Synthesis of a Therapeutic Amphiphilic Copolymer of SN38 via RAFT Polymerization and Its Self-Assembly to Peptomicelles for Fighting against Colon Adenocarcinoma

Abstract

Colorectal cancer (CRC) is the fourth most frequent type and third most lethal malignancy in the world. To increase the efficacy of chemotherapy while reducing its side effects, the self-assembly of polymer–drug conjugates can minimize systemic toxicity while enhancing therapeutic efficiency. In the present study, polyglutamic acid (PGA) was used to prepare the conjugate of a hydrophobic anticancer agent, SN38, by forming an ester bond between phenolic hydroxyl groups of SN38 and the activated carboxylic acid of PGA. Then, a polyhydroxypropyl methacrylamide (PHPMA) block was synthesized starting from the end of the PGA chain via the “grafting from” approach, implementing reversible addition–fragmentation chain transfer (RAFT) polymerization. The amphiphilicity of the synthesized block copolymer will induce self-assembly into peptomicelle (polypeptide-based micellar structure) structures. Then, the prepared SN38-conjugated PGA-PHPMA peptomicelles were tagged with an AS1411 aptamer to provide guided drug delivery to colon adenocarcinoma. The synthesis of the therapeutic diblock copolymer was confirmed by 1H-NMR. The DLS analysis showed the sizes of 61.44 and 59.10 nm with dispersity (Đ) values of 0.44 and 0.32 for targeted and nontargeted peptomicelles, respectively. In vitro drug release experiments of the prepared system showed a controlled release profile, which was significantly accelerated in citrate buffer (pH 5.4) in comparison with that of phosphate-buffered saline (PBS, 1×, pH 7.4). An in vitro cytotoxicity experiment (MTT) illustrated a higher cytotoxicity for aptamer-targeted peptomicelles in comparison with that of nontargeted ones against H29 and C26 as nucleolin-positive cell lines, which was statistically significant, while no difference was identified between the toxicity of aforementioned formulation against CHO as a nucleolin-negative cell line (p > 0.05). In vivo study on mice bearing C26 colon carcinoma confirmed the superior therapeutic index of the aptamer-targeted peptomicelles in comparison with nontargeted peptomicelles in terms of tumor growth suppression and survival rate. Polypeptide-based self-assembled therapeutic structures as an innovative platform represent a capable chemotherapy approach.