Currently, cancer treatments have limits: healthy cells are attacked, causing significant side effects and therapeutic efficacy is far from ideal. To address these issues, the drug must be released as close as possible to the tumor site, and in optimal amounts. Amphiphilic block copolymer micelles can be used to encapsulate (protect) drug in their core, while stealth properties of the hydrophilic corona, conferred generally by polyethylene glycol (PEG), allow improved lifetime in blood to reach the tumor site. (1) Furthermore, pH-responsive character of copolymer micelles is increasingly considered to trigger drug release in selective tumoral area (pH~5-6) and thus limit side effects. However, synthesis of block copolymers containing pH-labile moieties is often multistep/laborious, and copolymer PEG content raises increasing concerns of hypersensitivity. Thus, new safe-by-design and straightforward approaches to pH-responsive copolymer micelles are strongly needed. (2)
In this context, we focus on new and easily achievable pH-sensitive block copolymer micelles for anticancer drug delivery. The approach is based on an hetero bi-functional pH-sensitive initiator, able to initiate both controlled radical polymerization (for the hydrophilic part) and ring opening polymerization (for the hydrophobic part, i.e. polylactide (PLA)). The pH-sensitivity is brought by an imine function, undergoing hydrolysis at acidic pH, thus allowing cleavage at block junction. The initiator was obtained in a 2 steps synthesis (Figure 1, left). The dual initiator was used for nitroxide mediated polymerization (NMP) of 4-acryloylmorpholine (NAM) at 100 °C and ring opening polymerization (ROP) of D,L-lactide at room temperature in presence of DBU catalyst. (Figure 1, right). The PNAM-imine-PLA block copolymer formation was shown by 1H NMR and size exclusion chromatography (SEC). Micelles from the amphiphilic copolymers were prepared by the nanoprecipitation process. At physiological pH (7.4), micelles were about 100 nm in diameter and were stable. At tumor mimicking pH (5.5), micelles size increased over time, as a result of cleavage and formation of polymeric aggregates (Figure 2), demonstrating the relevance of our approach for triggering drug release in a cancer context.
(1) Cabral, H.; Miyata, K.; Osada, K.; Kataoka, K. Block Copolymer Micelles in Nanomedicine Applications. Chem Rev 2018, 118 (14), 6844–6892.
(2) Gigmes, D.; Trimaille, T. Advances in Amphiphilic Polylactide/Vinyl Polymer Based Nano-Assemblies for Drug Delivery. Adv. Colloid Interface Sci. 2021, 294, 102483.