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

Abstract

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.

CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia

“…46 TM-VS significantly reduced hemolysis to less than 5% at SOR concentrations ranging from 1 to 100 μg/mL, which was in sharp contrast to free VS (****p < 0.0001) bearing a rate up to 100% (Figure 4D). The encapsulation of inhibitors by TM significantly improved drug hemocompatibility, which is in line with the results of other studies, 43,47 and offers the potential for intravenous administration of ) into NSG mice, similar to our previous reports. 48 Ex vivo imaging revealed that TM-Cy5 efficiently accumulated in the hind/fore-limbs, liver, and spleen of mice where the leukemia cells highly enriched, at 8 h after i.v.…”

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma

“…N 3 -PEG-PAPA was obtained through the ring-opening polymerization of α-aminopalmitic acid N -carboxyanhydride (APA-NCA) using N 3 -PEG-NH 2 ( M n = 5.0 kg/mol) as an initiator (Scheme S1), similar to the synthesis of mPEG-polypeptide in previous reports. − As shown in Figure A, distinct 1 H NMR signals attributed to PEG (δ 3.85, 3.61) and PAPA (δ 4.62, 1.76, 1.27, 0.88) verified the characteristic structure of N 3 -PEG-PAPA. The degree of polymerization of the PAPA block determined by comparing the integral area of signals at δ 3.85 (methylene of PEG) and δ 0.88 (methyl peak of APA) was 19.2.…”

Co-Delivery of Hesperetin and Cisplatin via Hyaluronic Acid-Modified Liposome for Targeted Inhibition of Aggression and Metastasis of Triple-Negative Breast Cancer

“…Multiple large doses of CDDP or repeated administration within a short period of time may cause irreversible renal dysfunction and, in severe cases, lead to renal tubular necrosis. , Hesperetin (Hes), a kind of edible dihydroflavonoid compound that widely exists in citrus fruits, is easily available but with low solubility and bioavailability. Hes has been shown to have anti-cancer activity in gastric cancer, malignant glioma, prostate cancer, lung cancer, and other tumors by inhibiting cell proliferation and promoting cell cycle arrest or apoptosis. − To achieve synergistic and potent treatment, the ideas of the co-delivery system have been designed and acquired remarkable therapeutic outcomes. , It has been reported that the combination of flavonoid compounds like Hes with 5-fluorouracil, CDDP, and paclitaxel can effectively improve the cytotoxicity of anti-tumor drugs. , In parallel, Hes can inhibit the PI3K/Akt signaling pathway and reduce the expression of matrix metalloproteinases (MMPs), an important mesenchymal cell marker, implicating that the combined administration of Hes with CDDP may achieve better inhibitory effects on tumor growth and metastasis if these two drugs could be specifically co-delivered to the tumor site efficiently.…”

“…20−23 To achieve synergistic and potent treatment, the ideas of the co-delivery system have been designed and acquired remarkable therapeutic outcomes. 24,25 It has been reported that the combination of flavonoid compounds like Hes with 5-fluorouracil, CDDP, and paclitaxel can effectively improve the cytotoxicity of anti-tumor drugs. 26,27 In parallel, Hes can inhibit the PI3K/Akt signaling pathway 28 and reduce the expression of matrix metalloproteinases (MMPs), 29 an important mesenchymal cell marker, implicating that the combined administration of Hes with CDDP may achieve better inhibitory effects on tumor growth and metastasis if these two drugs could be specifically co-delivered to the tumor site efficiently.…”