Development of Facile and Versatile Platinum Drug Delivering Silicasome Nanocarriers for Efficient Pancreatic Cancer Chemo-Immunotherapy
Xiangsheng Liu
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorJinhong Jiang
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorChong Hyun Chang
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorYu-Pei Liao
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorJared J. Lodico
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Department of Physics and Astronomy, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorIvanna Tang
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorEmily Zheng
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorWaveley Qiu
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorMatthew Lin
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorXiang Wang
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorYing Ji
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorKuo-Ching Mei
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorCorresponding Author
Andre E. Nel
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Huan Meng
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
E-mail: [email protected], [email protected]
Search for more papers by this authorXiangsheng Liu
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorJinhong Jiang
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorChong Hyun Chang
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorYu-Pei Liao
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorJared J. Lodico
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
Department of Physics and Astronomy, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorIvanna Tang
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorEmily Zheng
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorWaveley Qiu
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorMatthew Lin
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorXiang Wang
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorYing Ji
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorKuo-Ching Mei
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
Search for more papers by this authorCorresponding Author
Andre E. Nel
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Huan Meng
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095 USA
California NanoSystems Institute, University of California, Los Angeles, CA, 90095 USA
E-mail: [email protected], [email protected]
Search for more papers by this authorAbstract
In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high-dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak-basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2-diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras-derived pancreatic cancer (PDAC) model is demonstrated. Not only does IV injection of the DACHPt silicasome provide more efficacious cytotoxic tumor cell killing, but can also demonstrate that chemotherapy-induced cell death is accompanied by the features of immunogenic cell death (ICD) as well as a dramatic reduction in bone marrow toxicity. The added ICD features are reflected by calreticulin and high-mobility group box 1 expression, along with increased CD8+/FoxP3+ T-cell ratios and evidence of perforin and granzyme B release at the tumor site. Subsequent performance of a survival experiment, demonstrates that the DACHPt silicasome generates a significant improvement in survival outcome, which can be extended by delayed administration of the anti-PD-1 antibody.
Conflict of Interest
A.E.N. and H.M. are co-founders, board members, and equity holders in Westwood Bioscience Inc. UCLA entered into a sponsored research agreement with Westwood Bioscience Inc. A.E.N. and H.M. are also co-founders and equity holders in NAMMI therapeutics. The remaining authors declared no conflict of interest.
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