Tuesday, May 7, 2024
5/7/2024
Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a notorious malignancy with no change to the dismal survival rate. Surgery is still the first option where most tumors are still unresctable and also highly resistant to chemo and radiotherapies. There is dire need for spatially and temporally localized therapies with low or non-overlapping toxicity such as photodynamic therapy (PDT) which has demonstrated 1) its effectiveness on chemo- and drug- resistant cells, 2) Enhanced drug penetration despite the stroma present in PDAC tumors and 3) decreased metastasis. PDT is a photochemistry-based modality that imparts preferential light-mediated cytotoxicity locally to target tissues via activation of a photosensitizer (PS) molecule by laser light of specific wavelength.7 Recent clinical studies also show PDT efficacy in reducing PDAC tumor volume, making previously unresectable tumors resectable.11–15 However,a major roadblock for PDT use in PDAC treatment is specific delivery of the PS to the tumor and accurate dosimetry that is based on PS accumulation in the tumor. In this proposal we overcome these two roadblocks for PDT via the use of biocompatible liquid metal nanoparticles (NPs), namely the eutectic alloy of gallium and indium (EGaIn, 75% Ga, 25% In) NPs as chaperones, breakdown in acidic tumor environment and deliver high payloads of PS to tumor sites. EGaIn NPs can be fabricated with ease and are extremely chemically and mechanically stable due to the presence of a gallium oxide skin on its surface4,5 which can be functionalized with targeting ligands and PS creating EGaPs (EGaIn + PS). These NPs not only provide high surface area for ligands and PS loading but also have higher optical absorption than blood in the near- infrared (NIR) region, making them conducive for photoacoustic imaging (PAI), a deep tissue imaging modality based on optical absorption coefficient. PAI can be transparently integrated with ubiquitously available ultrasound imaging (USPAI) as shown by us1-4 previously to obtain multi-parametric 3D information on tumor volume, nanoparticle uptake, vascular density, vascular perfusion and tumor oxygenation status simultaneously for designing an effective PDT dose. The overall hypothesis of this project is that photoacoustic image-guided PDT with EGaPs will yield superior results compared to passive PDT in PDAC models and will be achieved with the following 3 specific aims: Aim-1: We will synthesize, characterize and evaluate in vitro treatment efficacy of EGaPs; Aim-2: We will establish the pharmacokinetics, biodistribution and safety profile of EGaPs; and Aim-3: we will evaluate in vivo efficacy of EGaPs in orthotopic PDAC models with different pathophysiology. EGaPs integrated with clinically translatable USPAI will provide a novel treatment platform for PDAC. The insights on biodistribution of EGaPs, evaluation of drug uptake using photoacoustic imaging techniques, and design of dosimetry in a patient specific manner can be applied to broad range of solid tumor treatments.
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