Biomimetic Migrating Nanoparticles Targeting Tumor Stroma and Neural Invasion to Improve Pancreatic Cancer Therapy and Pain Control

Pancreatic cancer, characterized by aggressive behavior and poor survival, is hallmarked by desmoplastic stroma abundant in stromal cells, extracellular matrix, and neural invasion. A high level of intratumoral nerve density and the presence of cancer invaded nerves correlate with unfavorable prognosis, heightened risk of recurrence and metastasis. Dynamic interactions among cancer cells, nerves, and stromal cells establish a neuroinflammatory niche, promoting tumor growth, exacerbating perineural invasion and inflicting severe pain on cancer patients. The objective of this study is to develop new nanotherapeutic agents targeting tumor, stroma, and cancer nerve to overcome therapy resistance in pancreatic cancer while reducing neuropathic pain. We developed a tumor cell mimetic hyaluronic acid nanoparticle (HANP) drug delivery platform using a recombinant ATFmmp14 ligand containing the amino-terminal fragment (ATF) of uPA and MMP14 catalytic domain. We demonstrated that ATFmmp14 conjugated HANPs delivered 20-37% of the total carried drugs into stroma-rich pancreatic patient derived xenograft (PDX) tumors following systemic delivery. Intratumoral delivered ATFmmp14-HANP/drugs can penetrate through dense stroma to reach ductal tumor cells for drug delivery. Systemic administration of ATFmmp14-HANP carrying SN38 inhibited tumor growth for 83-97% and improved survival in the PDX tumor models. ATFmmp14-HANP/SN38 treated tumors also have significantly reduced neural invasion. To enhance therapeutic efficacy on drug resistant pancreatic cancer, we have produced novel ATFmmp14-HANPs carrying therapeutic agents that inhibit key neural signals and neuron-cancer interactions, including a â-adrenergic receptor (â-AR) inhibitor (Propranolol, Pro) that blocks sympathetic nervous signaling and a sensory nerve inhibitor (Gabapentin, GAB). Preliminary studies demonstrated their effects in vitro and therapeutic efficacy in the PDX models. Therefore, we hypothesize that biomimetic ATFmmp14-HANP mediated delivery of neural modulatory agents (Pro or GAB) and chemotherapy drug (SN38) induces strong therapeutic response in tumor cells, inhibits neural invasion, and reduces neuropathic pain. In the proposed research, we will optimize nanoformulations of ATFmmp14-HANP/Pro+SN38 (AM-HANP/PS) and ATFmmp14-HANPGAB/ SN38 (AM-HANP-G/S) in vitro using 3D co-cultures (Aim 1&2). The effects of AM-HANP/PS or AM-HANPG/ S on targeted delivery, tumor growth inhibition and cancer pain reduction will be evaluated in pancreatic PDX models (Aim 1&2). Changes in the density and activity of sympathetic and sensory nerves, neural invasion and â-AR activity of tumor cells will be investigated using histological, immunological, and molecular analyses (Aim 1&2). Finally, therapeutic response to AM-HANP/PS or AM-HANP-GS will be evaluated in the Kras/p53-driven mouse pancreatic cancer model to determine the effect on inhibiting tumor growth, reducing neural invasion, activating immune response (Aim 3). Success in the proposed study will develop novel targeted nanotherapeutic agents for the treatment of pancreatic cancer patients with therapy-resistant cancer and severe neuropathic pain. This research project will use pancreatic cancer PDX models in SCID mice and mouse tumor models to investigate therapeutic responses of targeted nanoparticles carrying dual drugs on tumor and stromal cells, and neural infiltrations. The objectives of the proposed research can only be achieved in animal tumor models for adequately determining targeted delivery, the effects of inhibition of tumor growth and neural invasion, activation of immune response, and evaluation of their effects on reduction of chronic cancer associated-pain. Project Number: 1R01CA315249-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Lily Yang | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $602,170 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MCST-U (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11447493