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Multiple myeloma (MM) is the second most common hematological malignancy. For relapsed and refractory MM, a proteasome inhibitor, carfilzomib (CFZ), has become one of the few clinical options. CFZ suffers, nevertheless, metabolic instability and poor bioavailability and may induce severe cardiovascular and renal adverse events. Here, we report that daratumumab (Dar)-decorated polypeptide micelles (Dar-PMs) mediate the targeted delivery of CFZ to CD38-positive MM, effectively boosting its anti-MM efficacy. CFZ-loaded Dar-PMs (Dar-PMs-CFZ) exhibited an average diameter of ca. 80 nm and Dar density-dependent cell endocytosis and anti-MM activity, in which over 6-fold greater inhibitory effect to LP-1 and MM.1S MM cells than nontargeted PMs-CFZ control was achieved at a Dar density of 3.2 (Dar 3.2 -PMs-CFZ). Interestingly, Dar 3.2 -PMs-CFZ markedly enhanced the growth inhibition of orthotopic LP-1 MM in mice and significantly extended the median survival time compared with PMs-CFZ and free CFZ (95 days vs 60 and 54 days, respectively). In line with its high MM targetability and anti-MM efficacy, Dar 3.2 -PMs-CFZ revealed little toxic effects and effectively prevented osteolytic lesions. The antibody-targeted nanodelivery of a proteasome inhibitor appears to be an appealing strategy to treat multiple myeloma.

The incorporation of a phenylboronic acid group has appeared as an attractive strategy to build smart drug delivery systems. Here, we report novel synthesis of phenylboronic acid-functionalized copolypeptides based on an l-boronophenylalanine N -carboxyanhydride (BPA-NCA) monomer and their application for robust co-encapsulation and responsive release of dual anticancer drugs. By employing different poly(ethylene glycol) (PEG) initiators and copolymerizing with varying NCA monomers, linear and star PEG-poly(l-boronophenylalanine) copolymers (PEG-PBPA, star-PEG-PBPA), PEG-poly(l-tyrosine- co -l-boronophenylalanine) [PEG-P(Tyr- co -BPA)], PEG-poly(l-lysine- co -l-boronophenylalanine) [PEG-P(Lys- co -BPA)], and PEG-poly(β-benzyl-l-aspartate- co -l-boronophenylalanine) [PEG-P(BLA- co -BPA)] were obtained with controlled compositions. Interestingly, PEG-PBPA self-assembled into uniform micellar nanoparticles that mediated robust co-encapsulation and hydrogen peroxide (H 2 O 2 ) and acid-responsive release of dual antitumor drugs, curcumin (Cur) and sorafenib tosylate (Sor). These dual drug-loaded nanoparticles (PBN-Cur/Sor) exhibited a greatly enhanced anticancer effect toward U87 MG-luciferase glioblastoma cells. The facile synthesis of phenylboronic acid-functionalized copolypeptides from BPA coupled with their robust drug loading and responsive drug release behaviors make them interesting for construction of smart cancer nanomedicines.