A Space-Time Conversion Vehicle for Programmed Multi-Drugs Delivery into Pancreatic Tumor to Overcome Matrix and
Taotao Huo1, Xiaoyi Zhang1, Min Qian1
1Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, P. R. China.
Abstract:
The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.
Insights
This study introduces a novel nanocarrier system for pancreatic cancer therapy. It overcomes biological barriers by sequentially releasing drugs, enhancing treatment effectiveness.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Pancreatic cancer treatment is hindered by biological barriers like poor drug penetration and efflux.
- Multifunctional delivery systems are needed to overcome these challenges effectively.
Purpose of the Study:
- To design a space-time conversion nanocarrier for programmed multi-drug delivery in pancreatic cancer.
- To overcome extracellular matrix and drug efflux barriers for enhanced chemotherapy.
Main Methods:
- Developed a multifunctional nanocarrier (MPCP) using covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a polyethyleneimine (PEI) layer.
- Incorporated gemcitabine (chemotherapy), LY 335979 (P-glycoprotein inhibitor), and losartan (ECM disruptor) into specific layers.
- Achieved programmed drug release through sequential degradation of the nanocarrier layers.
Main Results:
- The nanocarrier demonstrated sequential release of drugs, leading to extracellular matrix disruption and drug efflux inhibition.
- This programmed delivery enhanced chemotherapeutic outcomes in pancreatic cancer models.
- The system showed a significant change in nanoparticle surface charge, aiding therapeutic efficacy.
Conclusions:
- The designed MPCP nanocarrier offers a robust space-time conversion strategy for programmed multi-drug delivery.
- This approach represents a promising new avenue for pancreatic cancer treatment by overcoming key therapeutic barriers.
