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

Abstract

Poor permeability of the intestinal epithelium limits the oral absorption of many drugs. Here, a poly-L-glutamic acid (PGA)-based functional ternary nanocomplex (TC) is reported for enhancing the intestinal absorption of poorly permeable drug doxorubicin hydrochloride (Dox·HCl). The particle size and zeta potential of TC were 189.3 ± 13.7 nm and −29.1 ± 7.4 mV, respectively. The TC was shown to be more stable under simulated gastrointestinal changing pH or electrolyte content conditions than the binary nanocomplex Dox·HCl/PGA. Cellular uptake and the apparent permeability coefficient value (P_app) of the TC were determined to be 5.2- and 4.6-fold higher than that of Dox·HCl solutions, respectively. Mechanistic studies showed that active endocytosis caused by specific interactions between γ-glutamyl terminal groups of PGA and membrane-bound γ-glutamyl transferase contributed much to the TC-dependent Dox·HCl absorption. Studies on the rat model also demonstrated the highest efficiency for Dox·HCl absorption by the TC throughout the intestinal tract, with 2.6- and 4.2-fold higher C_max and AUC_0–24h values compared to Dox·HCl solutions. In conclusion, the TC is a promising carrier for improving Dox·HCl intestinal absorption, and the rational design of carriers with functional polymer PGA could implement the efficient active absorption of poorly permeable drugs.