利用组合纳米药物同时降解BRD4和破坏基质以对抗胰腺导管腺癌

Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer death by 2030 yet remains largely untreatable. Limited therapeutic options and desmoplastic microenvironment collectively result in poor clinical outcome. This necessitates dual targeting strategies that can simultaneously disrupt the microenvironment barrier and eliminate oncogenic protein drivers. Focal adhesion kinase inhibitor: PND 1186 was selected to compromise the tumor stromal barrier while BRD4 degrading PROTAC was explored to inhibit the proliferation. To overcome pharmacokinetic barriers, we designed a dual-route nanomedicine platform: oral self-nanoemulsifying PND-1186 (PNDnano, FAK inhibitor) and intravenous albumin-anchored ARV-825 nanoliposomes (AAnano, BRD4 PROTAC). This study aims to: (a) develop and characterize PND and ARV nanoformulations, (b) evaluate anticancer efficacy in 2D/3D PDAC models, and (c) assess therapeutic efficacy in xenograft studies. PNDnano was developed by screening different excipients and ones exhibiting superior solubility of PND were selected for developing SNEDDS. AAnano was formulated via modified hydration method using DGS-NTA-Ni for surface conjugation of histidine-tagged human serum albumin. Both nanoformulations showed 2-3-fold higher in-vitro cytotoxic effect in PDAC cells compared to individual drugs alone. Combenefit analysis revealed robust synergistic cytotoxicity between ARV and PND in MIA PaCa-2, achieving maximum synergy (score = 28) at 0.5 µM ARV and 2 µM PND with a combination index of 0.8. Scratch assay revealed potent anti-migratory effects, with ARV+PND achieving superior inhibition (1.9-fold in MIA PaCa-2; 2.7-fold in BxPC-3) versus monotherapies. Clonogenic assays demonstrated >90% reduction in the number and area of colonies in PDAC cells, with complete eradication in MIA PaCa-2, following ARV+PND treatment. Combination treatment showed 4.4-fold decrease in invadopodia length, enhancing inhibition in invasiveness of spheroids. 3D spheroid assays revealed significant growth inhibition with the monotherapies and ~63% reduction with combination therapy by day 8, demonstrating superior clinical relevance in PDAC. The anticancer effect of AAnano+PNDnano in the mice bearing subcutaneous tumor (MIA PaCa-2) xenograft model achieved 56.9% tumor suppression surpassing monotherapies. All treatment groups maintained stable body weights, indicating excellent tolerability with no systemic toxicity. This dual-targeting approach provides robust antitumor efficacy without systemic toxicity, addressing a critical unmet need in PDAC treatment. This strategy that simultaneously disrupts stromal barriers and eliminates oncogenic drivers, transcending conventional chemotherapy limitations and providing a translational framework for treating desmoplastic malignancies.