Development of Facile and Versatile Platinum Drug Delivering Silicasome Nanocarriers for Efficient Pancreatic Cancer Chemo-Immunotherapy.
Xiangsheng LiuJinhong JiangChong Hyun ChangYu-Pei LiaoJared J LodicoIvanna TangEmily ZhengWaveley QiuMatthew LinXiang WangYing JiKuo-Ching MeiAndre E NelHuan MengPublished in: Small (Weinheim an der Bergstrasse, Germany) (2021)
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.
Keyphrases
- cell death
- drug delivery
- high dose
- cancer therapy
- bone marrow
- chemotherapy induced
- photodynamic therapy
- low dose
- poor prognosis
- free survival
- ultrasound guided
- single cell
- cell cycle arrest
- mesenchymal stem cells
- regulatory t cells
- stem cell transplantation
- transcription factor
- machine learning
- locally advanced
- binding protein
- combination therapy
- drug release
- oxidative stress
- quantum dots
- cell therapy
- adverse drug
- high throughput
- emergency department
- drug induced
- stem cells
- drug discovery
- rectal cancer
- fatty acid
- signaling pathway
- radiation therapy