SCHEDULED MAINTENANCE
Multifunctional ATRP based pH responsive polymeric nanoparticles for improved doxorubicin chemotherapy in breast cancer by proton sponge effect/endo-lysosomal escape†
Abstract
Folic acid and trastuzumab functionalized pH responsive biodegradable polymeric nanosystem comprising of poly(dimethylaminoethyl methacrylate)-poly(polyethylene glycol methacrylate)-poly(caprolactone)-poly(polyethylene glycol methacrylate)-poly(dimethylaminoethyl methacrylate) [PDMAEMA-PPEGMA-PCL-PPEGMA-PDMAEMA] was designed and developed for improving the chemotherapeutic efficacy of doxorubicin while minimizing its cardiotoxicity in breast cancer therapy. The nanosystem consists of multiple polyethylene glycol chains, which impart stealth nature to the nanoparticles. The polymer-doxorubicin conjugate via acid responsive hydrazone linkage resulted in enhanced doxorubicin release (∼89%) at endo-lysosomal pH when compared to that at physiological pH (∼29%). The nanoparticles also exhibited a proton sponge effect leading to endo-lysosomal escape of the nanoparticles, which resulted in minimal drug degradation and faster drug action. Folic acid and trastuzumab were incorporated in the nanosystem to selectively target breast cancer cells. In vitro and in vivo studies in breast cancer cell lines and Ehrlich ascites tumor bearing Swiss albino mice showed enhanced cellular uptake and improved therapeutic efficacy of the nanosystem with nanoparticles achieving ∼92% tumor regression when compared to ∼36% tumor regression observed with free doxorubicin. This enhanced therapeutic efficacy was achieved with minimal cardiotoxicity as observed in histopathology and blood biochemistry. The findings highlight the potential of the nanosystem in the chemotherapeutic management of breast cancer with its high therapeutic efficacy and minimal cardiotoxicity.
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