Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid-Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia.

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/H2 O2 -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.

A polymeric IDO inhibitor based on poly(ethylene glycol)-b-poly(L-tyrosine-co-1-methyl-D-tryptophan) enables facile trident cancer immunotherapy.

Indoleamine 2,3-dioxygenase (IDO), with an immunoregulatory effect related to tryptophan metabolism, has emerged as an attractive target for cancer immunotherapy. Here, a polymeric IDO inhibitor based on the poly(ethylene glycol)-b-poly(L-tyrosine-co-1-methyl-D-tryptophan) copolymer (PEG-b-P(Tyr-co-1-MT)) was developed for facile trident cancer immunotherapy. PEG-b-P(Tyr-co-1-MT) could self-assemble into nanoparticles (NPs), which were subject to enzyme degradation and capable of retarding the metabolism of L-tryptophan (TRP) to L-kynurenine (KYN) in B16F10 cancer cells. Notably, cRGD-functionalized NPs showed efficient encapsulation and an enzyme-responsive release of doxorubicin (DOX) and the BET bromodomain inhibitor JQ1. DOX in drug-loaded nanoparticles (cRGD-NPDJ) could activate immunization by inducing the discernible immunogenic cell death (ICD) of cancer cells and promoting the secretion of interferon-γ (IFN-γ), which besides activating the antitumor cellular immunity often upregulates the expression of PD-L1 and IDO to accelerate tumor progression. The encapsulated JQ1 and polymeric 1-MT in cRGD-NPDJ could reverse the expression by disrupting the binding of BET proteins with chromatin and elevating the TRP/KYN ratio. In B16F10 tumor-bearing C57BL/6 mice, cRGD-NPDJ displayed significantly increased CD8+ T cells, matured dendritic cells (mDCs), and cytokines (IFN-γ, TNF-α), as well as reduced regulatory T cells and downregulated PD-L1 expression at tumor sites, generating immune cascade reactions and a distinct improvement of the tumor microenvironment (TME), leading to significant tumor suppression and survival prolongation. The polymeric IDO inhibitor provides a facile strategy for the co-delivery of chemotherapeutics and inhibitors for efficient and safe combination cancer immunotherapy.

Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release.

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(ß-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 (H2O2) 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.

Enzyme-responsive micellar JQ1 induces enhanced BET protein inhibition and immunotherapy of malignant tumors.

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 both c-MYC oncoprotein and programmed cell death ligand 1 (PD-L1), which play a crucial role in tumor growth and the immunosuppressive tumor microenvironment, respectively. The BET bromodomain inhibitors like JQ1 though exhibiting high selectivity and affinity show usually low bioavailability and efficacy in vivo due to fast clearance and inferior uptake by tumor cells. The therapeutic effect of JQ1 might further be lowered by drug resistance. Here, enzyme-responsive micellar JQ1 (mJQ1) was fabricated from a poly(ethylene glycol)-b-poly(L-tyrosine) copolypeptide to enhance JQ1 delivery and the immunotherapy of malignant melanoma. The in vitro results showed that mJQ1 induced clearly better repression of c-MYC and PD-L1 proteins, cell cycle arrest, cell inhibition, and apoptotic activity than free JQ1 in B16F10 cancer cells. The intratumoral administration of mJQ1 at 2.5 mg of JQ1 equiv. per kg was found to show better inhibition of B16F10 tumors in C57BL/6 mice than the intraperitoneal administration of free JQ1 at 50 mg kg-1. In particular, when combined with radiotherapy, mJQ1 effectively suppressed tumor growth and brought about strong local and systemic antitumor immunity as evidenced by elevated CD8+ T cells and increased ratios of CD8+ T cells to Tregs, affording significantly improved survival of B16F10 tumor-bearing mice than their JQ1 counterparts and marked growth suppression of distant tumors. The great potency of enzyme-responsive micellar JQ1 makes it interesting for immunotherapy of various tumors.

Screening and analysis on the protein interaction of the protein VP7 in grass carp reovirus.

Grass carp reovirus (GCRV) has caused serious economic losses for several decades in China. The protein VP7 is one of the important structural proteins in GCRV. Recent studies indicated that the protein VP7 had the commendable antigenicity and immunogenicity. The protein VP7 cooperated with VP5 could change the conformation of the cell membrane and facilitate entry of GCRV into host cells. We speculated that the protein VP7 should play an important role in the pathogenesis of GCRV. In order to explore the function of the protein VP7, the bait protein expression plasmid pGBKT7-vp7 and the cDNA library of CIK cells were constructed. By yeast two-hybrid system, after multiple screening with the high screening rate medium, rotary verification, sequencing and bioinformatics analysis, the interactions of the protein VP7 with ribosomal protein S20 (RPS20) and eukaryotic translation initiation factor 3 subunit b (eIF3b) in CIK cells were identified. RPS20 played the important roles in the generation of influenza B virus and a variety of diseases. eIF3b was relative to the infection of some viruses. This study suggested that the protein VP7 played the role in viral replication and most likely interacted with host proteins by RPS20 and eIF3b. The interaction mechanisms of the protein VP7 with RPS20 and eIF3b, and the subsequent effector mechanisms needed to be further studied. The corresponding protein interaction of the protein VP7 was not acquired in bioinformatics. The protein VP7 and its untranslated region may have the unknown special function. This study laid the foundation for deeply exploring the function of the protein VP7 in GCRV and had the important scientific significance for exploring the pathogenic mechanism of GCRV.