Second-generation new-chemical-entity nanomedicine to target treatment resistance in pancreatic cancer

Abstract public domain (NIH RePORTER)

Title: Second-generation new-chemical-entity nanomedicine to target treatment resistance in pancreatic cancer Project Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with treatment resistance posing a major challenge to effective clinical management. Cells that survive therapy—such as pancreatic cancer stem- like cells (PCSCs) and drug-tolerant persister (DTP) cells—play a critical role in driving drug resistance, tumor recurrence, and metastasis. Notably, both cell populations depend heavily on elevated autophagy, a self- digestion process that enables survival under stress. Therefore, targeting autophagy pathways holds significant promise for improving treatment outcomes in PDAC. Autophagy inhibition with aminoquinoline drugs, such as chloroquine (CQ) or hydroxychloroquine (HCQ), have limited potency for autophagy inhibition, and the concentrations of CQ/HCQ required to inhibit autophagy are not consistently achievable in the clinic. The overall goal of this application is to develop a second-generation new-chemical-entity nanomedicine as an effective autophagy inhibitor to improve the treatment of PDAC in preclinical animal models, providing validation regarding the feasibility for clinical translation. Recently, we have developed an Autophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition and specific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that contains pure bisaminoquinoline (BAQ) derivative as the building block which has outstanding autophagy inhibiting- and lysosomal disrupting- capabilities. AiSN (BAQ13 nanoparticle, BAQ13 NP) is 20-30 times more effective than HCQ in a panel of PDAC cell lines. It preferentially accumulated at PDAC tumor sites with dense fibrotic stromal tissue. It was efficacious in various PDAC models and prevented cancer stem-like cell mediated tumorigenesis in mice. The FDA has recently approved our Investigation New Drug (IND) application (IND#165331) for moving the AiSN (BAQ13 NP) into clinical trials. The FDA has also granted Orphan Drug Designation for BAQ13 for the treatment of pancreatic cancer. Using BAQ13 as the lead compound, we have recently designed and synthesized 30 new compounds as the second-generation AiSNs, among which BAQ42 and BAQ152 have shown better potency than BAQ13, improving the IC50 value from micromolar to nanomolar levels. Furthermore, our study demonstrated that autophagy is significantly upregulated in DTP cells of PDAC. Although DTP cells exhibit resistance to gemcitabine, they can be effectively eliminated by BAQ42. These results have laid a strong foundation for this R01 application, where we plan to: 1) optimize the structure and formulation of second-generation AiSNs to enhance their anti-PDAC potency and nanoparticle-forming properties; 2) characterize their pharmacokinetics and spatiotemporal distribution; and 3) validate their pharmacology and toxicology in various PDAC models. Successful completion of this research will make this new generation AiSN ready for IND-enabling studies seeking IND approval. The novel design of AiSNs, with significantly improved potency and targeted delivery capabilities, is expected to greatly enhance efficacy while minimizing toxicity in PDAC treatment.

Public health relevance public domain (NIH RePORTER)

Project Narrative Elevated autophagy activity in pancreatic cancer stem-like cells (PCSCs) and drug-tolerant persister (DTP) cells drives their resistance to chemotherapy, cancer recurrence, and metastasis, creating major challenges in treating pancreatic ductal adenocarcinoma (PDAC). To address this, innovative self-therapeutic nanoparticles are being developed in this project to specifically target PDAC tumors by inhibiting autophagy and lysosomal functions in chemotherapy-resistant cells, achieving remarkable treatment outcomes without increasing toxicity. This novel therapy has the potential to significantly improve patient outcomes by enhancing response rates, extending progression-free survival, and minimizing long-term side effects.