Abstract:Polymers with advanced topological architectures are promising materials for wide applications due to their structure-generated unique properties different from that of the linear analogues. The elegant integration of stimuli-responsive polymers with such advanced architectures can create novel materials with virtues from both moieties, are thus a hot subject of research for both fundamental and practical investigations. To fabricate cyclic brush polymer-based intelligent materials for biomedical applications, herein, we designed and synthesized thermo-sensitive cyclic brush polymers with poly(N-isopropylacrylamide) (PNIPAAm) brushes by controlled living radical polymerization using cyclic multimacroinitiator. The thermo-induced phase transition behaviors of the resultant cyclic brush polymers with different compositions were investigated in detail by temperature-dependent optical transmittance measurements, and compared with the properties of bottlebrush and linear counterparts. Interestingly, the cloud point transition temperature (T cp ) of cyclic brush PNIPAAm could be regulated by the chain length of PNIPAAm brush. Although the bottlebrush polymers with the same composition exhibited similarly structurally dependent T cp s behaviors to the cyclic brush polymers, the cyclic brush PNIPAAm did show higher critical aggregation concentration (CAC) and enhanced stability against dilution than the bottlebrush counterpart. The readily tailorable T cp s together with the ability to form highly stable nanoparticles makes thermo-sensitive cyclic brush PNIPAAm a promising candidate for controlled drug delivery.

The preparation of various types of miktoarm star polymers with precisely controlled structures (A2B, ABC, AB2C2, etc.) has made significant progress due to the considerable advances in the synthetic strategies, including multistep protections/deprotections, orthogonality, and integration of different polymerization techniques. However, compared to the well-developed synthesis methodologies, the investigations on miktoarm star copolymers as drug delivery vehicles remain relatively unexplored, especially for the relationship of their branched structures and properties as drug delivery systems. To elucidate this structure–property relationship of amphiphilic miktoarm star polymers, we prepared four different amphiphilic miktoarm star copolymers with the respectively identical molecular weights (MWs) of hydrophilic and hydrophobic moieties but different star structures using heteroinitiators that were synthesized by protection/deprotection strategies for integrated ring-opening polymerization of hydrophobic ε-caprolactone and atom transfer radical polymerization of hydrophilic oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA). Further screening of an optimal formulation for anticancer drug delivery by the stability of micelles, in vitro drug loading capacity, drug release properties, cellular uptake efficacy, and cytotoxicity of doxorubicin (DOX)-loaded micelles showed that PCL3POEGMA1 micelles possessed the lowest critical micelle concentration, the highest drug loading content, and enhanced therapeutic efficiency for DOX release of all the synthesized four star copolymer constructs. This study thus provides preliminary guidelines and rationalities for the construction of amphiphilic miktoarm star polymers toward enhanced anticancer drug delivery.

Conjugation of various active targeting ligands to the surface of nanocarriers to realize specific recognition by the corresponding receptors localized on the membrane of the cancer cells has provided a powerful means toward enhanced cancer therapy. Folic acid (FA) is one of the most used targeting ligands due to the overexpressed FA receptors in many cancer cell lines. However, conjugation of hydrophobic FA to the surface of nanocarriers usually alters the hydrophilic/hydrophobic balance of the stabilized nanoparticles, leading to their thermodynamic instability and subsequent formation of aggregates, which apparently compromises the in vivo long circulation and minimized side effects of nanocarriers. The currently leading strategy to overcome this issue is to incorporate a protecting hydrophilic stealth that can be deshielded to expose the targeting ligand at the desired tumor site, which generally involves multistep chemical modifications, conjugations, and purifications. To develop a simple alternative toward FA-mediated enhanced anticancer drug delivery, a combination strategy of micelle complex and reducible conjugation was reported in this study. FA was first conjugated to the terminus of the hydrophilic block of a reduction-sensitive miktoarm star-shaped amphiphilic copolymer, PCL3-SS-POEGMA1, with the previously optimized star structure by click coupling via a reducible disulfide link. The resulting PCL3-SS-POEGMA1-SS-FA was further mixed with the parent PCL3-SS-POEGMA1 to afford a micelle complex with both reducibly conjugated and relatively low amount of FA-targeting ligands toward excellent FA-mediated targeted drug delivery without compromised salt stability in vitro and in vivo. Therefore, the combined strategy developed herein provides a simple and powerful means to promote FA-mediated anticancer drug delivery.

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Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.