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Developing a novel P-glycoprotein inhibitor and pairing it with oral paclitaxel liposomes for enhanced cancer therapy
Sikai Deng1, Weiwei Li1, Qiyu Chen1
1School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
Abstract:
The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1H NMR, 13C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e., the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.
Insights
A novel P-glycoprotein inhibitor (PgpI) enhances oral paclitaxel (PTX) delivery. This combination therapy significantly improves PTX bioavailability and antitumor efficacy for lung cancer treatment.
Area of Science:
- Pharmacology and Drug Delivery
- Nanomedicine
- Cancer Therapeutics
Background:
- Oral administration of paclitaxel (PTX) faces bioavailability challenges due to the intestinal mucus layer and epithelium.
- P-glycoprotein (P-gp) efflux pumps in the intestine limit the absorption of many drugs, including PTX.
- Developing strategies to overcome these barriers is crucial for effective oral chemotherapy.
Purpose of the Study:
- To synthesize and characterize a novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI).
- To evaluate the efficacy and in vivo toxicity of an oral combination of PgpI with modified PTX liposomes (R8-PEG@PLs) for lung cancer treatment.
- To investigate the interaction between PgpI and R8-PEG@PLs and their cellular uptake mechanisms.
Main Methods:
- Synthesis and structural characterization of PgpI using NMR and mass spectrometry.
- Evaluation of R8-PEG@PLs&PgpI combination in Caco-2 cells and A549 tumor-bearing mice models.
- Physiology-based cellular kinetic modeling to determine drug internalization rates.
- Investigation of endocytic pathways using lipid raft and macropinocytosis assessments.
Main Results:
- The external combination of PgpI with R8-PEG@PLs (R8-PEG@PLs&PgpI) showed unaffected PgpI affinity for intestinal P-gp.
- R8-PEG@PLs&PgpI primarily utilized lipid raft and macropinocytosis pathways for cellular uptake.
- A 2.3-fold increase in PTX net internalization rate was observed with R8-PEG@PLs&PgpI compared to unmodified liposomes (PLs).
- In vivo studies demonstrated a 2.2-fold increase in antitumor efficacy in lung cancer models.
Conclusions:
- The external combination strategy (R8-PEG@PLs&PgpI) maximizes the efficacy and safety of PgpI for oral PTX delivery.
- This approach overcomes the limitations of oral PTX bioavailability, offering a promising therapeutic option for lung cancer.
- R8-PEG@PLs&PgpI demonstrates potential to address drug concentration deficits in tumor tissues compared to normal tissues.
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