Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer.
Clinical effectiveness of gemcitabine in pancreatic cancer is hindered due to its rapid plasma metabolism and development of chemo-resistance. We have previously delineated the significant role of miRNAs in mediating the growth and proliferation of cancer stem cells (CSCs) which in turn result in chemo-resistance, invasion and metastasis. Here, we designed self-assembling, gemcitabine conjugated cationic copolymers for co-delivery of a tumor suppressor miRNA-205 (miR-205) and evaluated their in vivo efficacy in a pancreatic cancer ectopic tumor model developed using gemcitabine resistant MIA PaCa-2(R) cells. Combination formulations showed mean a particle size of <100 nm and gemcitabine payload of >10% w/w, exhibited miRNA complexation at N/P ratio of 4/1, sustained release of gemcitabine for >10 days, transfection efficiency of >90%, extended miRNA and drug stability in serum. Functional assays in gemcitabine resistant MIA PaCa-2(R) and CAPAN-1(R) pancreatic cancer cells revealed that the combination formulations effectively reversed chemo-resistance, invasion and migration. In pancreatic tumor model, the combination formulation treated group showed significant inhibition of tumor growth. Immuno-hiostochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-205 and gemcitabine combination.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Anupama
A
Mittal
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Deepak
D
Chitkara
Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Stephan W
SW
Behrman
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: ram.mahato@unmc.edu.
Ram I
RI
Mahato
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008819:Mice, Nude; D008823:Micelles; D035683:MicroRNAs / Q000737:chemistry* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis; D011108:Polymers / Q000737:chemistry; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D003841:Deoxycytidine; D008024:Ligands; D008823:Micelles; D035683:MicroRNAs; D011092:Polyethylene Glycols; D011108:Polymers; D000093542:Gemcitabine; C534425:MIR205, human
Cancer; Gemcitabine; Micelles; Pancreas; miR-205; miRNA