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A multi-functional nano-system combining PI3K-110α/β inhibitor overcomes P-glycoprotein mediated MDR and improves
Ruikun Lin1, Lei Zhang2, Biwei Ye1
1State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China.
Abstract:
P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR) in cancers severely limit chemotherapeutic efficacy. We recently reported that phosphatidylinositol-3-kinase (PI3K) 110α and 110β subunits can be novel targets for reversal of P-gp mediated MDR in cancers, and BAY-1082439 as an inhibitor specific for PI3K 110α and 110β subunits could reverse P-gp-mediated MDR by downregulating P-gp expression in cancer cells. However, BAY-1082439 has very low solubility, short half-life and high in-vivo clearance rate. Till now, nano-system with the functions to target PI3K P110α and P110β and reverse P-gp mediated MDR in cancers has not been reported. In our study, a tumor targeting drug delivery nano-system PBDF was established, which comprised doxorubicin (DOX) and BAY-1082439 respectively encapsulated by biodegradable PLGA-SH nanoparticles (NPs) that were grafted to gold nanorods (Au NRs) modified with FA-PEG-SH, to enhance the efficacy to reverse P-gp mediated MDR and to target tumor cells, further, to enhance the efficiency to inhibit MDR tumors overexpressing P-gp. In-vitro experiments indicated that PBDF NPs greatly enhanced uptake of DOX, improved the activity to reverse MDR, inhibited the cell proliferation, and induced S-phase arrest and apoptosis in KB-C2 cells, as compared with free DOX combining free BAY-1082439. In-vivo experiments further demonstrated that PBDF NPs improved the anti-tumor ability of DOX and inhibited development of KB-C2 tumors. Notably, the metastasis of KB-C2 cells in livers and lungs of nude mice were inhibited by treatment with PBDF NPs, which showed no obvious in-vitro or in-vivo toxicity.
Insights
A novel nanoparticle system effectively reverses multidrug resistance (MDR) in cancers by targeting phosphatidylinositol-3-kinase (PI3K) P110α/β subunits and P-glycoprotein (P-gp). This system enhances chemotherapy efficacy and reduces tumor metastasis with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR) is a major obstacle in cancer chemotherapy.
- Phosphatidylinositol-3-kinase (PI3K) 110α and 110β subunits are identified as novel targets for reversing P-gp-mediated MDR.
- BAY-1082439, a PI3K 110α/β inhibitor, shows potential but suffers from poor pharmacokinetic properties.
Purpose of the Study:
- To develop a tumor-targeting nanodelivery system to overcome the limitations of BAY-1082439.
- To enhance the efficacy of reversing P-gp-mediated MDR and targeting P-gp-overexpressing tumors.
- To improve the therapeutic potential of doxorubicin (DOX) in combination with a PI3K inhibitor.
Main Methods:
- Fabrication of a tumor-targeting nanodelivery system (PBDF NPs) encapsulating doxorubicin (DOX) and BAY-1082439.
- PLGA-SH nanoparticles grafted to gold nanorods (Au NRs) modified with FA-PEG-SH for targeted delivery.
- In vitro assays to evaluate drug uptake, MDR reversal, cell proliferation, cell cycle arrest, and apoptosis.
- In vivo studies to assess anti-tumor efficacy, metastasis inhibition, and toxicity in a mouse model.
Main Results:
- PBDF NPs significantly enhanced DOX uptake and MDR reversal in KB-C2 cells compared to free drugs.
- PBDF NPs inhibited KB-C2 cell proliferation, induced S-phase arrest, and promoted apoptosis.
- In vivo studies demonstrated improved anti-tumor activity, inhibition of tumor development, and reduced metastasis of KB-C2 cells.
- The PBDF NPs exhibited no significant in vitro or in vivo toxicity.
Conclusions:
- The developed PBDF nanodelivery system effectively targets tumors and reverses P-gp-mediated MDR.
- This nano-system overcomes the pharmacokinetic limitations of BAY-1082439, enhancing anti-cancer efficacy.
- PBDF NPs represent a promising strategy for improving chemotherapy outcomes in MDR cancers.
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