小粒径纳米胶束的构建及其在转移性乳腺癌和胰腺癌治疗中的应用
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摘要
转移性乳腺癌和胰腺癌是致死率很高的两种癌症。传统的手术和放化疗手段对于这两种肿瘤的治疗效果十分有限,目前进步也不大。尽管纳米给药系统在治疗大多数肿瘤方面取得了很多成果,但对于转移性乳腺癌和胰腺癌患者的治疗效果却不显著,这与其无法在乳腺癌继发转移灶和胰腺癌原发灶部位富集有关。乳腺癌继发转移灶与胰腺癌原发灶都存在新生血管发育较少、肿瘤组织血液低灌注的特点,而传统纳米给药系统往往粒径较大,无法在这两类癌灶发挥其EPR效应优势。因此,必须寻求新的方法来治疗这两类肿瘤。
文献报道,小粒径纳米粒在像胰腺癌这样的血液低灌注肿瘤中具有较高的肿瘤组织渗透性,能够发挥较好的肿瘤治疗效果,提示我们设计小粒径纳米粒可能是治疗转移性乳腺癌和胰腺癌的突破口。在本文中,我们以两亲性聚合物mPEG2000-b-PDLLA1300为载体材料、以多西紫杉醇为模型药物、通过薄膜分散法制备得到了粒径约为16nm的胶束(DTX-PM),大大小于以往报道的多西紫杉醇载药胶束：DTX-PM还具有极高的载药量和良好的复溶稳定性,极具_工业和临床应用价值。我们进而使用TAT肽、RGD肽和NGR肽修饰DTX-PM的表面,得到了TAT-PM、RGD-PM和NGR-PM,以增强其渗透性和主动靶向性,它们的粒径大小也在16nm左右。
我们使用4T1小鼠转移性乳腺癌细胞系、能够稳定表达荧光素酶的4T1luc小鼠转移性乳腺癌细胞系以及Capan-2luc人胰腺癌细胞系作为药理测试模型,同时构建了更加贴近临床治疗实际情况的4T1&4T1luc乳腺癌原位自发转移动物模型、4T1&4T1luc乳腺癌术后化疗动物模型和Capan-2luc原位移植胰腺癌动物模型,考察了小粒径纳米胶束对转移性乳腺癌和胰腺癌的体内治疗效果。转移性乳腺癌体内实验结果表明,DTX-PM的抗转移作用显著优于现有市售药物多帕菲(?),达到了我们的实验预期；但DTX-PM也优于肿瘤组织渗透性更强的TAT-PM和具备主动靶向作用NGR-PM、RGD-PM,这提示我们,小粒径胶束对于转移性乳腺癌的治疗作用可能缘于阻断了乳腺癌肿瘤的淋巴播撒途径,这个推测需要进一步的机制研究来汪明。胰腺癌体内实验结果表明,4种小粒径胶束的治疗效果无差别,但均远优于市售多帕菲(?),表明小粒径胶束在血液低灌注的胰腺癌肿瘤组织中有较高的渗透水平,增加了药物的蓄积量,与我们当初的实验设想一致。
鉴于TAT-PM、RGD-PM和NGR-PM对于转移性乳腺癌和胰腺癌的治疗效果并不优于DTX-PM,这可能与3种胶束表面修饰短肽序列后降低了它们的体内稳定性有关,因此,我们认为小粒径胶束的体内稳定性问题应该引起重视。因此,我们又进一步设计了两类小粒径胶束,试图进一步增加DTX-PM的稳定性,进一步阐明稳定性对于小粒径胶束在血液低灌注肿瘤治疗中的作用,但并未获得成功。设计在体内比DTX-PM更稳定的小粒径纳米给药系统将是我们下一步的工作重点。
综上所述,本文明确了小粒径DTX-PM在转移性乳腺癌和胰腺癌治疗方面的作用,揭示了小粒径胶束在治疗转移性乳腺癌和胰腺癌方面的巨大潜力,同时探讨了其抗恶性乳腺癌转移的潜在机制,为纳米药物在临床治疗肿瘤转移的应用提供依据。
Metastatic breast cancer and Pancreatic cancer are the major leading cause of cancer mortality. The benefit of traditional surgery, chemmotherapy and raidotherapy is small, and little progress has been made on the treatment. Although advances in nanomedicine have provided a promising strategy for the drug delivery to most primary solid tumor, the traditional nano-carrier drug delivery systems (NDDS) have provided only modest survival benefits for the patients suffering these two kinds of tumors. Importantly, these drugs have little therapeutic effect on cancer metastasis because of their low accumulation in breast cancer metastasis foci and pancreatic tumor. Small metastases and pancreatic tumor are poorly vascularized and hypoperfused, therefore they are not well accessed by big-sized nanoparticles via the EPR effect. Therefore, alternative methods against these two tumors are necessary.
Discribed by some literatures, decreasing the size of nanoparticle statistically significantly increased its tumor vascular permeability, especially in the poorly vascularized and hypoperfused pancreatic tumor, which provides us a new reference to design NDDS against metastatic breast cancer and pancreatic cancer. Here, a small-sized docetaxel-loaded PM DDS (DTX-PM) has been constructed using amphilic copolymer mPEG2000-b-PDLLA1300, whose size is determined as16nm by Dynamic light scattering method and smaller than the NDDS ever reported. Moreover, DTX-PM with a high loading capacity for DTX is very stable and can be easily lyophilized, which is vital for the clinical use. TAT, RGD and NGR peptides were respectively attached to the distal tips of PEG moieties of DTX-PM, which provided us TAT-PM, RGD-PM and NGR-PM with different PM surface characteristics.
4T1cell line,4T1luc cell line and Capan-2luc cell line that stably expressed luciferase were used as tumor cell model. Furthermore, we established4T1&4T1luc spontaneous metastasis breast cancer model,4T1luc post-surgery breast cancer therapy model and Capan-2luc orthotopic transplantation model of huaman pancreatic cancer model, which are deemed as patient-like model, was used in the in vivo study. Compared to free-DTX (commercialized product Duopafei(?)), the small-sized DTX-PM was found to be very effective against metastasis in vivo on4T1spontaneous metastatic model and4T1luc post-surgery therapy model, which complied with our hypothesis; however, TAT-PM, RGD-PM and NGR-PM had the poorer performance in4T1metastasis therapy compared to DTX-PM, which reminded us that DTX-PM may block the lymphatic metastasis way rather than attack the small metastases foci. More experiments are needed to prove this underlying mechanism. In the in vivo study for Capan-2luc pancreatic cancer, Duopafei(?) almost failed, while DTX-PM had much better therapeutic effect attributed to its hyperpermeability in the hypoperfused tumor. However, TAT-PM, RGD-PM and NGR-PM all had an equal therapeutic effect with DTX-PM.
Accordin to our initial hypothesis, TAT-PM, RGD-PM and NGR-PM shall deserve better therapeutic effects against malignant breast cancer and pancreatic cancer. The unexpected negative result may attribute to the in vivo stability problem of the three small-sized PM. To verify this speculation, we designed two more new NDDSs, whose stablity were further strengthened compared to DTX-PM, but failed us. How to design the new small-sized NDDS with higher in vivo stability will be our focus in the future.
As a whole, this study designed a series of small-sized PM loaded with DTX, one of which, DTX-PM show much better therapeutic effect against malignant breast cancer metastasis and pancreatic cancer. Moreover, this study revealed the great potential of small-sized PM in the treatment of malignant breast cancer metastasis as well as pancreatic cancer, which may provide new strategy in the development of nanomedicine for diagnosis and therapy for cancer.
文献报道,小粒径纳米粒在像胰腺癌这样的血液低灌注肿瘤中具有较高的肿瘤组织渗透性,能够发挥较好的肿瘤治疗效果,提示我们设计小粒径纳米粒可能是治疗转移性乳腺癌和胰腺癌的突破口。在本文中,我们以两亲性聚合物mPEG2000-b-PDLLA1300为载体材料、以多西紫杉醇为模型药物、通过薄膜分散法制备得到了粒径约为16nm的胶束(DTX-PM),大大小于以往报道的多西紫杉醇载药胶束：DTX-PM还具有极高的载药量和良好的复溶稳定性,极具_工业和临床应用价值。我们进而使用TAT肽、RGD肽和NGR肽修饰DTX-PM的表面,得到了TAT-PM、RGD-PM和NGR-PM,以增强其渗透性和主动靶向性,它们的粒径大小也在16nm左右。
我们使用4T1小鼠转移性乳腺癌细胞系、能够稳定表达荧光素酶的4T1luc小鼠转移性乳腺癌细胞系以及Capan-2luc人胰腺癌细胞系作为药理测试模型,同时构建了更加贴近临床治疗实际情况的4T1&4T1luc乳腺癌原位自发转移动物模型、4T1&4T1luc乳腺癌术后化疗动物模型和Capan-2luc原位移植胰腺癌动物模型,考察了小粒径纳米胶束对转移性乳腺癌和胰腺癌的体内治疗效果。转移性乳腺癌体内实验结果表明,DTX-PM的抗转移作用显著优于现有市售药物多帕菲(?),达到了我们的实验预期；但DTX-PM也优于肿瘤组织渗透性更强的TAT-PM和具备主动靶向作用NGR-PM、RGD-PM,这提示我们,小粒径胶束对于转移性乳腺癌的治疗作用可能缘于阻断了乳腺癌肿瘤的淋巴播撒途径,这个推测需要进一步的机制研究来汪明。胰腺癌体内实验结果表明,4种小粒径胶束的治疗效果无差别,但均远优于市售多帕菲(?),表明小粒径胶束在血液低灌注的胰腺癌肿瘤组织中有较高的渗透水平,增加了药物的蓄积量,与我们当初的实验设想一致。
鉴于TAT-PM、RGD-PM和NGR-PM对于转移性乳腺癌和胰腺癌的治疗效果并不优于DTX-PM,这可能与3种胶束表面修饰短肽序列后降低了它们的体内稳定性有关,因此,我们认为小粒径胶束的体内稳定性问题应该引起重视。因此,我们又进一步设计了两类小粒径胶束,试图进一步增加DTX-PM的稳定性,进一步阐明稳定性对于小粒径胶束在血液低灌注肿瘤治疗中的作用,但并未获得成功。设计在体内比DTX-PM更稳定的小粒径纳米给药系统将是我们下一步的工作重点。
综上所述,本文明确了小粒径DTX-PM在转移性乳腺癌和胰腺癌治疗方面的作用,揭示了小粒径胶束在治疗转移性乳腺癌和胰腺癌方面的巨大潜力,同时探讨了其抗恶性乳腺癌转移的潜在机制,为纳米药物在临床治疗肿瘤转移的应用提供依据。
Metastatic breast cancer and Pancreatic cancer are the major leading cause of cancer mortality. The benefit of traditional surgery, chemmotherapy and raidotherapy is small, and little progress has been made on the treatment. Although advances in nanomedicine have provided a promising strategy for the drug delivery to most primary solid tumor, the traditional nano-carrier drug delivery systems (NDDS) have provided only modest survival benefits for the patients suffering these two kinds of tumors. Importantly, these drugs have little therapeutic effect on cancer metastasis because of their low accumulation in breast cancer metastasis foci and pancreatic tumor. Small metastases and pancreatic tumor are poorly vascularized and hypoperfused, therefore they are not well accessed by big-sized nanoparticles via the EPR effect. Therefore, alternative methods against these two tumors are necessary.
Discribed by some literatures, decreasing the size of nanoparticle statistically significantly increased its tumor vascular permeability, especially in the poorly vascularized and hypoperfused pancreatic tumor, which provides us a new reference to design NDDS against metastatic breast cancer and pancreatic cancer. Here, a small-sized docetaxel-loaded PM DDS (DTX-PM) has been constructed using amphilic copolymer mPEG2000-b-PDLLA1300, whose size is determined as16nm by Dynamic light scattering method and smaller than the NDDS ever reported. Moreover, DTX-PM with a high loading capacity for DTX is very stable and can be easily lyophilized, which is vital for the clinical use. TAT, RGD and NGR peptides were respectively attached to the distal tips of PEG moieties of DTX-PM, which provided us TAT-PM, RGD-PM and NGR-PM with different PM surface characteristics.
4T1cell line,4T1luc cell line and Capan-2luc cell line that stably expressed luciferase were used as tumor cell model. Furthermore, we established4T1&4T1luc spontaneous metastasis breast cancer model,4T1luc post-surgery breast cancer therapy model and Capan-2luc orthotopic transplantation model of huaman pancreatic cancer model, which are deemed as patient-like model, was used in the in vivo study. Compared to free-DTX (commercialized product Duopafei(?)), the small-sized DTX-PM was found to be very effective against metastasis in vivo on4T1spontaneous metastatic model and4T1luc post-surgery therapy model, which complied with our hypothesis; however, TAT-PM, RGD-PM and NGR-PM had the poorer performance in4T1metastasis therapy compared to DTX-PM, which reminded us that DTX-PM may block the lymphatic metastasis way rather than attack the small metastases foci. More experiments are needed to prove this underlying mechanism. In the in vivo study for Capan-2luc pancreatic cancer, Duopafei(?) almost failed, while DTX-PM had much better therapeutic effect attributed to its hyperpermeability in the hypoperfused tumor. However, TAT-PM, RGD-PM and NGR-PM all had an equal therapeutic effect with DTX-PM.
Accordin to our initial hypothesis, TAT-PM, RGD-PM and NGR-PM shall deserve better therapeutic effects against malignant breast cancer and pancreatic cancer. The unexpected negative result may attribute to the in vivo stability problem of the three small-sized PM. To verify this speculation, we designed two more new NDDSs, whose stablity were further strengthened compared to DTX-PM, but failed us. How to design the new small-sized NDDS with higher in vivo stability will be our focus in the future.
As a whole, this study designed a series of small-sized PM loaded with DTX, one of which, DTX-PM show much better therapeutic effect against malignant breast cancer metastasis and pancreatic cancer. Moreover, this study revealed the great potential of small-sized PM in the treatment of malignant breast cancer metastasis as well as pancreatic cancer, which may provide new strategy in the development of nanomedicine for diagnosis and therapy for cancer.
引文
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