Efficient lung cancer-targeted drug delivery via a nanoparticle/MSC system
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摘要
Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.
Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.
Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.
引文
1.Cheng W,Nie JP,Gao NS,Liu G,Tao W,Xiao XJ,et al.Amultifunctional nanoplatform against multidrug resistant cancer:merging the best of targeted chemo/gene/photothermal therapy.Adv Funct Mater 2017;27:1704135.
2.Zhang M,Kim YK,Cui PF,Zhang JL,Qiao JB,He YJ,et al.Folateconjugated polyspermine for lung cancer-targeted gene therapy.Acta Pharm Sin B 2016;6:336-43.
3.Huang ZX,Xie Q,Guo QP,Wang KM,Meng XX,Yuan BY,et al.DNA aptamer selected for specific recognition of prostate cancer cells and clinical tissues.Chin Chem Lett 2017;28:1252-7.
4.Islam MN,Das SR,Emin MT,Wei M,Sun L,Westphalen K,et al.Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury.Nat Med2012;18:759-65.
5.Qiao L,Xu Z,Zhao T,Zhao Z,Shi M,Zhao RC,et al.Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.Cell Res 2008;18:500-7.
6.Lee M,Jeong SY,Ha J,Kim M,Jin HJ,Kwon SJ,et al.Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo.Biochem Biophys Res Commun 2014;446:983-9.
7.Pessina A,Leonetti C,Artuso S,Benetti A,Dessy E,Pascucci L,et al.Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model.J Exp Clin Cancer Res 2015;34:82.
8.Zhao Y,Tang S,Guo J,Alahdal M,Cao S,Yang Z,et al.Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy.Sci Rep 2017;7:44758.
9.Gao J,Dennis JE,Muzic RF,Lundberg M,Caplan AI.The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.Cells Tissues Organs 2001;169:12-20.
10.Barbash IM,Chouraqui P,Baron J,Feinberg MS,Etzion S,Tessone A,et al.Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium:feasibility,cell migration,and body distribution.Circulation 2003;108:863-8.
11.Bos JL.Ras oncogenes in human cancer-a review.Cancer Res1989;49:4682-9.
12.Avruch J,Zhang XF,Kyriakis JM.Raf meets Ras-completing the framework of a signal-transduction pathway.Trends Biochem Sci1994;19:279-83.
13.Khosravifar R,Der CJ.The Ras signal transduction pathway.Cancer Metastas-Rev 1994;13:67-89.
14.Mills NE,Fishman CL,Rom WN,Dubin N,Jacobson DR.Increased prevalence of K-Ras oncogene mutations in lung adenocarcinoma.Cancer Res 1995;55:1444-7.
15.Pellegata NS,Sessa F,Renault B,Bonato M,Leone BE,Solcia E,et al.K-Ras and p53 gene-mutations in pancreatic-cancer-ductal and nonductal tumors progress through different genetic lesions.Cancer Res 1994;54:1556-60.
16.Pessina A,Piccirillo M,Mineo E,Catalani P,Gribaldo L,Marafante E,et al.Role of SR-4987 stromal cells in the modulation of doxorubicin toxicity to in vitro granulocyte-macrophage progenitors(CFU-GM).Life Sci 1999;65:513-23.
17.Pascucci L,Cocce V,Bonomi A,Ami D,Ceccarelli P,Ciusani E,et al Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth:a new approach for drug delivery.J Control Release 2014;192:262-70.
18.Cocce V,Farronato D,Brini AT,Masia C,Gianni AB,Piovani Get al.Drug loaded gingival mesenchymal stromal cells(GinPa-MSCs)inhibit in vitro proliferation of oral squamous cell carcinoma.Sci Rep2017;7:9376.
19.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan MUzunel M,et al.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lance2004;363:1439-41.
20.Horwitz EM,Prockop DJ,Fitzpatrick LA,Koo WW,Gordon PL,Nee M,et al.Transplantability and therapeutic effects of bone marrowderived mesenchymal cells in children with osteogenesis imperfecta Nat Med 1999;5:309-13.
21.Shi YF,Hu GZ,Su JJ,Li WZ,Chen Q,Shou PS,et al.Mesenchyma stem cells:a new strategy for immunosuppression and tissue repair Cell Res 2010;20:510-8.
22.Prockop DJ.Marrow stromal cells as stem cells for continual renewa of nonhematopoietic tissues and as potential vectors for gene therapy.JCell Biochem 1998;72:S284-5.
23.Dezawa M,Ishikawa H,Itokazu Y,Yoshihara T,Hoshino M,Takeda S,et al.Bone marrow stromal cells generate muscle cells and repair muscle degeneration.Science 2005;309:314-7.
24.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,et al.Multilineage potential of adult human mesenchymal stem cells.Science 1999;284:143-7.
25.Squillaro T,Peluso G,Galderisi U.Clinical trials with mesenchyma stem cells:an update.Cell Transplant 2016;25:829-48.
26.Giordano A,Galderisi U,Marino IR.From the laboratory bench to the patients bedside:an update on clinical trials with mesenchymal stem cells.J Cell Physiol 2007;211:27-35.
27.Bartolucci J,Verdugo FJ,Larrea R,Abarzua E,Goset C,Rojo P,et al.Phase 1/2 randomized clinical trial of intravenous infusion of umbilical cord mesenchymal stem cells in patients with chronic cardiopathy with stable heart failure(RIMECARD).Eur Heart J2016;37:527.
28.Zhu HB,Cao BR,Zhen ZP,Laxmi AA,Li D,Liu SR,et al.Controlled growth and differentiation of MSCs on grooved films assembled from monodisperse biological nanofibers with genetically tunable surface chemistries.Biomaterials 2011;32:4744-52.
29.Sonabend AM,Ulasov IV,Tyler MA,Rivera AA,Mathis JM,Lesniak MS.Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma.Stem Cells 2008;26:831-41.
30.Kidd S,Spaeth E,Dembinski JL,Dietrich M,Watson K,Klopp A,et al.Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging.Stem Cells 2009;27:2614-23.
31.Dwyer RM,Potter-Beirne SM,Harrington KA,Lowery AJ,Hennessy E,Murphy JM,et al.Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells.Clin Cancer Res 2007;13:5020-7.
32.Jang SC,Kim OY,Yoon CM,Choi DS,Roh TY,Park J,et al.Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors.ACS Nano 2013;7:7698-710.
33.Rani S,Ryan AE,Griffin MD,Ritter T.Mesenchymal stem cellderived extracellular vesicles:toward cell-free therapeutic applications.Mol Ther 2015;23:812-23.
2.Zhang M,Kim YK,Cui PF,Zhang JL,Qiao JB,He YJ,et al.Folateconjugated polyspermine for lung cancer-targeted gene therapy.Acta Pharm Sin B 2016;6:336-43.
3.Huang ZX,Xie Q,Guo QP,Wang KM,Meng XX,Yuan BY,et al.DNA aptamer selected for specific recognition of prostate cancer cells and clinical tissues.Chin Chem Lett 2017;28:1252-7.
4.Islam MN,Das SR,Emin MT,Wei M,Sun L,Westphalen K,et al.Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury.Nat Med2012;18:759-65.
5.Qiao L,Xu Z,Zhao T,Zhao Z,Shi M,Zhao RC,et al.Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.Cell Res 2008;18:500-7.
6.Lee M,Jeong SY,Ha J,Kim M,Jin HJ,Kwon SJ,et al.Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo.Biochem Biophys Res Commun 2014;446:983-9.
7.Pessina A,Leonetti C,Artuso S,Benetti A,Dessy E,Pascucci L,et al.Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model.J Exp Clin Cancer Res 2015;34:82.
8.Zhao Y,Tang S,Guo J,Alahdal M,Cao S,Yang Z,et al.Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy.Sci Rep 2017;7:44758.
9.Gao J,Dennis JE,Muzic RF,Lundberg M,Caplan AI.The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.Cells Tissues Organs 2001;169:12-20.
10.Barbash IM,Chouraqui P,Baron J,Feinberg MS,Etzion S,Tessone A,et al.Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium:feasibility,cell migration,and body distribution.Circulation 2003;108:863-8.
11.Bos JL.Ras oncogenes in human cancer-a review.Cancer Res1989;49:4682-9.
12.Avruch J,Zhang XF,Kyriakis JM.Raf meets Ras-completing the framework of a signal-transduction pathway.Trends Biochem Sci1994;19:279-83.
13.Khosravifar R,Der CJ.The Ras signal transduction pathway.Cancer Metastas-Rev 1994;13:67-89.
14.Mills NE,Fishman CL,Rom WN,Dubin N,Jacobson DR.Increased prevalence of K-Ras oncogene mutations in lung adenocarcinoma.Cancer Res 1995;55:1444-7.
15.Pellegata NS,Sessa F,Renault B,Bonato M,Leone BE,Solcia E,et al.K-Ras and p53 gene-mutations in pancreatic-cancer-ductal and nonductal tumors progress through different genetic lesions.Cancer Res 1994;54:1556-60.
16.Pessina A,Piccirillo M,Mineo E,Catalani P,Gribaldo L,Marafante E,et al.Role of SR-4987 stromal cells in the modulation of doxorubicin toxicity to in vitro granulocyte-macrophage progenitors(CFU-GM).Life Sci 1999;65:513-23.
17.Pascucci L,Cocce V,Bonomi A,Ami D,Ceccarelli P,Ciusani E,et al Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth:a new approach for drug delivery.J Control Release 2014;192:262-70.
18.Cocce V,Farronato D,Brini AT,Masia C,Gianni AB,Piovani Get al.Drug loaded gingival mesenchymal stromal cells(GinPa-MSCs)inhibit in vitro proliferation of oral squamous cell carcinoma.Sci Rep2017;7:9376.
19.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan MUzunel M,et al.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lance2004;363:1439-41.
20.Horwitz EM,Prockop DJ,Fitzpatrick LA,Koo WW,Gordon PL,Nee M,et al.Transplantability and therapeutic effects of bone marrowderived mesenchymal cells in children with osteogenesis imperfecta Nat Med 1999;5:309-13.
21.Shi YF,Hu GZ,Su JJ,Li WZ,Chen Q,Shou PS,et al.Mesenchyma stem cells:a new strategy for immunosuppression and tissue repair Cell Res 2010;20:510-8.
22.Prockop DJ.Marrow stromal cells as stem cells for continual renewa of nonhematopoietic tissues and as potential vectors for gene therapy.JCell Biochem 1998;72:S284-5.
23.Dezawa M,Ishikawa H,Itokazu Y,Yoshihara T,Hoshino M,Takeda S,et al.Bone marrow stromal cells generate muscle cells and repair muscle degeneration.Science 2005;309:314-7.
24.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,et al.Multilineage potential of adult human mesenchymal stem cells.Science 1999;284:143-7.
25.Squillaro T,Peluso G,Galderisi U.Clinical trials with mesenchyma stem cells:an update.Cell Transplant 2016;25:829-48.
26.Giordano A,Galderisi U,Marino IR.From the laboratory bench to the patients bedside:an update on clinical trials with mesenchymal stem cells.J Cell Physiol 2007;211:27-35.
27.Bartolucci J,Verdugo FJ,Larrea R,Abarzua E,Goset C,Rojo P,et al.Phase 1/2 randomized clinical trial of intravenous infusion of umbilical cord mesenchymal stem cells in patients with chronic cardiopathy with stable heart failure(RIMECARD).Eur Heart J2016;37:527.
28.Zhu HB,Cao BR,Zhen ZP,Laxmi AA,Li D,Liu SR,et al.Controlled growth and differentiation of MSCs on grooved films assembled from monodisperse biological nanofibers with genetically tunable surface chemistries.Biomaterials 2011;32:4744-52.
29.Sonabend AM,Ulasov IV,Tyler MA,Rivera AA,Mathis JM,Lesniak MS.Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma.Stem Cells 2008;26:831-41.
30.Kidd S,Spaeth E,Dembinski JL,Dietrich M,Watson K,Klopp A,et al.Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging.Stem Cells 2009;27:2614-23.
31.Dwyer RM,Potter-Beirne SM,Harrington KA,Lowery AJ,Hennessy E,Murphy JM,et al.Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells.Clin Cancer Res 2007;13:5020-7.
32.Jang SC,Kim OY,Yoon CM,Choi DS,Roh TY,Park J,et al.Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors.ACS Nano 2013;7:7698-710.
33.Rani S,Ryan AE,Griffin MD,Ritter T.Mesenchymal stem cellderived extracellular vesicles:toward cell-free therapeutic applications.Mol Ther 2015;23:812-23.