Mechanisms of chitosan-coated poly(lactic-co-glycolic acid) nanoparticles for improving oral absorption of 7-ethyl-10-hydroxycamptothecin

Abstract

Chitosan-modified poly(lactic-co-glycolic acid) nanoparticles (CHI/PLGA NPs) loaded with 7-ethyl-10-hydroxycamptothecin (SN-38), named CHI/PLGA/SN-38 NPs, were successfully prepared using an oil-in-water (O/W) solvent evaporation method. The physicochemical properties of the novel NPs were characterized by DLS, Zeta potential, SEM, DSC, XRD, and FTIR. The encapsulation efficiency and drug loading content were 71.83 (±2.77)% and 6.79 (±0.26)%, respectively. In vitro drug release in the simulated gastric juice was lower than that in the intestinal juice. In situ single-pass intestinal perfusion (SPIP) studies indicated a dramatic improvement of drug absorption as a result of the synergistic effect between CHI and PLGA on P-glycoprotein (Pgp) inhibition. CHI/PLGA NPs showed high cellular uptake and low efflux for drugs in Caco-2 cells. The cytotoxicity studies revealed that CHI/PLGA NPs had a transient effect on the membrane integrity, but did not have an influence on cell viability. Based on the in vitro release studies, SPIP, and intracellular drug accumulation and transport investigations, we speculate rationally that CHI/PLGA NPs were mainly internalized in the form of intact NPs, thus escaping the recognition of enterocyte Pgp and avoiding efflux into the apical part of the enterocytes. After partial release of drugs inside the enterocytes, CHI/PLGA interfered with the microenvironment of Pgp and further weakened the Pgp-mediated efflux. Then, the drug-loaded NPs exited via the exocytose effect from the basal part of the enterocytes and entered the blood circulation. These results showed that CHI/PLGA NPs would be smart oral delivery carriers for antineoplastic agents that are also Pgp substrates.

Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles

“…We confirmed the qualification of CS on P188-CS (0.5, 1 and 2) at 1,645 (N-H bend). In a previous study, Chitosan/PLGA NPs was appeared new peak at 1652 cm -1 (N-H bend) compared to the chitosan and PLGA (Guo et al, 2013). Moreover, the peaks of ABZ at N-H bending vibrations at 1,622 cm -1 showed significantly reduced intensity in P188-20 and P188-CS (0.5, 1 and 2).…”

“…Thus, the P188-CS2 NPs were selected as the optimized formulation according to their particle size and encapsulation efficiency (Guo et al, 2013).…”

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

“…Therefore, the intracellular precision release of NDDS-loaded P-gp substrates is still a demanding issue. There were a variety of drug delivery techniques to reduce the efflux associated with P-gp, such as using biological materials with interference of P-gp function, like vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), and adding P-gp inhibitor, [24][25][26][27] like verapamil. Recently, we have reported that a type of NPs can carry a drug as the P-gp substrate into the nucleus and release it in the nucleus of MDR cell.…”

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

“…13,39 In our study, the water-insoluble drug was directly linked to chitosan by a covalent bond. The force of the Dsc spectra of (A) sN38, (B) physical mixture of sN38 and chitosan (17:83, w/w), (C) chitosan, (D) cs-(10s)sN38, and (E) cs-(20s)sN38 (drug loading is about 17%).…”