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Acid-degradable (or acid-cleavable) polymeric nanoassemblies have witnessed significant progress in anti-cancer drug delivery. However, conventional nanoassemblies designed with acid-cleavable linkages at a single location have several challenges, such as, sluggish degradation, undesired aggregation of degraded products, and difficulty in controlled and on-demand drug release. Herein, a strategy that enables the synthesis of acid-cleavable nanoassemblies labeled with acetaldehyde acetal groups in both hydrophobic cores and at core/corona interfaces, exhibiting synergistic response to acidic pH at dual locations and thus inducing rapid drug release is reported. The systematic analyses suggest that the acid-catalyzed degradation and disassembly are further enhanced by decreasing copolymer concentration (i.e., increasing proton/acetal mole ratio). Moreover, incorporation of acid-ionizable imidazole pendants in the hydrophobic cores improve the encapsulation of doxorubicin, the anticancer drug, through π-π interactions and enhance the acid-catalyzed hydrolysis of acetal linkages situated in the dual locations. Furthermore, the presence of the imidazole pendants induce the occurrence of core-crosslinking that compensates the kinetics of acetal hydrolysis and drug release. These results, combined with in vitro cell toxicity and cellular uptake, suggest the versatility of the dual location acid-degradation strategy in the design and development of effective intracellular drug delivery nanocarriers.

The development of biocompatible polylactide (PLA)-based block copolymers for constructing self-assembled nanoaggregates degradable in response to endogenous stimuli found in cell environments is promising for enhanced/controlled drug delivery in pharmaceutical science. Despite advances in the synthesis of various PLA-based nanoassemblies featured with only a single stimulus response, the design and development of advanced nanoassemblies integrated with two endogenous stimuli-responsive cleavable linkages for dual stimuli response is challenging. Here we report an approach to the synthesis of a new PLA-based diblock copolymer having dual reduction-cleavable disulfide and acid-labile acetal linkages at the block junction. Key to the approach is the use of a double-head initiator designed uniquely with both acetal and disulfide linkages as well as with both OH and bromine terminal groups. Our comprehensive results from structural analysis and degradation through chemical transition suggest the requirement of a rational combination of controlled polymerization techniques and facile coupling reactions for the synthesis of well-controlled PLA-based diblock copolymer having both disulfide and acetal linkages. The main reason is attributed to the instability of acetal linkages under ROP condition with a tin catalyst at an elevated temperature. The resultant copolymer self-assembles to form shell-sheddable nanoassemblies that are disintegrated in response to dual acid/reduction. This work demonstrates the importance in the development of efficient polymerization strategies by utilizing well-established polymerization techniques to synthesize novel functional copolymers with complicated architectures and various functionalities sensitive to reaction environments.

Polylactide (PLA)-based amphiphilic block copolymers and their nanoassemblies designed with stimuli-responsive degradation (SRD) hold great potential as promising candidates for tumor-targeting drug delivery. However, most of the smart PLA-based nanoassemblies are designed to respond to a single stimulus (typically reduction or acidic pH). Herein, a new strategy is reported to synthesize PLA-based block copolymer micelles exhibiting dual SRD at dual locations (DL-DSRD). The strategy utilizes a combination of ring opening polymerization, controlled radical polymerization, and facile coupling reactions to synthesize an ABA-type PLA-based triblock copolymer with a hydrophilic polymethacrylate (A) and PLA (B) blocks. Incorporation of an acidic pH-responsive ketal linkage in the center of PLA block and reduction-responsive disulfide linkages at PLA/hydrophilic polymethacrylate blocks ensure the formation of smart nanoassemblies featured with ketal linkages in the PLA cores and disulfide linkages at core/corona interfaces, thus attaining DL-DSRD. Such dual acidic pH/reduction-responses at dual locations lead to not only shedding of coronas at interfaces but also destabilization of cores, resulting in the synergistic and accelerated release of encapsulated model drugs, compared with the single stimulus systems. These results, along with lower cytotoxicity, suggest that DL-DSRD strategy can offer versatility in the development of tumor-targeting drug delivery nanocarriers.

Polylactide (PLA) is biocompatible and FDA-approved for clinical use and thus has been a choice of the materials valuable for extensive applications in biomedical fields. However, conventionally designed PLA-based amphiphilic block copolymer (ABP) nanoassemblies exhibit slow and uncontrolled release of encapsulated drugs because of the slow biodegradation of hydrophobic PLA in physiological conditions. To improve potentials for clinical use and commercialization of conventional PLA-based nanoassemblies, stimulus-responsive degradation (SRD) platform has been introduced into the design of PLA-based nanoassemblies for enhanced/controlled release of encapsulated drugs. This review summarizes recent strategies that allow for the development of PLA-based ABPs and their self-assembled nanostructures exhibiting SRD-induced enhanced drug release. The review focuses on the design, synthesis, and evaluation of the nanoassemblies as intracellular drug delivery nanocarriers for cancer therapy. Further, the outlook is briefly discussed on the important aspects for the current and future development of more effective SRD PLA-based nanoassemblies toward tumor-targeting intracellular drug delivery.