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 Ncarboxyanhydride (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-aspartateco-L-boronophenylalanine) [PEG-P(BLA-co-BPA)] were obtained with controlled compositions. Interestingly, PEG-PBPA selfassembled into uniform micellar nanoparticles that mediated robust co-encapsulation and hydrogen peroxide (H 2 O 2 ) and acidresponsive 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.

A polymeric IDO inhibitor has been developed for the first time from copolypeptides for facile trident cancer immunotherapy.

The bromodomain and extra-terminal (BET) proteins are attractive targets for treating various malignancies including melanoma. The inhibition of BET bromodomains e.g. with JQ1 is found to downregulate the expression of...

Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, B-N coordination, and 𝝅-𝝅 stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro-apoptotic reactions by promoting the dissociation of the pro-apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor-loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H 2 O 2 -triggered drug release, and significant cytotoxicity toward MOLM-13-Luc and MV-411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL −1 , respectively. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.