Stimuli-responsive mucin1-specific nanoparticles for efficacious combinatorial chemotherapy of pancreatic ductal adenocarcinoma

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating malignant disease of the exocrine
pancreas which is characterized by invasiveness, early metastasis and profound resistance to therapies. PDAC
is the fourth-leading cause of cancer-related mortality in the United States, with approximately 60,430 new cases
and 48,220 deaths anticipated in 2021. Unfortunately, despite the tremendous scientific efforts, it is shocking to
note that PDAC has the worst prognosis with 5-year survival rate of 10% which has not significantly improved
from the past 40 years. Further, the PDAC burden is projected to increase in the next decade and is anticipated
to be the second-leading cause of cancer-related deaths by 2030. The high mortality and awful prognosis of
PDAC can be attributed to multifactorial reasons like its intrinsic and acquired resistant behavior, early
micrometastatic dissemination, desmoplastic effect and heterogeneities in tumors, rendering the current
treatments rather ineffective. Developing reliable methods for the effective treatment of PDAC will have a major
impact on the clinical outcome for this deadly disease. We have designed, synthesized and characterized a
target-specific, stimuli-responsive MSN platform for the controlled delivery of cisplatin (cisPt) and gemcitabine
(Gem) (TAB004-Gem-cisPt-MSNs) with an optimal drug ratio. Our preliminary data demonstrates that this
delivery system effectively targets tumor associated MUC1 (tMUC1), increases therapeutic efficiency with
reduced toxicity in both a syngeneic and a spontaneous mouse model that overexpressed tMUC1. In this project,
we are proposing to develop novel MSN-based sequential delivery systems for the effective treatment of PDAC.
The hypothesis underlying this proposal is that by developing a sequential nanoparticle-based regimen where
the primary nanoplatform targets the tumor stroma to deliver a SHh inhibitor; and the secondary nanocarrier,
hTAB004-Gem-cisPt-MSNs, is used to release chemotherapeutics to PDAC cells, the treatment of PDAC will be
dramatically improved. The main goal of this project will be accomplished by the completion of three Aims: 1)
Study the effect of hTAB004-Gem-cisPt-MSNs on the biological stability of Gem and its mechanistic role on DNA
damage repair in PDAC cells; 2) Investigate the pharmacokinetics, biodistribution and safety of CyP-MSNs and
hTAB004-Gem-cisPt-MSNs; and the therapeutic efficacy of the sequential therapy in patient derived xenograft
(PDX) mice; and 3) Evaluate the targeting, therapeutic efficacy and effectiveness against tumor metastasis of
the sequential therapy CyP-MSNs and hTAB004-Gem-cisPt-MSNs in a transgenic spontaneous PDA.MUC1
mice model. This data will be the proof of concept for successful bench to bedside translation of this platform.