Investigation On Electrospun Ultrafine Biodegradable Fibers As Potential Carriers Of Hydroxycamptothecin

Currently, systematical administration of the antineoplasma agent is one of the main strategies for chemotherapy. But it can be hardly delivered to target region, leading to strong side effects and low compliance and therapeutic efficacy. Hydroxycamptopthecin (HCPT) has wide antitumor spectrum, but it is insoluble in both water and physiological acceptable organic solvents and tends to change into inactive carboxylate form, which restricted the clinical application. HCPT loaded ultrafine fibers were prepared in this thesis through the electrospinning process as an implantable dosage. Blend and emulsion electrospinning process were used to prepare ultrafine fibers with selected biodegradable polymers by the addition of different amounts of HCPT and excipients. The drug loaded ultrafine fibrous mats were systematically investigated with respect to the drug release behaviors, degradation profiles, the structural integrity and antitumor activity of the released HCPT.By examining the effect of HCPT on cancer cell proliferation, the the half maximal inhibitory concentration (IC50) of HCPT on MCF-7 cells was detected, which was used to determine the drug loading amount into fibers. Poly(DL-lactide) (PDLLA) was selected as drug carrier to prepared HCPT-loaded ultrafine fibers. The results showed that HCPT can be entirely entrapped into the electrospun fibers, which had smooth surface, well-distributed diameter and the encapsulated efficacy of 97.2%. A slow and sustained release was detected from electrospun PDLLA fibers with a low initial burst release.To enhance the HCPT release from electrospun fibers, blend electrospinning process were used to prepare HCPT-loaded poly(DL-lactide)-poly(ethylene glycol) (PELA) ultrafine fibers with different drug loading amounts and the addition of hydroxypropyl-β-Cyclodextrin (HP-β-CD) as an excipient. Drug was homogeneously dispersed and distributed amorphously within ultrafine fibers, with the loading efficiency of over 90%. The active lactone form of HCPT was determined in ultrafine fibers, which was maintained over 85% during incubation in the media for over 1 month. HCPT release rate increased with the increase in the drug contents, and the drug release could be adjusted by the addition of different amounts of HPCD. The degradation of drug-loaded electrospun PELA fibers indicated a behavior between surface erosion and typical bulk degradation. In vitro cytotoxicity test showed the antitumor activity for HCPT-loaded electrospun fibers was at least 7 times higher than that of free drug during 72 h incubation.HCPT-loaded emulsion electrospun fibers were prepared through the formation of water in oil (w/o) emulsion, resulting in fibers with smooth surface and average diameter of 540 nm. The laser scanning confocal microscope (LSCM) observation showed the emulsion electrospun fibers were core-sheath structured, while HCPT random existed as granulars and gathered in some areas. The drug encapsulation effeciency and accumulated release amount increased with the increasee in the proportion of HPCD. The drug release and polymer degradation rates of HCPT-loaded emulsion electrospun fibers were higher than those of blend electrospun fibers. The fast release of HCPT from emulsion elecstrospun fibers during the early stage enhaced the inhibition effect, and at least 20 times higher antitumor activity was indicated for HCPT-loaded electrospun fibers than that for free drug during 72 h incubation.