ABSTRACT
Thermosensitive nanoparticles based on poly(N-isopropylacrylamide-co-((2-dimethylamino)ethylmethacrylate)) (poly(NIPA-co-DMAEMA)) copolymers were successfully fabricated by free radical polymerization. The lower critical solution temperature (LCST) of the synthesized nanoparticles was 41 °C and a temperature above which would cause the nanoparticles to undergo a volume phase transition from 140 to 100 nm, which could result in the expulsion of encapsulated drugs. Therefore, we used the poly(NIPA-co-DMAEMA) nanoparticles as a carrier for the controlled release of a hydrophobic anticancer agent, 7-ethyl-10-hydroxy-camptothecin (SN-38). The encapsulation efficiency and loading content of SN-38-loaded nanoparticles at an SN-38/poly(NIPA-co-DMAEMA) ratio of 1/10 (D/P = 1/10) were about 80% and 6.293%, respectively. Moreover, the release profile of SN-38-loaded nanoparticles revealed that the release rate at 42 °C (above LCST) was higher than that at 37 °C (below LCST), which demonstrated that the release of SN-38 could be controlled by increasing the temperature. The cytotoxicity of the SN-38-loaded poly(NIPA-co-DMAEMA) nanoparticles was investigated in human colon cancer cells (HT-29) to compare with the treatment of an anticancer drug, Irinotecan(®) (CPT-11). The antitumor efficacy evaluated in a C26 murine colon tumor model showed that the SN-38-loaded nanoparticles in combination with hyperthermia therapy efficiently suppressed tumor growth. The results indicate that these thermo-responsive nanoparticles are potential carriers for controlled drug delivery.
Subject(s)
Camptothecin/analogs & derivatives , Methacrylates/chemistry , Nanoparticles/chemistry , Nanotechnology/methods , Polymethacrylic Acids/chemistry , Temperature , Absorption/drug effects , Animals , Antineoplastic Agents/pharmacology , Camptothecin/pharmacology , Cell Death/drug effects , Delayed-Action Preparations , Endocytosis/drug effects , Female , Fluorescence , HT29 Cells , Humans , Irinotecan , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Nanoparticles/ultrastructure , Particle Size , Static Electricity , ThermogravimetryABSTRACT
Colorectal cancer is one of the leading causes of cancer death and often goes undetected with current colonoscopy practices. Improved methods of detecting dysplasia and tumors during colonoscopy could significantly improve mortality. Herein, we report a high-performance nanoparticle for photodynamic detection of colorectal cancer, where alginate is physically complexed with folic acid-modified chitosan to form nanoparticles with improved drug release in the cellular lysosome. The incorporated alginate molecules could complex stably with chitosan via electrostatic attraction, and the z-average diameter and zeta-potential of the prepared nanoparticles (fCAN) was 115 nm and 22 mV, respectively, enough to keep the nanoparticles stable in aqueous suspension without aggregation. When loaded with 5-aminolevulinic acid (5-ALA; 27% loading efficiency), the nanoparticles (fCANA) displayed no differences in particle size or zeta-potential compared to fCAN. Moreover, the fCANA nanoparticles were readily taken up by colorectal cancer cells via folate receptor-mediated endocytosis. Subsequently, the loaded 5-ALA was release in the lysosome, and this was promoted by the reduced attraction intensity between chitosan and 5-ALA via the deprotonated alginate, resulting in a higher intracellular PpIX accumulation for the photodynamic detection. These studies demonstrate that the alginate incorporated and folic acid-conjugated chitosan nanoparticles are excellent vectors for colorectal-specific delivery of 5-ALA for fluorescent endoscopic detection.
