Title: Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancerThe 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is less than 10% and the lack of effectivetreatment is one of the major impediments for the clinical management of PDAC. Pancreatic cancer stem-likecells (PCSCs) have been linked to tumor metastasis, drug resistance, and aggressive behaviors and theenrichment of PCSC after chemotherapy is associated with more aggressive tumor rebound. Autophagy is theprocess of "self-digestion" and it is especially needed for the rapid proliferation in cancer cells. PDAC cells,particularly PCSCs, highly rely on elevated autophagy. Therefore, autophagy is a promising target in PDAC toimprove treatment and overcome chemoresistance. Autophagy inhibition with aminoquinoline drugs, such aschloroquine (CQ) or hydroxychloroquine (HCQ), have been tested in several clinical trials including PDACpatients. Promisingly, an initial clinical benefit was observed when combined with chemotherapeutic drugs, suchas gemcitabine and Abraxane in neoadjuvant setting. However, CQ/HCQ have limited potency for autophagyinhibition and potential side effects, and the concentrations of CQ/HCQ required to inhibit autophagy are notconsistently achievable in the clinic due to the lack of a specific delivery approach. The overall goal of this SBIRphase I application is to develop sub-100 nm and scalable self-therapeutic nanoparticles as next-generationautophagy inhibitors to improve PDAC treatment in preclinical animal models, providing validation regarding thefeasibility for Phase II studies that will eventually lead to an IND filing to FDA. Recently, we have developed anAutophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition andspecific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that containspure bisaminoquinoline (BAQ) derivative itself as the building block which has outstanding autophagy inhibiting-and lysosomal disrupting- capabilities. AiSN is 30x more effective than CQ and HCQ in vitro, and effectively killsPCSCs. As a self-delivered nanoparticle without a carrier, AiSN can efficiently accumulate at the PDAC tumorsites and effectively inhibit autophagy in PDAC animal models. AiSN successfully prevented tumorigenesis inPCSC-derived animal models and demonstrated superior anti-cancer efficacy in both PDAC- and PCSC-derivedxenograft models as both a monotherapy and a combination therapy. These results were recently published inNature Communications and built a strong foundation for this Phase I application, in which we plan to 1) developa microfluidic approach for optimization of the AiSN formulation (smaller size, better stability and reproducibility)to further enhance its tumor penetration and support future large scale-production, and 2) investigate thepharmacokinetics, tumor penetration, and anti-cancer efficacy of the microfluidic assisted manufacturing AiSNin animal models. The successful completion of the proposed research will make the AiSN ready for next stepof IND-enabling studies seeking IND approval. The proposed AiSN with greatly enhanced potency and specificdelivery properties will significantly improve the efficacy and minimize the toxicity in the treatment of PDAC.
Public Health Relevance Statement: Project Narrative
The significantly elevated autophagy in pancreatic cancer cells and pancreatic cancer stem cells leads to
chemotherapy resistance, cancer recurrence, and metastasis, all of which are major challenges in the treatment
of pancreatic ductal adenocarcinoma (PDAC). The proposed novel self-therapeutic nanoparticles could target
PDAC tumor sites and effectively inhibit autophagy and lysosomal activities in both cancer cells and cancer stem
cells, resulting in a remarkable therapeutic outcome without increased toxicity. This project is poised to
significantly improve the clinical outcomes for pancreatic cancer patients by improving the response rate,
prolonging the progression-free survival, and decreasing the long-term toxicity, therefore it has great commercial
potentials to lead to a marketable nano-formulation to improve the treatment of PDAC.
Project Terms: <µfluidic> | 