULLIS P R. Liposomal nanomedicines [J]. Expert Opin Drug Del,2008,5(1): 25-44.
[64]ELOUAHABI A, RUYSSCHAERT J M. Formation and intracellular trafficking of lipoplexes and polyplexes [J]. Mol Ther,2005,11(3):336-47.
[65]WU S Y, MCMILLAN N A J. Lipidic systems for in vivo siRNA delivery [J]. Aaps J,2009,11(4): 639-52.
[66]LANDEN C N, CHAVEZ-REYES A, BUCANA C, et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery [J]. Cancer Res,2005,65(15): 6910-8.
[67]HALDER J, KAMAT A A, LANDEN C N, et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy [J]. Clin Cancer Res,2006,12(16):4916-24.
[68]OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Nanomedicine based approaches for the delivery of siRNA in cancer [J]. J Intern Med,2010,267(1):44-53.
[69]KOSTARELOS K, EMFIETZOGLOU D, PAPAKOSTAS A, et al. Binding and interstitial penetration of liposomes within avascular tumor spheroids [J]. Int J Cancer,2004,112(4):713-21.
[70]DOKKA S, TOLEDO D, SHI X Q et al. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes [J]. Pharm Res,2000,17(5):521-5.
[71]SPAGNOU S, MILLER A D, KELLER M. Lipidic carriers of siRNA:Differences in the formulation, cellular uptake, and delivery with plasmid DNA [J]. Biochemistry-Us,2004,43(42): 13348-56.
[72]LV H T, ZHANG S B, WANG B, et al. Toxicity of cationic lipids and cationic polymers in gene delivery [J]. J Control Release,2006,114(1):100-9.
[73]UNER M, YENER G Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives [J]. Int J Nanomed,2007,2(3):289-300.
[74]SANTEL A, ALEKU M, KEIL O, et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy [J]. Gene Ther,2006,13(18): 1360-70.
[75]SANTEL A, ALEKU M, KEIL O, et al. A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium [J]. Gene Ther,2006,13(16):1222-34.
[76]ALEKU M, SCHULZ P, KEIL O, et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression [J]. Cancer Res,2008,68(23):9788-98.
[77]BROWER V. RNA interference advances to early-stage clinical trials [J]. J Natl Cancer I,2010, 102(19):1459-61.
[78]ALABI C, VEGAS A, ANDERSON D. Attacking the genome:emerging siRNA nanocarriers from concept to clinic [J]. Curr Opin Pharmacol,2012,12(4):427-33.
[79]JIN J, BAE K H, YANG H, et al. In vivo specific delivery of c-met siRNA to glioblastoma using cationic solid lipid nanoparticles [J]. Bioconjugate Chem,2011,22(12):2568-72.
[80]ZIMMERMANN T S, LEE A C H, AKINC A, et al. RNAi-mediated gene silencing in non-human primates [J]. Nature,2006,441(7089):111-4.
[81]JUDGE A D, ROBBINS M, TAVAKOLI I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice [J]. J Clin Invest,2009,119(3):661-73.
[82]EGUSQUIAGUIRRE S P, IGARTUA M, HERNANDEZ R M, et al. Nanoparticle delivery systems for cancer therapy:Advances in clinical and preclinical research [J]. Clin Transl Oncol, 2012,14(2):83-93.
[83]WANG Y, LI Z G, HAN Y, et al. Nanoparticle-based delivery system for application of siRNA in vivo [J]. Curr Drug Metab,2010,11(2):182-96.
[84]YUAN X D, NAGUIB S, WU Z Q. Recent advances of siRNA delivery by nanoparticles [J]. Expert Opin Drug Del,2011,8(4):521-36.
[85]DAVIS M E, BREWSTER M E. Cyclodextrin-based pharmaceutics:Past, present and future [J]. Nat Rev Drug Discov,2004,3(12):1023-35.
[86]HU-LIESKOVAN S, HEIDEL J D, BARTLETT D W, et al. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma [J]. Cancer Res,2005,65(19):8984-92.
[87]HOWARD K A, RAHBEK U L, LIU X D, et al. RNA interference in vitro and in vivo using a chitosan/siRNA nanoparticle system [J]. Mol Ther,2006,14(4):476-84.
[88]LIU X D, HOWARD K A, DONG M D, et al. The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing [J]. Biomaterials,2007,28(6): 1280-8.
[89]JEAN M, SMAOUI F, LAVERTU M, et al. Chitosan-plasmid nanoparticle formulations for IM and SC delivery of recombinant FGF-2 and PDGF-BB or generation of antibodies [J]. Gene Ther, 2009,16(9):1097-110.
[90]KATAS H, ALPAR H O. Development and characterisation of chitosan nanoparticles for siRNA delivery [J]. J Control Release,2006,115(2):216-25.
[91]MERKEL O M, BEYERLE A, BECKMANN B M, et al. Polymer-related off-target effects in non-viral siRNA delivery [J]. Biomaterials,2011,32(9):2388-98.
[92]MOGHIMI S M, SYMONDS P, MURRAY J C, et al. A two-stage poly(ethylenimine)-mediated cytotoxicity:Implications for gene transfer/therapy [J]. Mol Ther,2005,11(6):990-5.
[93]HUNTER A C, MOGHIMI S M. Cationic carriers of genetic material and cell death:A mitochondrial tale [J]. Bba-Bioenergetics,2010,1797(6-7):1203-9.
[94]WOODROW K A, CU Y, BOOTH C J, et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA [J]. Nat Mater,2009,8(6): 526-33.
[95]SINGHA K, NAMGUNG R, KIM W J. Polymers in Small-Interfering RNA Delivery [J]. Nucleic Acid Ther,2011,21(3):133-47.
[96]WU Z W, CHDEN C T, LIU C Y, et al. Recent progress in copolymer-mediated siRNA delivery [J]. J Drug Target,2012,20(7):551-60.
[97]KESHARWANI P, TEKADE R K, GAJBHIYE V, et al. Cancer targeting potential of some ligand-anchored polypropylene imine) dendrimers:a comparison [J]. Nanomed-Nanotechnol, 2011,7(3):295-304.
[98]LEE J H, CHA K E, KIM M S, et al. Nanosized polyamidoamine (PAMAM) dendrimer-induced apoptosis mediated by mitochondrial dysfunction [J]. Toxicol Lett,2009,190(2):202-7.
[99]TARATULA O, GARBUZENKO O B, KIRKPATRICK P, et al. Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery [J]. J Control Release,2009, 140(3):284-93.
[100]AGRAWAL A, MIN D H, SINGH N, et al. Functional delivery of siRNA in mice using dendriworms [J]. Acs Nano,2009,3(9):2495-504.
[101]JEONG J H, MOK H, OH Y K, et al. siRNA conjugate delivery systems [J]. Bioconjugate Chem, 2009,20(1):5-14.
[102]ROZEMA D B, LEWIS D L, WAKEFIELD D H, et al. Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes [J]. P Natl Acad Sci USA,2007,104(32):12982-7.
[103]MUDD S R, TRUBETSKOY V S, BLOKHIN A V, et al. Hybrid PET/CT for noninvasive pharmacokinetic evaluation of dynamic PolyConjugates, a synthetic siRNA delivery system [J]. Bioconjug Chem,2010,21(7):1183-9.
[104]LIU P X, CHENG H L, ROBERTS T M, et al. Targeting the phosphoinositide 3-kinase pathway in cancer [J]. Nat Rev Drug Discov,2009,8(8):627-44.
[105]BOLLAG G, HIRTH P, TSAI J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma [J]. Nature,2010,467(7315):596-9.
[106]ROBERTS P J, DER C J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer [J]. Oncogene,2007,26(22):3291-310.
[107]STREBHARDT K, ULLRICH A. Opinion-Targeting polo-like kinase 1 for cancer therapy [J]. Nat Rev Cancer,2006,6(4):321-30.
[108]MALUMBRES M, BARBACID M. Cell cycle, CDKs and cancer:a changing paradigm [J]. Nat Rev Cancer,2009,9(3):153-66.
[109]HARTWELL L H, KASTAN M B. Cell-cycle control and cancer [J]. Science,1994,266(5192): 1821-8.
[110]VERDINE G L, WALENSKY L D. The challenge of drugging undruggable targets in cancer: Lessons learned from targeting BCL-2 family members [J]. Clin Cancer Res,2007,13(24): 7264-70.
[111]YANO J, HKABAYASHI K, NAKAGAWA S, et al. Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer [J]. Clin Cancer Res,2004,10(22): 7721-6.
[112]ZEIDAN Y H, JENKINS R W, KORMAN J B, et al. Molecular targeting of acid ceramidase: Implications to cancer therapy [J]. Curr Drug Targets,2008,9(8):653-61.
[113]HUWILER A, ZANGEMEISTER-WITTKE U. Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy [J]. Crit Rev Oncol Hemat,2007, 63(2):150-9.
[114]MORALES A, PARIS R, VILLANUEVA A, et al. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo [J]. Oncogene,2007,26(6):905-16.
[115]CARMELIET P, JAIN R K. Molecular mechanisms and clinical applications of angiogenesis [J]. Nature,2011,473(7347):298-307.
[116]HU M, POLYAK K. Microenvironmental regulation of cancer development [J]. Curr Opin Genet Dev,2008,18(1):27-34.
[117]REDDY A, KAELIN W G. Using cancer genetics to guide the selection of anticancer drug targets [J]. Curr Opin Pharmacol,2002,2(4):366-73.
[118]KAELIN W G. Choosing anticancer drug targets in the postgenomic era [J]. J Clin Invest,1999, 104(11):1503-6.
[119]KAELIN W G The concept of synthetic lethality in the context of anticancer therapy [J]. Nat Rev Cancer,2005,5(9):689-98.
[120]YOUNG A, LYONS J, MILLER A L, et al. Ras Signaling and Therapies [J]. Adv Cancer Res, 2009,102(1-17.
[121]LUO J, EMANUELE M J, LI D N, et al. A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene [J]. Cell,2009,137(5):835-48.
[122]KARNOUB A E, WEINBERG R A. Ras oncogenes:split personalities [J]. Nat Rev Mol Cell Bio, 2008,9(7):517-31.
[123]MIZUARAI S, KOTANI H. Synthetic lethal interactions for the development of cancer therapeutics:biological and methodological advancements [J]. Hum Genet,2010,128(6):567-75.
[124]CHAN D A, GIACCIA A J. Harnessing synthetic lethal interactions in anticancer drug discovery [J]. Nat Rev Drug Discov,2011,10(5):351-64.
[125]QIU L Y, BAE Y H. Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs [J]. Biomaterials,2007,28(28):4132-42.
[126]SHUAI X T, MERDAN T, UNGER F, et al. Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG:Synthesis, characterization, and potential as efficient nonviral gene delivery vectors [J]. Macromolecules,2003,36(15):5751-9.
[127]WANG Y, GAO S J, YE W H, et al. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer [J]. Nat Mater,2006,5(10):791-6.
[128]WANG Y, WANG L S, GOH S H, et al. Synthesis and characterization of cationic micelles self-assembled from a biodegradable copolymer for gene delivery [J]. Biomacromolecules,2007, 8(3):1028-37.
[129]WANG Y, KE C Y, BEH C W, et al. The self-assembly of biodegradable cationic polymer micelles as vectors for gene transfection [J]. Biomaterials,2007,28(35):5358-68.
[130]ZHU C H, JUNG S, LUO S B, et al. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers [J]. Biomaterials,2010,31(8):2408-16.
[131]SEGURA T, HUBBELL J A. Synthesis and in vitro characterization of an ABC triblock copolymer for siRNA delivery [J]. Bioconjugate Chem,2007,18(3):736-45.
[132]XIONG X B, ULUDAG H, LAVASANIFAR A. Biodegradable amphiphilic polyethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery [J]. Biomaterials,2009,30(2):242-53.
[133]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[134]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic Iriblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials,2011,32(11):3124-33.
[135]SUN T M, DU J Z, YAO Y D, et al. Simultaneous delivery of siRNA and paclitaxel via a "Two-in-One" micelleplex promotes synergistic tumor suppression [J]. ACS Nano,2011,5(2): 1483-94.
[136]WANG H X, XIONG M H, WANG Y C, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. J Control Release,2013,166(2):106-14.
[137]LIU X Q, XIONG M H, SHU X T, et al. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth [J]. Mol Pharm,2012,9(10):2863-74.
[1]LANDTHALER M, YALCIN A, TUSCHL T. The human DiGeorge syndrome critical region gene 8 and its D-melanogaster homolog are required for miRNA biogenesis [J]. Curr Biol,2004,14(23): 2162-7.
[2]MCCAFFREY A P, NAKAI H, PANDEY K, et al. Inhibition of hepatitis B virus by RNA interference in mice [J]. Mol Ther,2003,7(5):S312-S3.
[3]JACQUE J M, TRIQUES K, STEVENSON M. Modulation of HIV-1 replication by RNA interference [J]. Nature,2002,418(6896):435-8.
[4]STEVENSON M. Therapeutic potential of RNA interference [J]. New Engl J Med,2004,351(17): 1772-7.
[5]KIM D H, ROSSI J J. Strategies for silencing human disease using RNA interference [J]. Nat Rev Genet,2007,8(3):173-84.
[6]HANNON G J, ROSSI J J. Unlocking the potential of the human genome with RNA interference [J]. Nature,2004,431(7006):371-8.
[7]MICHIENZI A, CASTANOTTO D, LEE N, et al. RNA-mediated inhibition of HIV in a gene therapy setting [J]. Ann Ny Acad Sci,2003,1002(1):63-71.
[8]RAOUL C, ABBAS-TERKI T, BENSADOUN J C, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS [J]. Nat Med,2005,11(4):423-8.
[9]MINAKUCHI Y, TAKESHITA F, KOSAKA N, et al. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo [J]. Nucleic Acids Res, 2004,32(13):
[10]MEDAROVA Z, PHAM W, FARRAR C, et al. In vivo imaging of siRNA delivery and silencing in tumors [J]. Nat Med,2007,13(3):372-7.
[11]SONG E W, ZHU P C, LEE S K, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors [J]. Nat Biotechnol,2005,23(6):709-17.
[12]DYKXHOORN D M, LIEBERMAN J. Running interference:Prospects and obstacles to using small interfering RNAs as small molecule drugs [J]. Annu Rev Biomed Eng,2006,8(377-402.
[13]DE FOUGEROLLES A, VORNLOCHER H P, MARAGANORE J, et al. Interfering with disease: A progress report on siRNA-based therapeutics [J]. Nat Rev Drug Discov,2007,6(6):443-53.
[14]JULIANO R, BAUMAN J, KANG H, et al. Biological barriers to therapy with antisense and siRNA oligonucleotides [J]. Mol Pharmaceut,2009,6(3):686-95.
[15]CASTANOTTO D, ROSSI J J. The promises and pitfalls of RNA-interference-based therapeutics [J]. Nature,2009,457(7228):426-33.
[16]BARTLETT D W, SU H, HILDEBRANDT I J, et al. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging [J].P Natl Acad Sci USA,2007,104(39):15549-54.
[17]AKINC A, ZUMBUEHL A, GOLDBERG M, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics [J]. Nat Biotechnol,2008,26(5):561-9.
[18]KUMAR P, WU H Q, MCBRIDE J L, et al. Transvascular delivery of small interfering RNA to the central nervous system [J]. Nature,2007,448(7149):39-43.
[19]ZHANG S B, ZHAO B, JIANG H M, et al. Cationic lipids and polymers mediated vectors for delivery of siRNA [J]. J Control Release,2007,123(1):1-10.
[20]GAO K, HUANG L. Nonviral methods for siRNA delivery [J]. Mol Pharmaceut,2009,6(3): 651-8.
[21]DAVIS M E. The First Targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle:From concept to clinic [J]. Mol Pharmaceut,2009,6(3):659-68.
[22]ALSHAMSAN A, HADDADI A, INCANI V, et al. Formulation and delivery of siRNA by oleic acid and stearic acid modified polyethylenimine [J]. Mol Pharmaceut,2009,6(1):121-33.
[23]KUMAR P, BAN H S, KIM S S, et al. T cell-specific siRNA delivery suppresses HTV-1 infection in humanized mice [J]. Cell,2008,134(4):577-86.
[24]ROTHDIENER M, MULLER D, CASTRO P G, et al. Targeted delivery of siRNA to CD33-positive tumor cells with liposomal carrier systems [J]. J Control Release,2010,144(2): 251-8.
[25]LI S D, HUANG L. Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells [J]. Mol Pharmaceut,2006,3(5):579-88.
[26]QIU L Y, BAE Y H. Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs [J]. Biomaterials,2007,28(28):4132-42.
[27]SHUAI X T, MERDAN T, UNGER F, et al. Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG:Synthesis, characterization, and potential as efficient nonviral gene delivery vectors [J]. Macromolecules,2003,36(15):5751-9.
[28]WANG Y, GAO S J, YE W H, et al. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer [J]. Nat Mater,2006,5(10):791-6.
[29]WANG Y, WANG L S, GOH S H, et al. Synthesis and characterization of cationic micelles self-assembled from a biodegradable copolymer for gene delivery [J]. Biomacromolecules,2007, 8(3):1028-37.
[30]WANG Y, KE C Y, BEH C W, et al. The self-assembly of biodegradable cationic polymer micelles as vectors for gene transfection [J]. Biomaterials,2007,28(35):5358-68.
[31]ZHU C H, JUNG S, LUO S B, et al. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers [J]. Biomaterials,2010,31(8):2408-16.
[32]SEGURA T, HUBBELL J A. Synthesis and in vitro characterization of an ABC triblock copolymer for siRNA delivery [J]. Bioconjugate Chem,2007,18(3):736-45.
[33]XIONG X B, ULUDAG H, LAVASANIFAR A. Biodegradable amphiphilic polyethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery [J]. Biomaterials,2009,30(2):242-53.
[34]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[35]SAAD A F, MEACHAM W D, BAI A, et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy [J]. Cancer Biol Ther,2007,6(9):1455-60.
[36]ZEIDAN Y H, JENKINS R W, KORMAN J B, et al. Molecular targeting of acid ceramidase: Implications to cancer therapy [J]. Curr Drug Targets,2008,9(8):653-61.
[37]KOLESNICK R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway [J]. J Clin Invest,2002,110(1):3-8.
[38]HUWILER A, ZANGEMEISTER-WITTKE U. Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy [J]. Crit Rev Oncol Hemat,2007, 63(2):150-9.
[39]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials, 2011,32(11):3124-33.
[40]MORALES A, PARIS R, VILLANUEVA A, et al. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo [J]. Oncogene,2007,26(6):905-16.
[41]SELZNER M, BIELAWSKA A, MORSE M A, et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer [J]. Cancer Res,2001,61(3):1233-40.
[42]COHEN G M, SUN X M, SNOWDEN R T, et al. Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation [J]. Biochem J,1992,286(331-4.
[43]ORMEROD M G, PAUL F, CHEETHAM M, et al. Discrimination of apoptotic thymocytes by forward light scatter [J]. Cytometry,1995,21(3):300-4.
[44]LI P, NIJHAWAN D, BUDIHARDJO I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade [J]. Cell,1997,91(4):479-89.
[45]CHENG E H Y A, WEI M C, WEILER S, et al. BCL-2, BCL-X-L sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis [J]. Mol Cell,2001,8(3): 705-11.
[46]GROSS A, YIN X M, WANG K, et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-X-L prevents this release but not tumor necrosis factor-Rl/Fas death [J]. J Biol Chem,1999,274(2):1156-63.
[47]CARDONE M, ROY N, STENNICKE H, et al. Regulation of cell death protease caspase-9 by Akt-mediated protein phosphorylation. [J]. Mol Biol Cell,1998,9(246a-a.
[48]REINERS J J, CARUSO J A, MATHIEU P, et al. Release of cytochrome c and activation of pro-caspase-9 following lysosomal photodamage involves bid cleavage [J]. Cell Death Differ, 2002,9(9):934-44.
[49]HU Y M, BENEDICT M A, WU D Y, et al. Bcl-X-L interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation [J]. P Natl Acad Sci USA,1998,95(8):4386-91.
[50]KRAJEWSKI S, KRAJEWSKA M, ELLERBY L M, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia [J]. P Natl Acad Sci USA,1999, 96(10):5752-7.
[51]RENN M, POECK H, MAIHOEFER C, et al.5'-triphosphate-siRNA:Turning gene silencing and RIG-I activation against melanoma [J]. Exp Dermatol,2009,18(3):315-.
[52]JUDGE A D, SOOD V, SHAW J R, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA [J]. Nat Biotechnol,2005,23(4):457-62.
[53]MARQUES J T, WILLIAMS B R G. Activation of the mammalian immune system by siRNAs [J]. Nat Biotechnol,2005,23(11):1399-405.
[1]FERLAY J, SHIN H R, BRAY F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 [J]. Int J Cancer,2010,127(12):2893-917.
[2]JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics [J]. Ca-Cancer J Clin,2011, 61(2):69-90.
[3]TRAVIS W D, BRAMBILLA E, NOGUCHI M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma [J]. J Thorac Oncol,2011,6(2):244-85.
[4]GOVINDAN R, PAGE N, MORGENSZTERN D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years:Analysis of the surveillance, epidemiologic, and end results database [J]. J Clin Oncol,2006,24(28):4539-44.
[5]SIEGEL R, NAISHADHAM D, JEMAL A. Cancer statistics,2012 [J]. Ca-Cancer J Clin,2012, 62(1):10-29.
[6]KELLAND L. The resurgence of platinum-based cancer chemotherapy [J]. Nat Rev Cancer,2007, 7(8):573-84.
[7]SCHILLER J H, HARRINGTON D, BELANI C P, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer [J]. New Engl J Med,2002,346(2):92-8.
[8]SHEPHERD F A, PEREIRA J R, CIULEANU T, et al. Erlotinib in previously treated non-small-cell lung cancer [J]. New Engl J Med,2005,353(2):123-32.
[9]SOMERFEELD M R, IHDE D C, PFISTER D G, et al. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer [J]. J Clin Oncol,1997,15(8):2996-3018.
[10]PAZ-ARES L. Beyond first-line NSCLC therapy:Chemotherapy or erlotinib? [J]. Lancet Oncol, 2012,13(3):225-7.
[11]PAO W, MILLER V, ZAKOWSKI M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib [J]. P Natl Acad Sci USA,2004,101(36):13306-11.
[12]MURPHY M, STORDAL B. Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer:A systematic review [J]. Drug Resist Update,2011,14(3):177-90.
[13]COUDERT B, CIULEANU T, PARK K, et al. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy [J]. Ann Oncol,2012,23(2):388-94.
[14]COHEN M H, JOHNSON J R, CHEN Y F, et al. FDA drug approval summary:Erlotinib (Tarceva (R)) tablets [J]. Oncologist,2005,10(7):461-6.
[15]SORDELLA R, BELL D W, HABER D A, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways [J]. Science,2004,305(5687):1163-7.
[16]GAZDAR A F. Activating and resistance mutations of EGFR in non-small-cell lung cancer:role in clinical response to EGFR tyrosine kinase inhibitors [J]. Oncogene,2009,28(S24-S31.
[17]GUHA U, CHAERKADY R, MARIMUTHU A, et al. Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS [J]. P Natl Acad Sci USA,2008,105(37):14112-7.
[18]MASSARELLI E, VARELLA-GARCIA M, TANG X M, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer [J]. Clin Cancer Res,2007,13(10):2890-6.
[19]YOUNG A, LYONS J, MILLER A L, et al. Ras Signaling and Therapies [J]. Adv Cancer Res, 2009,102(1-17.
[20]LUO J, EMANUELE M J, LI D N, et al. A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene [J]. Cell,2009,137(5):835-48.
[21]KARNOUB A E, WEINBERG R A. Ras oncogenes:split personalities [J]. Nat Rev Mol Cell Bio, 2008,9(7):517-31.
[22]ENGELMAN J A, CHEN L, TAN X H, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PK3CA H1047R murine lung cancers [J]. Nat Med,2008,14(12): 1351-6.
[23]SOLIMINI N L, LUO J, ELLEDGE S J. Non-oncogene addiction and the stress phenotype of cancer cells [J]. Cell,2007,130(6):986-8.
[24]HARTWELL L H, SZANKASI P, ROBERTS C J, et al. Integrating genetic approaches into the discovery of anticancer drugs [J]. Science,1997,278(5340):1064-8.
[25]KAELIN W G. The concept of synthetic lethality in the context of anticancer therapy [J]. Nat Rev Cancer,2005,5(9):689-98.
[26]LUO B, CHEUNG H W, SUBRAMANIAN A, et al. Highly parallel identification of essential genes in cancer cells [J]. P Natl Acad Sci USA,2008,105(51):20380-5.
[27]SCHOLL C, FROHLING S, DUNN I F, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells [J]. Cell,2009,137(5):821-34.
[28]BARBIE D A, TAMAYO P, BOEHM J S, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J]. Nature,2009,462(7269):108-U22.
[29]WANG Y, NGO V N, MARANI M, et al. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells [J]. Oncogene,2010,29(33): 4658-70.
[30]PUYOL M, MARTIN A, DUBUS P, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma [J]. Cancer Cell,2010, 18(1):63-73.
[31]SUN T M, DU J Z, YAN L F, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. Biomaterials,2008,29(32): 4348-55.
[32]MAO C Q, DU J Z, SUN T M, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy [J]. Biomaterials, 2011,32(11):3124-33.
[33]JACKMAN D M, MILLER V A, CIOFFREDI L A, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-Small cell lung cancer patients:Results of an online tumor registry of clinical trials [J]. Clin Cancer Res,2009, 15(16):5267-73.
[34]RAPONI M, WINKLER H, DRACOPOLI N C. KRAS mutations predict response to EGFR inhibitors [J]. Curr Opin Pharmacol,2008,8(4):413-8.
[35]TORRANCE C J, AGRAWAL V, VOGELSTEIN B, et al. Use of isogenic human cancer cells for high-throughput screening and drug discovery [J]. Nat Biotechnol,2001,19(10):940-5.
[36]DOLMA S, LESSNICK S L, HAHN W C, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells [J]. Cancer Cell, 2003,3(3):285-96.
[37]SIMONS A, DAFNIN, DOTAN I, et al. Establishment of a chemical synthetic lethality screen in cultured human cells [J]. Genome Res,2001,11(2):266-73.
[38]WANG H X, XIONG M H, WANG Y C, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery [J]. J Control Release,2013,166(2):106-14.
[39]LIU X Q, XIONG M H, SHU X T, et al. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth [J]. Mol Pharm,2012,9(10):2863-74.