Drug Delivery Devices for Cancer and Posterior Eye
Type of DegreePhD Dissertation
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Skin cancer is by far the most common of all cancers. Among all types of skin cancer, malignant melanoma causes most of the deaths. Likewise, breast cancer is the most common cancer in women after skin cancer and the second leading cause of cancer death in women after lung cancer. Currently, conventional cancer treatments include chemotherapy, immunotherapy and targeted therapy. However, inefficient drug delivery and tumor penetration can reduce the response rate for these treatments. Stimuli-responsive lipid-based nanoparticles are a promising strategy for intratumor drug delivery. Enzymes, acidic tumor pH, mild hyperthermia and light can be utilized to trigger drug accumulation at the tumor site for deep penetration and effective tumor targeting. Different stimuli-responsive liposomes and their application in cancer treatment have been reviewed. The ability of C6-ceramide to alter cancer cells membrane permeability was utilized to enhance the cellular uptake of daunorubicin toward B16-BL6 melanoma cells. Daunorubicin was encapsulated within liposomes where C6-ceramide acted as a component of the lipid bilayer. Liposomal formulation with ceramide exhibited a higher cytotoxic effect on B16-BL6 cell line than free daunorubicin, liposomes without ceramide and liposomes similar to DaunoXome®. Cardiolipin increases membrane fluidity as its presence introduces a higher unsaturation degree to the membrane bilayer. pH-sensitive daunorubicin liposomal formulation enriched with cardiolipin was designed to target the tumor site and enhance the cellular uptake of daunorubicin toward B16-BL6 melanoma cells. Cardiolipin enriched liposomes exhibited a higher cytotoxic and cellular uptake effect on B16-BL6 cell line than liposomes similar to DaunoXome® and free daunorubicin. Thermosensitive daunorubicin liposomal formulation enriched with cardiolipin was formulated to enhance the cellular uptake of daunorubicin, as cardiolipin triggers structural changes in the cell membrane making it more permeable, and to target the tumor site by release of their contents upon exposure to mild hyperthermia. Thermosensitive daunorubicin liposomal formulation with cardiolipin exhibited greater cellular uptake and higher cytotoxic effect on MDA-MB-231 breast cancer cells than the same formulation without cardiolipin, DaunoXome® , and free daunorubicin. Ocular drug delivery to the posterior segment of the eye has been a major challenge due to a large number of ocular barriers. It is highly desirable to achieve effective drug concentration in the posterior eye in a noninvasive manner. The basics and recent developments of formulation in ocular drug delivery to the posterior segment have been reviewed. Cyclosporine A loaded in polyvinyl pyrrolidone (PVP) based microneedles for delivery to the posterior segment of the eye were formulated. They promptly dissolved upon instillation in the eye and released their Cyclosporine A content. Microneedles containing different amounts of PVP were evaluated for dissolution, failure force and drug content. Perfusion studies were performed using whole porcine eyes to determine Cyclosporine A distribution in the individual ocular tissues. Cyclosporine A concentration in different posterior segment tissues was significantly greater compared to the Cyclosporine A ophthalmic emulsion Restasis®.