Chain-shattering polymeric therapeutics with on-demand drug-release capability.

Polymer–drug conjugates are an important polymeric therapeutic (PT) platform with drug molecules being attached by cleavable linkages to the pendant functional groups of linear, branched, brushed polymers that are typically synthesized prior to drug conjugation. The synthesis and conjugation processes developed to date, however, may not provide precise control over the composition and the structure of the conjugates. When a polymer with a large number of conjugation-amenable, functional side groups is used, for example, the site of conjugation usually cannot be controlled. As such, batch-to-batch variations of drug loading and release profiles are often observed with polymer–drug conjugates, and these variations may present a key bottleneck to the clinical translation of PTs. To address these challenges, we recently reported drug-initiated ring-opening polymerization of lactide and other cyclic esters in the presence of a zinc catalyst, a technique that can provide excellent control over drug loading. Hydroxy-group-containing drugs are conjugated to polyesters or polycarbonates by an ester linkage, and drug loading can be controlled by tuning the monomer/initiator ratio. Although this technique provides excellent control over drug loading and affords polymer–drug conjugates with controlled structures and compositions, the ability to control drug release from the resulting conjugates is limited: drug molecules are released by means of hydrolysis or enzymatic cleavage of the ester linkage. Incorporating a linker that allows trigger-responsive, active release of the terminally conjugated drug remains synthetically challenging. To develop a new PTwith precise control over both drug loading and release, we attempted to incorporate a triggerresponsive domain (TRD) into PTs, aiming to achieve a specific PT structure and to use the TRD to precisely control drug release. One feasible approach would be using multiple drug and TRD molecules as monomers to construct an A/B (TRD/drug) type of condensation polymer. The resulting PT would have specific repeating units, and therefore specific molecular structure and composition. Drug release would be precisely controlled by the TRD. Application of an external trigger would activate the TRD, which would subsequently induce a chain-shattering type of degradation of the polymer and release of the neighboring drug molecules (Scheme 1). Herein, we report the use of this approach for the design of chain-shattering polymeric therapeutics (CSPTs) and demonstrate the trigger-induced anticancer activity of CSPTs in vitro and in vivo.