Computational Modeling of PancreaSolve-HNX: A Theoretical Framework for Multi-Modal Nanotherapy Dynamics in Pancreatic Ductal Adenocarcinoma Treatment

Pancreatic ductal adenocarcinoma (PDAC) persists as one of the deadliest solid malignancies, characterized by a 5-year relative survival rate of only 13%, primarily due to its densely fibrotic and immunosuppressive tumor microenvironment (TME) that confers profound resistance to conventional chemotherapeutics [siegel2025]. The desmoplastic stroma, accounting for 80--90% of the tumor mass, erects a substantial physical and immunological barrier, severely limiting drug penetration and efficacy [collins2022]. In this study, we propose \textbf{PancreaSolve-HNX}, a rationally engineered multi-modal hybrid organic--inorganic nanoparticle system featuring a gold core integrated with sonosensitizers, a porous silica interlayer for structural stability, and a Zr^{4+}-based metal-organic framework (MOF) shell that facilitates ultra-high loading capacities exceeding 70% w/w for gemcitabine monophosphate (GMP) [ischyropoulou2023]. The nanoparticle surface is meticulously functionalized with hyaluronidase-PEG conjugates to enable targeted degradation of hyaluronan-rich extracellular matrix [jakobsen2021], iRGD peptides to promote deep tumor penetration [sugahara2010], and bispecific anti-CD47/PD-L1 nanobodies to disrupt immune checkpoint signaling and enhance antitumor immunity [williams2023].To evaluate the therapeutic potential of this design, we develop a multi-scale system of ordinary differential equations (ODEs) that extends validated frameworks for PDAC TME interactions [kozminsky2020]. The model is calibrated using Bayesian inference via Hamiltonian Monte Carlo sampling in PyMC, incorporating rigorous uncertainty quantification [dehond2023]. Global sensitivity analysis employing Sobol indices elucidates the dominant parameters influencing efficacy. Numerical simulations predict that a single intravenous administration of PancreaSolve-HNX, combined with three sequential focused ultrasound sessions, achieves greater than 95% ablation of viable tumor cells by day 7 through synergistic chemo-sonodynamic-photothermal mechanisms and induction of immunogenic cell death (ICD) [neofytou2023]. This is followed by near-complete stromal depletion by day 10, robust systemic antitumor immune activation by day 14, and sustained tumor regression extending to 28 days. These outcomes, although contingent upon empirical validation, demonstrate strong concordance with preclinical data for constituent modalities [conte2025, ischyropoulou2023] and highlight the transformative potential of integrated synergies in surmounting PDAC therapeutic barriers [li2025].