Nanocarriers that circumvent the stromal barrier in pancreatic ductal adenocarcinoma (PDAC) to allow (i) ratiometric control of a synergistic gemcitabine (GEM)/paclitaxel PTX) combination, (ii) overcome rate limiting steps in gemcitabine (GEM) metabolism, and (iii) reduce FOLFIRINOX toxicity (a potent 4-drug regimen that includes irinotecan) could significantly impact PDAC survival. The long-term goal of our multidisciplinary approach is to use rational-designed mesoporous silica nanoparticles (MSNP) to provide efficacious, safe and life-prolonging chemotherapy to PDAC patients. Our objectives are to develop and implement MSNP nanocarriers in advanced preclinical studies to: (i) achieve stable and high dose GEM or irinotecan loading, using a supported lipid bilayer (LBL); (ii) provide synergistic PTX/GEM delivery from a single MSNP carrier, with efficacy testing in human-derived PDAC tumors as well as the spontaneous Kras (KPC) transgenic model in mice; (iii) provide high dose encapsulated irinotecan delivery to reduce toxicity in the same animal models; (iv) achieve carrier targeting or transcytosis by iRGD peptide, which may also prevent metastasis; (v) deliver a small molecule TGF- inhibitor (TGF-i) that provides vascular access by interference in pericyte coverage. In order to attain these objectives, Aim 1 will use LBL-coated MSNP nanocarriers to optimize GEM delivery and efficacy in human derived PDAC tumors in mice as well as the spontaneous KPC model. The working hypothesis, based on preliminary data showing that LBL-coated MSNPs can deliver a synergistic GEM/PTX combination, is that stromal perturbation by PTX-induced oxidative stress will enhance GEM uptake. We will also deliver nano-enabled GEM-bisphosphonate to tumors with reduced expression of a rate-limiting enzyme (dCK) that is responsible for GEM activation through phosphorylation.
Aim 2 will endeavor to demonstrate how the biocompatability of LBL-coated nanocarriers can be used to improve the toxicity profile and efficacy of irinotecan delivery in GEM-resistant tumors. The working hypothesis, based on preliminary data showing a high degree of MSNP biocompatibility, is that the high drug loading capacity and stability of LBL-MSNP will dramatically reduce irinotecan toxicity. This could lead to the expanded use of the potent FOLFIRINOX regimen.
Aim 3 will endeavor to demonstrate that targeted delivery of iRGD-MSNP, promotion of nanocarrier transcytosis by iRGD co-delivery, or improvement of vascular access by TGF-i can enhance the chemotherapeutic efficacy of MSNP nanocarriers, including the carriers developed in Aims 1 and 2. We anticipate the delivery of GEM/PTX and irinotecan by multifunctional MSNPs will improve survival and reduce chemotherapy toxicity in robust animal models simulating human PDAC. These results are expected to have an immediate positive impact by providing efficacious and safe nanocarriers that can be placed into the pipeline of novel diagnostics and therapeutics being tested in human PDAC patients by our multidisciplinary team (that includes materials scientists, chemists, tumor biologists, an oncologist, and a surgeon).
Our research addresses the treatment of pancreatic ductal adenocarcinoma (PDAC), which is frequently incurable and resists cancer drugs due to an impenetrable stroma, blocked vasculature, metabolic inactivation or failure to activate the first line chemo-therapeutic agent, gemcitabine (GEM). While a four-drug regimen with the acronym, FOLFIRINOX, is potentially more efficacious, it is very toxic and can only be used in a small subset of PDAC patients. We have developed a series of mesoporous silica nanocarriers (that resemble hollow glass bubbles with a lipid bilayer coating) to deliver high loads of GEM and the most toxic FOLFIRINOX component, irinotecan, to the PDAC site, with the objective to improve survival outcome based on smart design features that overcome the specific cancer resistance mechanisms.
|Hartshorn, Christopher M; Bradbury, Michelle S; Lanza, Gregory M et al. (2018) Nanotechnology Strategies To Advance Outcomes in Clinical Cancer Care. ACS Nano 12:24-43|
|Lu, Jianqin; Liu, Xiangsheng; Liao, Yu-Pei et al. (2018) Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway. ACS Nano 12:11041-11061|
|Meng, Huan; Leong, Wei; Leong, Kam W et al. (2018) Walking the line: The fate of nanomaterials at biological barriers. Biomaterials 174:41-53|
|Shahin, Sophia A; Wang, Ruining; Simargi, Shirleen I et al. (2018) Hyaluronic acid conjugated nanoparticle delivery of siRNA against TWIST reduces tumor burden and enhances sensitivity to cisplatin in ovarian cancer. Nanomedicine 14:1381-1394|
|Liu, Xiangsheng; Lin, Paulina; Perrett, Ian et al. (2017) Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer. J Clin Invest 127:2007-2018|
|Lu, Jianqin; Liu, Xiangsheng; Liao, Yu-Pei et al. (2017) Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. Nat Commun 8:1811|
|Sugimoto, Motokazu; Hines, O Joe; Dawson, David W et al. (2017) Preoperative Treatment With FOLFIRINOX and Successful Resection for a Patient With Mixed Acinar-Endocrine Carcinoma of the Pancreas. Pancreas 46:e32-e34|
|Liu, Xiangsheng; Jiang, Jinhong; Ji, Ying et al. (2017) Targeted drug delivery using iRGD peptide for solid cancer treatment. Mol Syst Des Eng 2:370-379|
|Liu, Xiangsheng; Jiang, Jinhong; Nel, Andre E et al. (2017) Major effect of transcytosis on nano drug delivery to pancreatic cancer. Mol Cell Oncol 4:e1335273|
|Pelaz, Beatriz; Alexiou, Christoph; Alvarez-Puebla, Ramon A et al. (2017) Diverse Applications of Nanomedicine. ACS Nano 11:2313-2381|
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