AS1411 Aptamer and Folic Acid Functionalized pH-Responsive ATRP Fabricated pPEGMA–PCL–pPEGMA Polymeric Nanoparticles for Targeted Drug Delivery in Cancer Therapy

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.

Assessment of PVA/silver nanocomposite hydrogel patch as antimicrobial dressing scaffold: Synthesis, characterization and biological evaluation

“…Biuret protein assay [63][64][65] was used to detect the protein leakage from bacterial cells. The concentration of AgNPs was adjusted to MIC value for the respective bacteria and 10 8 CFU/mL bacterial cells were taken.…”

Folate-decorated hydrophilic three-arm star-block terpolymer as a novel nanovehicle for targeted co-delivery of doxorubicin and Bcl-2 siRNA in breast cancer therapy

“…The phenomenon should be attributed to the acidic catalytic cleavage of the hydrazone linkage between DOX and the terpolymer, thus releasing the conjugated DOX [31]. In addition, because of the basic nature of DOX (pKa = 8.3) [49], the released DOX would become water-soluble in the acidic environments due to the protonation of 3'-NH 2 of DOX, which facilitated DOX diffusion out of the nanocarriers.…”

“…Undoubtedly, these copolymers can self-assemble into more stable nanoparticles with similar topological structures to those assembled from the corresponding linear block analogues [29]. Such star-block copolymers are usually synthesized by ring-opening polymerization (ROP) of lactone monomers, 'living polymerization' like reversible addition-fragmentation chain transfer (RAFT) and atom transfer radical polymerization, or their combination which are currently the finest methods for the synthesis of copolymers with well-defined multiple-block architecture and predetermined molecular weight [30,31]. Nonetheless, the pursuit of more sophisticated nanovehicles capable of simultaneously delivering chemotherapy drug and siRNA still continues.…”

Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform

“…When exposed under external stimuli, the polymers will undergo physiochemical structural changes, and therefore lose the well-defined nanoarchitectures releasing drugs directly onto the tumor cells. Among the external stimuli, pH gradients have been widely used for controlled release, relying on the abnormally low pH of endosomes or tumor tissues compared with healthy tissues 12–15…”