1. AS1411 aptamer and folic acid functionalized pH-responsive ATRP fabricated pPEGMA-PCL-pPEGMA polymeric nanoparticles for targeted drug delivery in cancer therapy.
- Author
-
Lale SV, R G A, Aravind A, Kumar DS, and Koul V
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Apoptosis drug effects, Aptamers, Nucleotide, Biocompatible Materials administration & dosage, Biocompatible Materials chemistry, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Doxorubicin administration & dosage, Doxorubicin chemistry, Drug Screening Assays, Antitumor, Folic Acid administration & dosage, Folic Acid chemistry, Humans, Hydrogen-Ion Concentration, MCF-7 Cells, Molecular Structure, Nanoparticles administration & dosage, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides chemistry, Particle Size, Polymerization, Structure-Activity Relationship, Surface Properties, Antineoplastic Agents pharmacology, Biocompatible Materials pharmacology, Doxorubicin pharmacology, Drug Delivery Systems, Folic Acid pharmacology, Nanoparticles chemistry, Oligodeoxyribonucleotides pharmacology
- Abstract
Nonspecificity and cardiotoxicity are the primary limitations of current doxorubicin chemotherapy. To minimize side effects and to enhance bioavailability of doxorubicin to cancer cells, a dual-targeted pH-sensitive biocompatible polymeric nanosystem was designed and developed. An ATRP-based biodegradable triblock copolymer, poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate) (pPEGMA-PCL-pPEGMA), conjugated with doxorubicin via an acid-labile hydrazone bond was synthesized and characterized. Dual targeting was achieved by attaching folic acid and the AS1411 aptamer through EDC-NHS coupling. Nanoparticles of the functionalized triblock copolymer were prepared using the nanoprecipitation method, resulting in an average particle size of ∼140 nm. The biocompatibility of the nanoparticles was evaluated using MTT cytotoxicity assays, blood compatibility studies, and protein adsorption studies. In vitro drug release studies showed a higher cumulative doxorubicin release at pH 5.0 (∼70%) compared to pH 7.4 (∼25%) owing to the presence of the acid-sensitive hydrazone linkage. Dual targeting with folate and the AS1411 aptamer increased the cancer-targeting efficiency of the nanoparticles, resulting in enhanced cellular uptake (10- and 100-fold increase in uptake compared to single-targeted NPs and non-targeted NPs, respectively) and a higher payload of doxorubicin in epithelial cancer cell lines (MCF-7 and PANC-1), with subsequent higher apoptosis, whereas a normal (noncancerous) cell line (L929) was spared from the adverse effects of doxorubicin. The results indicate that the dual-targeted pH-sensitive biocompatible polymeric nanosystem can act as a potential drug delivery vehicle against various epithelial cancers such as those of the breast, ovary, pancreas, lung, and others.
- Published
- 2014
- Full Text
- View/download PDF