Synthesis of novel amphiphilic poly(N-isopropylacrylamide)-b-poly(aspartic acid) nanomicelles for potential targeted chemotherapy in ovarian cancer

Abstract

The purpose of this study was to merge amino terminated poly(N-isopropylacrylamide) (PNIPAm-NH2) with L-Aspartic acid-N-carboxyanhydride (L-Asp-NCA) using thermal ring-cleavage polymerization to synthesize a pH and thermo-responsive amphiphilic PNIPAm-b-PAsp copolymer for self-assembling nanomicelles. The stimuli-responsive nanomicelles are intended for targeted delivery of methotrexate (MTX) for potential application in ovarian cancer chemotherapy. Rheological profiles of various concentrations of the block copolymer were evaluated. The thermal ring-opening polymerization of L-Asp-NCA onto PNIPAm-NH2 yielded a copolymer with an inherent viscosity of 494.527mPas that was confirmed by advanced rheometry with a high mean molecular weight (MW = 2.217 × 106kDa) computed by the partially-proportional Mark-Houwink formula. Scanning electron microscopy (SEM) elucidated the copolymer topography and pore distribution. Vibrational Fourier Transform Infrared (FTIR), Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC), and Thermal Gravimetric Analysis (TGA) confirmed the synthesis of the amphiphilic block copolymer. The PNIPAm-b-PAsp nanomicelles were 90 nm in size with a zeta potential value of −0.539 mV (PdI ≤0), a yield of 94% and a DEE value of >77%. The in vitro release profile of MTX displayed constant release of MTX over 72 h. The critical micelle concentration (CMC) was computed to be 0.09 mg/mL. Furthermore, the potential of the amphiphilic PNIPAm-b-PAsp copolymeric nanomicelles to target delivery of MTX for ovarian cancer cell destruction was evaluated following determination of cytotoxicity and internalization in an ovarian cancer cell line (NIH:OVAR-5). Overall, results demonstrated that the novel PNIPAm-b-PAsp copolymer synthesized was practical for nanomicelle formation and for the potential application as a stimuli-responsive nanocarrier system for the targeted delivery of MTX in ovarian cancer.