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Increasing the anticancer performance of bufalin (BUF) by introducing an endosome-escaping polymer and tumor-targeting peptide in the design of a polymeric prodrug
- Shi, Xiao-jing, Qiu, Yan-yan, Yu, Hui, Liu, Cheng, Yuan, Yu-xia, Yin, Pei-hao, Liu, Tao
- Colloids and surfaces 2018 v.166 pp. 224-234
- angiogenesis, animal models, antineoplastic agents, apoptosis, aqueous solutions, cell viability, chemical bonding, colloids, colorectal neoplasms, composite polymers, drug delivery systems, endosomes, esterases, hemolysis, histology, hydrolysis, hydrophilicity, immunochemistry, lysosomes, moieties, nanoparticles, pH, polymerization, zeta potential
- A well-defined multifunctional brush-type polymeric prodrug covalently linked with an anticancer drug (bufalin, BUF), a tumor-targeting peptide (RGD), and an endosome-escaping polymer, poly(N,N-diethylaminoethyl methacrylate-co-butyl methacrylate (P(DEA-co-BMA)), was developed. Its anticancer performance against colon cancer was investigated in vitro and in vivo. Reversible addition-fragmentation transfer (RAFT) polymerization of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), 2-((3-(tert-butoxy)-3-oxopropyl)thio)ethyl methacrylate (BSTMA), and 2-(2-bromoisobutyryloxy)ethylmethacrylate (BIEM) afforded the multifunctional random copolymer, P(OEGMA-co-BSTMA-co-BIEM), in which hydrophilic POEGMA can stabilize nanoparticles in water, PBSTMA can be converted into carboxyl groups, and PBIEM can be employed as a macromolecular atom radical transfer polymerization (ATRP) initiator. The ATRP of DEA and BMA using P(OEGMA-co-BSTMA-co-BIEM) as a macromolecular ATRP initiator led to the formation of the pH-responsive brush-type copolymer, P(OEGMA-co-BSTMA)-g-P(DEA-co- BMA). After hydrolysis by trifluoroacetic acid and post-functionalization the final polymeric prodrug, P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA), was obtained with a drug content of ∼7.8 wt%. P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA) can be assembled into nanoparticles (BUF- NP-RGD) in aqueous solution with a diameter of 148.4 ± 0.7 nm and a zeta potential of −7.6 ± 0.4 mV. BUF-NP-RGD exhibited controlled drug release in the presence of esterase. Additionally, P(OEGMA-co- BSMA)-g-P(DEA-co-BMA) showed a significant hemolysis effect at a pH comparable to that of endosomes/lysosomes. Cell viability and a tumor-bearing nude mouse model were employed to evaluate the anticancer efficacy of BUF-NP-RGD. It was revealed that BUF-NP-RGD showed improved anticancer performance compared with that of free BUF both in vitro and in vivo. Histological and immunochemical analysis further demonstrated that BUF-NP-RGD exhibited improved cell apoptosis, angiogenesis inhibition, and an anti-proliferation effect.