Electrospun Polymeric Ultrafine Fibers Loaded With Anticancer Drugs For Local Tumor Treatment

Currently, the main strategies for treatment of malignant cancer remains to be surgical excision,supplemented by chemotherapy and/or radiotherapy to avoid tumor recurrence and metastasis. However, the therapeutic efficacy is far from satisfactory after postoperative systemic administration of anti-neoplasma agents due to the shortcomings such as fast drug metabolism, short half-life, low bioavailability and strong side effect. The local tumoral implants with drug loaded can improve the bioavailability of chemotherapeutic drugs and reduce systemic side effect. Electrospun ultrafine fibers have shown great potential as drug delivery carriers because their high specific surface area and nanoscale stucture for drug loading and release control. Thus, electrospun fibers loaded with chemotherapeutic drugs were investigated in this thesis as an implantable formulation. Based on the adidic microenvironment in tumor tissues, acid-liable polymeric fibers were used to load anticancer drugs to achieve a responsive release to local stimuli. To solve the problems of tumor metastasis through blood vessels, electrospun fibers with loaded both chemotherapeutic and vascular disruption agents were developed to enhance the tumor suppression efficacy and anti-metastasis activity. To optimize the drug targeting and stimulus-responsive release, drug-loaded micelle carriers were incorporated into electrospun fibers to achieve a sustained release and substantial formation of micelles. The antitumor efficacy determined form in vitro tests on tumor cells and in vivo evaluation on tumor-bearing animal models should provide a scientific foundation for further development of implantable formulations of anticancer drugs.The acidosis of tumor microenvironments is one of the universal phenomena of solid tumors, and the increased acidity may be in fact essential intermediates in the progression of tumor growth and several lethal phenotypic traits of tumors, such as invasion and metastasis. Acid-labile polymers PBELA with incorporating acetal groups into biodegradable backbone of poly(D,L-lactide)-poly(ethylene glycol) (PELA) were utilized to load hydroxycamptothecin (HCPT) into electrospun fibers for intratumoral chemotherapy. Compared with that under a simulated physiological condition of pH 7.4, the incubation of PBELA fibers in acidic media resulted in larger mass loss and molecular weight reduction of fiber matrices, and enhanced HCPT release from fibers. In vitro cytotoxicity assay of HCPT-loaded PBELA fibers indicated 6-fold higher inhibitory activity against HepG2 cells after incubation in pH 6.8 media than that of pH 7.4, while there was no significant difference for free HCPT and HCPT-loaded PELA fibers. The tumor growth, tumor cell apoptosis and animal survival rate after intratumoral implantation of HCPT-loaded PBELA fibers indicated a superior in vivo antitumor activity to and fewer side effects than other treatment.The vasculature in tumor microenvironment plays important roles in the tumor growth and metastasis, and the combination of vascular disrupting agents with chemotherapeutic drugs should be effective in inhibiting tumor progression. But the dosing schedules are essential to achieve a balance between vascular collapse and intratumoral uptake of chemotherapeutic agents. Thus, emulsion and blend electrospinning were used to create compartmental fibers accommodating both combretastatin A-4 (CA4) and HCPT. The release durations of CA4 and HCPT were modulated through the structure of fibers for dual drug loadings and the inoculation of 2-hydroxypropyl-β-cyclodextrin (HPCD) in fiber matrices. Under a noncontact cell coculture in Transwell, the sequential release of CA4 and HCPT indicated a sequential killing of endothelial and tumor cells. In an orthotopic breast tumor model, all the CA4/HCPT-loaded fibers showed superior antitumor efficacy and higher survival rate than fibers with loaded individual drug. Compared with fibrous mats with infiltrated free CA4 and fibers with extended release of CA4 for over 30 days, fibers with sustained release of CA4 for 3-7 days from CA4/HCPT-loaded fibers resulted in the most significant antitumor efficacy, tumor vasculature destruction, and the least tumor metastasis to lungs.To address the issues that drug-loaded fibers are not feasible for surgical implantation into some cancer patients, injectable short fibers of 20 μm long were successfully prepared through cryo-cutting. The release schedules of CA4 were successfully modulated by inoculation of different concentration of HPCD, and the sequential release of CA4 and HCPT was achieved by mixing CA4-loaded short fibers with different release schedules and HCPT-loaded short fibers. In vitro cell cytotoxicity indicated a sequential killing of endothelial and tumor cells and disruption of the microtubules of endothelial cells. In vivo experiments indicated the injection of the mixture of CA4 and HCPT-loaded fibers around the tumors resulted in a delayed growth of tumors and inhibition of tumor metastasis to lungs.In order to provide a basis for the following research on micelle-loaded fibers, both the drug encapsulation micelles (DEM) and drug conjugation micelles (DCM) were systematically evaluated both in vitro and in vivo. DCM was found to be much more stable in media containing human serum albumin, and the structural integrity of lactone ring of CPT was much higher for the release product from DCM than that of free CPT released form DEM. In vitro cytotoxicity assay indicated that DCM had a higher cytotoxicity to tumor cells than that of DEM. In vivo study indicated that, compared with the DEM, DCM showed a longer circulation time in the bloodstream, a higher drug accumulation in the tumor tissues, a stronger ability to inhibit tumor growth, and a lower metastasis of tumor cells into lungs.To realize the target location and stimulus-responsive release of drugs released from fibers, the micelle carrier polymer was loaded in electrospun ultrafibers through blend electrospinning, and the release profiles of the polymer carriers were modulated by the inoculation of different amounts of hydrophilic poly(ethylene oxide) into fibers. The drug-loaded polymer carriers could self-assemble into micelles after release from fibers. In addition, the formed micelles indicated obvious reduction sensitivity, and could be efficiently endocytosis into tumor cells, continuously inhibit the proliferation and induce the apoptosis of tumor cells.