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Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part I. Synthesis, characterization and in
Lalit Mohan Negi1, Sushama Talegaonkar1, Manu Jaggi2
1Nano Research Lab, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India.
Abstract:
Over expression of P-glycoprotein (P-gp) in cancer cells often results in highly aggressive, multi-drug resistant (MDR) phenotype. Such tumors are very difficult to treat with conventional therapy and often lead to failure of the treatment. In this work, we fabricated surface engineered hybrid lipid nanoparticles grafted with novel AL-HA polymer by mineralization technique. AL-HA graft polymer was prepared by covalent conjugation of alendronate sodium and hyaluronic acid. Compritol ATO 888 and capmule MCM C8 hybrid lipid mix was employed to prepare irinotecan containing nanostructured lipid carrier (NLC) by using functional excipients with P-gp inhibition activity. AL-HA was successfully grafted over NLC-Ir (uncoated irinotecan loaded NLC) by calcium-assisted mineralization. HA-NLC-Ir (hyaluronic acid coated irinotecan loaded NLC) particles have a nanoscale size of 386±2.2 nm along with a zeta potential value of 19.7±1.2 mV. NLC-Ir as well as HA-NLC-Ir showed a slow and sustained drug release. In vitro cell line studies performed on HT-29 and Colo-320 colon cancer cells revealed a reduced IC50 even in MDR cells. Flowcytometry studies demonstrated the capability of the developed nanocarriers to deliver the P-gp substrate moieties in MDR cancer cells. Furthermore, the targeting potential of HA-NLC was confirmed by CLSM studies. The cell line studies also revealed that NLC formulation had a potential of inhibiting P-gp by affecting ATPase activity and MDR1 gene expression.
Insights
Surface-engineered hybrid lipid nanoparticles loaded with irinotecan overcome multi-drug resistance (MDR) in colon cancer. Hyaluronic acid coating enhances P-glycoprotein (P-gp) inhibition and drug delivery in MDR cells.
Area of Science:
- Nanotechnology
- Biomedical Engineering
- Cancer Research
Background:
- Overexpression of P-glycoprotein (P-gp) in cancer cells leads to a multi-drug resistant (MDR) phenotype, complicating treatment.
- Conventional therapies often fail against aggressive, MDR tumors, necessitating novel drug delivery strategies.
Purpose of the Study:
- To fabricate surface-engineered hybrid lipid nanoparticles (NLCs) for enhanced delivery of irinotecan in P-gp overexpressing colon cancer cells.
- To investigate the P-gp inhibitory potential and targeting capabilities of hyaluronic acid-grafted NLCs (HA-NLC-Ir).
Main Methods:
- Hybrid lipid nanoparticles (NLCs) were prepared using Compritol ATO 888 and Capmul MCM C8, loaded with irinotecan (NLC-Ir).
- AL-HA graft polymer was synthesized and conjugated onto NLC-Ir via calcium-assisted mineralization to form HA-NLC-Ir.
- In vitro studies included particle characterization, drug release, cytotoxicity assays (IC50), flow cytometry, and P-gp activity inhibition assays.
Main Results:
- HA-NLC-Ir nanoparticles exhibited a nanoscale size (386±2.2 nm) and sustained drug release.
- In vitro studies on HT-29 and Colo-320 colon cancer cells, including MDR variants, showed reduced IC50 values for HA-NLC-Ir.
- Flow cytometry and CLSM confirmed enhanced cellular uptake and targeting of MDR cells by HA-NLC-Ir, demonstrating P-gp inhibition.
Conclusions:
- Surface-engineered hybrid lipid nanoparticles, particularly HA-NLC-Ir, show significant potential in overcoming P-gp mediated multi-drug resistance in colon cancer.
- The developed nanocarrier system effectively delivers irinotecan to MDR cancer cells and inhibits P-gp activity, offering a promising therapeutic strategy.
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