A poly-l-glutamic acid functionalized nanocomplex for improved oral drug absorption

Area of Science:

• Biomaterials Science
• Drug Delivery
• Nanotechnology

Background:

• Intestinal epithelial barrier function limits oral drug absorption.
• Poorly permeable drugs, such as doxorubicin hydrochloride (Dox·HCl), require enhanced delivery strategies.
• Poly-l-glutamic acid (PGA) offers potential for drug carrier development.

Purpose of the Study:

• To develop and evaluate a functional ternary nanocomplex (TC) using PGA for enhanced intestinal absorption of Dox·HCl.
• To investigate the stability and cellular uptake of the developed TC.
• To elucidate the mechanism of enhanced drug absorption and assess in vivo efficacy.

Main Methods:

• Fabrication and characterization of PGA-based ternary nanocomplexes (TC).
• In vitro assessment of TC stability under simulated gastrointestinal conditions.
• Evaluation of cellular uptake and apparent permeability coefficient (P_app) in intestinal models.
• In vivo pharmacokinetic studies in a rat model.

Main Results:

• TC exhibited optimal particle size and negative zeta potential for stability.
• TC demonstrated superior stability compared to binary complexes under varying pH and electrolyte conditions.
• Cellular uptake and P_app of TC were significantly higher than Dox·HCl solutions (5.2- and 4.6-fold, respectively).
• In vivo studies showed a 2.6-fold higher C_max and 4.2-fold higher AUC_0-24h for TC-delivered Dox·HCl in rats.

Conclusions:

• The functional ternary nanocomplex (TC) based on PGA is a promising carrier for improving the intestinal absorption of Dox·HCl.
• The enhanced absorption is attributed to active endocytosis mediated by PGA's interaction with γ-glutamyl transferase.
• Rational design of functional polymer-based carriers can facilitate efficient active absorption of poorly permeable drugs.