title: 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.
authors.affiliation: Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing 210023, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Guo
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Rong
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.forename: Dong-Fang
authors.initials: DF
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Shu-Qin
authors.initials: SQ
authors.lastname: Yu
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000042:Absorption / Q000187:drug effects; D000818:Animals; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D020099:Coated Materials, Biocompatible / Q000737:chemistry*; D003374:Coumarins / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007422:Intestines / Q000187:drug effects; D000077146:Irinotecan; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity; D014961:X-Ray Diffraction
chemical_list: D020099:Coated Materials, Biocompatible; D003374:Coumarins; D020112:Rhodamine 123; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000077146:Irinotecan; D048271:Chitosan; C030123:coumarin; D002166:Camptothecin