| Although the most effective treatment for patients with localizedliver cancer is surgical resection, long-term survival is dismal if thedisease recurs. The risk of local recurrence in early-stage liver cancer iscorrelated with the distance between the surgical margin and the primarytumor. Residual microscopic tumor cells at the surgical margin have beenidentified postoperatively in39%of patients following “curative” wedgeresection, suggesting that local recurrence arises from nearby occulttumor cells that remain after surgery.thus concurrent treatment withradiation and/or chemotherapy is often utilized with more aggressivecancer types, in an attempt to prevent recurrent tumor growth.For this reason,neoadjuvant chemotherapy and/or external beamradiation therapy are sometimes used to shrink particularlylarge tumors and/or ‘control’ regional disease prior to surgical excision,effectively ‘down-staging’ the disease before surgery in some patients.Radiation treatment, although generally associated with lower5-yearsurvival than surgery, can be curative for early stage cancers and is utilized as an alternative to resection in late stage patients includingprostate, breast, and lung cancers or those unable to tolerate surgery.Unfortunately, the acute and long-term toxicities and limited efficacyassociated with these adjuvant therapies have prevented their routine useas prophylactic interventions in all patients.Given that intravenous systemic chemotherapy is not specificallytargeted to the tumor, it is very difficult to achieve therapeutic levels ofdrug within or adjacent to the tumor. Furthermore, significantconcentrations of drug frequently accumulate in healthy tissue, leading tosevere side effects and dose-limiting toxicity. For example, almost halfthe dose of an intravenous injection of paclitaxel is eliminated during thefirst24hours, with less than0.5%of the total dose locally available totreat tumor within the lung. The use of radiation and chemotherapy alsosignificantly adds to the cost of cancer care due to the high material costsand the need for appropriate specialists including radiation and medicaloncologists and a robust support staff for delivery of therapy, appropriatemonitoring,and treatment of side effects. These treatments are timeconsuming for both patients and personnel, requiring frequent visits overmonths of therapy.Treatment failure in early and intermediate stage cancers, includinghigh locoregional recurrence rates, is indicative of the shortcomings seenwith the current standard of care for some malignancies. The potential benefits of localized chemotherapy at the tumor site are numerous and areintended to both enhance the efficacy of treatment and reduce patientmorbidity. Drug-loaded implants are administered directly at the site ofdisease, offering the following advantages over traditional systemicdelivery:1) stabilization of embedded drug molecules and preservation ofanticancer activity,2) controlled and prolonged drug release to ensureadequate diffusion and uptake into cancer cells over many cycles oftumor cell division,3) loading and release of water-insolublechemotherapeutics,4) direct delivery to the site of disease, resulting inless waste of drug,5) one-time administration of the drug, and6)diminished side effects due to the avoidance of systemic circulation ofchemotherapeutic drugs.In this study our objectives were to investigate the potential use ofpolymer nanofibers. Therefore, this thesis consists of the following threeparts:The first part was the successful incorporation and sustained releaseof Paclitaxel using “traditional solution-electrospinning”.As far as Paclitaxel is hydrophobic drug, it can be dissolved in thehydrophobic polymer/organic solvent system forming a transparent andhomogenous mixed solution. When the solution was electrospun bytraditional electrospinning setup, the drug could be perfectly incorporatedinto the hydrophobic polymer fibers. This case is termed as “traditional solution-electrospinning”.Paclitaxel/PEG750-PLA electrospun fiber mats were successfullyprepared by electrospinning. Paclitaxel/PEG-PLA fibers showed a rapidenough paclitaxel release at the very beginning and then provided asustained release of paclitaxel. For the delivery of antineoplastic drugs,certain amount of initial burst is actually required to achieve enoughinitial dosage. Of course, for the cancer cells that survive the initial stage,sustained drug release is necessary. So paclitaxel/PEG-PLA fiber mats aresuitable for liver cancer therapy. They can inhibit the propagation of therat H22liver cancer cells and induce the cell apoptosis. After treated withpaclitaxel/PEG-PLA fiber mats, the life span of the rats bearing cancerwas extended, and the volumes of tumors were distinctly shrunk.The second part was concentrated on incorporating cisplatin intohydrophobic polymer fibers by “emulsion electrospinning”.“Emulsionelectrospinn-ing”, i.e., to prepare an aqueous solution of a drug, toemulsify this aqueous solution in a polymer solution and to electrospinthe emulsion. Because the water may be evaporated quickly during thefiber stretching and solidification, the hydrophilic drug is expected to beencapsulated in the fibers.Cis-loaded PEG-PLA nanofibers with different Cis loadings wereprepared by “emulsion-electrospinning”. Cis was molecularly distributedinto the drug-loaded fibers, forming a reservoir-type drug-loaded system. Experimental results show: Cis/PEG-PLA fiber mat has significant effectof inhibition and killing on tumor cells in rats with H22induced liver, hasobvious anti-tumor effects compared with paclitaxel.It is the effectivelocal chemotherapy after liver resection for hepatocellular carcinoma, andcan prolong the survival of mice,inhibit tumor growth, the tumor volumegrowth is slow and even no growth. But in the early stages of release,"outbreak" released of cisplatin has caused systemic toxicity.The third part was the application of multilayer modifiedCisplatin-loaded polylactide electrospun nanofibers.MultilayeredCisplatin-loaded polylactide electrospun nanofibers is used in after theoperation of local liver cancer resection in mice.Experiments show that:multilayer modified Cisplatin-loaded polylactide electrospun nanofibersreduced cisplatin first "outbreak" release, reduced systemic toxicity, andprolonged the drug release to increasing tumor cell killing effect. Theseresults provide an encouraging prospect of using multilayered,drug-loaded electrospun nanofiber mats in local chemotherapy to preventtumor recurrence following HCC surgery, alone or combined withpresently employed treatment protocol. |
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