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Principal Investigator: Tzu-yin Lin
Organization: THERANOSTEC, INC.
Fiscal Year: 2022
Award: $399,999
Funding agency: National Cancer Institute
Title: Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer
Project Summary
The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is less than 10% and the lack of effective
treatment is one of the major impediments for the clinical management of PDAC. Pancreatic cancer stem-like
cells (PCSCs) have been linked to tumor metastasis, drug resistance, and aggressive behaviors and the
enrichment of PCSC after chemotherapy is associated with more aggressive tumor rebound. Autophagy is the
process 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 to
improve treatment and overcome chemoresistance. Autophagy inhibition with aminoquinoline drugs, such as
chloroquine (CQ) or hydroxychloroquine (HCQ), have been tested in several clinical trials including PDAC
patients. Promisingly, an initial clinical benefit was observed when combined with chemotherapeutic drugs, such
as gemcitabine and Abraxane in neoadjuvant setting. However, CQ/HCQ have limited potency for autophagy
inhibition and potential side effects, and the concentrations of CQ/HCQ required to inhibit autophagy are not
consistently achievable in the clinic due to the lack of a specific delivery approach. The overall goal of this SBIR
phase I application is to develop sub-100 nm and scalable self-therapeutic nanoparticles as next-generation
autophagy inhibitors to improve PDAC treatment in preclinical animal models, providing validation regarding the
feasibility for Phase II studies that will eventually lead to an IND filing to FDA. 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 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 kills
PCSCs. As a self-delivered nanoparticle without a carrier, AiSN can efficiently accumulate at the PDAC tumor
sites and effectively inhibit autophagy in PDAC animal models. AiSN successfully prevented tumorigenesis in
PCSC-derived animal models and demonstrated superior anti-cancer efficacy in both PDAC- and PCSC-derived
xenograft models as both a monotherapy and a combination therapy. These results were recently published in
Nature Communications and built a strong foundation for this Phase I application, in which we plan to 1) develop
a 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 the
pharmacokinetics, tumor penetration, and anti-cancer efficacy of the microfluidic assisted manufacturing AiSN
in animal models. The successful completion of the proposed research will make the AiSN ready for next step
of IND-enabling studies seeking IND approval. The proposed AiSN with greatly enhanced potency and specific
delivery properties will significantly improve the efficacy and minimize the toxicity in the treatment of PDAC.
Terms: <Abraxane><Address><Aggression><Aggressive behavior><Aminoquinolines><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Autophagocytosis><Body Tissues><COVID-19><COVID19><CV-19><CV19><Cancer Cause><Cancer Drug><Cancer Etiology><Cancer cell line><Cancers><Cell Body><Cells><Cessation of life><Chemicals><Chemoresistance><Chlorochin><Chloroquine><Clinic><Clinical><Clinical Management><Clinical Trials><Combined Modality Therapy><Communication><Death><Development><Difluorodeoxycytidine><Digestion><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug resistance><Drugs><Dysfunction><Exhibits><Feasibility Studies><Filtration><Filtration Fractionation><Formulation><Foundations><Freeze Drying><Freeze Dryings><Functional disorder><Future><Generalized Growth><Goals><Growth><Hydroxychlorochin><Hydroxychloroquine><In Vitro><Induction Therapy><Khingamin><Lead><Link><Liposomal><Liposomes><Lyophilization><Lysosomes><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Microfluidics><Modality><Molecular><Multimodal Therapy><Multimodal Treatment><NEOADJ><Names><Nature><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Nutrient><Oncogenesis><Outcome><Oxychlorochin><Oxychloroquine><PDAC cancer cell><PDAC cell><PDX model><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Penetration><Performance><Permeability><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Phase><Physiopathology><Preparation><Process><Progression-Free Survivals><Property><Publishing><RNA vaccine><RNA-based vaccine><Recurrence><Recurrent><Reporting><Reproducibility><Research><Resistance><Role><SBIR><Secondary Neoplasm><Secondary Tumor><Series><Side><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Solid><Starvation><Sterilization><Survival Rate><System><Testing><Therapeutic><Tissue Growth><Tissues><Toxic effect><Toxicities><Translating><Treatment Failure><Tumor-Specific Treatment Agents><Validation><Xenograft Model><anti-cancer><anti-cancer activity><anti-cancer drug><anticancer><anticancer activity><anticancer agent><anticancer drug><autophagy><base><cGMP production><cancer cell><cancer metastasis><cancer progenitor cells><cancer recurrence><cancer stem cell><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><clinical applicability><clinical application><clinical translation><combination therapy><combined modality treatment><combined treatment><commercialization><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><dFdC><dFdCyd><design><designing><developmental><drug resistant><drug/agent><effective therapy><effective treatment><experience><first in man><first-in-human><gemcitabine><heavy metal Pb><heavy metal lead><improved><in vivo><inhibition of autophagy><inhibitor><large scale production><mRNA vaccine><mRNA-based vaccine><malignancy><malignant stem cell><microfluidic technology><model of animal><model organism><multi-modal therapy><multi-modal treatment><nano carrier><nano drug><nano formulation><nano medicinal><nano medicine><nano particle><nano particle delivery><nano-sized particle><nanocarrier><nanodrug><nanoformulation><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanopharmaceutical><nanosized particle><neoplasm/cancer><next generation><novel><ontogeny><pancreatic cancer cells><pancreatic cancer patients><pancreatic ductal adenocarcinoma cell><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><pathophysiology><pathway><patient derived xenograft model><patients with pancreatic cancer><phase 2 study><phase II study><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><resistance to Drug><resistant><resistant to Drug><response><scale up><side effect><social role><standard of care><stem-like cell><systemic toxicity><targeted agent><therapeutic nanoparticles><therapeutic outcome><therapy failure><therapy outcome><tumor><tumor cell metastasis><tumorigenesis><xenograft transplant model><xenotransplant model><µfluidic><µfluidic technology>