Self-assembly of degradable amphiphilic polymers have played a crucial role in the development of advanced drug delivery systems. This process is directly governed by the polymer properties and conditions present during the self-assembly process. In this work, we report the synthesis of PEGylated macro-chain transfer agents that were used to produce novel degradable amphiphilic diblock copolymers. The length of the hydrophobic blocks, comprised of RAFT-terpolymerized 2-methylene-1,3-dioxepane (MDO), vinyl acetate (VAc) and vinyl bromobutanoate (VBr), was varied to obtain functional copolymers at different hydrophilic-lipophilic balance (HLB). We thoroughly characterized the formed polymers before utilizing them in several solvent-switch self-assembly events to produce defined nanomaterial species. Morphological phase-diagrams were constructed utilizing the obtained higher-order structures at variable polymer HLB, types of drug(s) sequestered, and types of common solvent(s) used to dissolve the amphiphilic blocks. We utilized these phase diagrams to optimize the conditions to produce pH-sensitive, core-crosslinked polymersomes that can sequester the antineoplastic drugs: doxorubicin (hydrophilic or hydrophobic), camptothecin (hydrophobic), or a combination of both at high encapsulation efficiencies (Fig.1). We finally compared the in vitro performance of these vesicles in terms of their drug encapsulation efficiencies, release profiles, cellular uptake and dose-dependent cytotoxicity when tested against MDA-MB-468 breast cancer cells. This work highlights the potential application of these nanoparticles in the area of cancer research, where the efficient drug loading of a wide range of cargo, sustained drug release, favourable cellular internalization and synergy obtained when multiple drugs are used confirm that our tuneable delivery systems hold great potential as next-generation cancer therapeutics.

Precision design of degradable RAFT-based amphiphilic diblock copolymers and their self-assembly into tunable polymersomes for chemotherapeutic drug delivery

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