Somatostatin receptor-mediated tumor-targeting drug delivery using octreotide-PEG-deoxycholic acid conjugate-modified N-deoxycholic acid-O, N-hydroxyethylation chitosan micelles.
In this study, a ligand-PEG-lipid conjugate, octreotide-polyethene glycol-deoxycholic acid (OCT(Phe)-PEG-DOCA, or OPD) was successfully synthesized and used as a targeting molecule for N-deoxycholic acid-O, N-hydroxyethylation chitosan (DAHC) micelles for efficient cancer therapy. DAHC micelles exhibited good loading capacities for doxorubicin (DOX), a model anti-cancer drug, and the modification of OPD showed no significant effect on drug load while slightly increasing the particle size and partly shielding the positive charges on the surface of micelles. Accelerated release rate of DOX from micelles were also observed after OPD modification and the release profile exhibited pH-sensitive properties. Compared with DAHC-DOX micelles, OPD-DAHC-DOX micelles exhibited significantly stronger cytotoxicity to MCF-7 cells (SSTRs overexpression) but with hardly any difference from WI-38 cells (no SSTRs expression). The results of flow cytometry and confocal laser scanning microscopy further revealed that OPD-DAHC-DOX micelles could be selectively taken into tumor cells by SSTRs-mediated endocytosis. In vivo investigation of micelles on nude mice bearing MCF-7 cancer xenografts confirmed that OPD-DAHC micelles possessed much higher tumor-targeting capacity than the DAHC control and exhibited enhanced anti-tumor efficacy and decreased systemic toxicity. These results suggest that OPD-DAHC micelles might be a promising anti-cancer drug delivery carrier for targeted cancer therapy.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
Meirong
M
Huo
Aifeng
A
Zou
Chengli
C
Yao
Yong
Y
Zhang
Jianping
J
Zhou
Jing
J
Wang
Qinnv
Q
Zhu
Jing
J
Li
Qiang
Q
Zhang
D000818:Animals; D002152:Calorimetry, Differential Scanning; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D048271:Chitosan / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005434:Flow Cytometry; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012542:Scattering, Radiation; D016896:Treatment Outcome; D014961:X-Ray Diffraction
D008823:Micelles; D017481:Receptors, Somatostatin; D003840:Deoxycholic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; D048271:Chitosan; D015282:Octreotide