Formulation of Controlled Liposomal Drug Delivery System
Abstract
The ultimate goal of drug delivery is to increase the bioavailability and reduce the toxic side effects of the active pharmaceutical ingredient (API) by releasing at a specific site of action. Liposomes have been considered as favored carrier systems because they are easily manufactured in a size controlled manner, can be produced in high drug/lipid ratios by remote loading, are rendered long-circulating by the incorporation of stealth coating, and are typically composed of naturally-derived phospholipids that mimic the properties of biological membranes. They can also be further engineered with functional moieties to improve their performances in terms of circulation longevity, target-specific delivery, enhanced intracellular penetration, contrast enhancement for image-guided therapy, and stimuli-sensitivity. The small molecule, cerivastatin, can be passively loaded into the liposomes for local accumulation and sustained release for the treatment of pulmonary arterial hypertension. Nano-liposome encapsulated cerivastatin inhibited in vitro proliferation of pulmonary artery smooth muscle cells without producing cytotoxicity. Inhaled nano-liposomal cerivastatin was more effective in reducing pulmonary artery pressure and parameters of right ventricular functions when compared to inhaled free cerivastatin. These studies show that local pulmonary delivery of nano-liposomal cerivastatin may be an effective therapeutic strategy for the treatment of PAH. Liposomal formulation of a hydrophobic drug delivery system can be novel to overcome the limitation of low bioavailability in the therapeutic application. The controlled encapsulation of hydrophobic anticancer drug (β-lap) through the remote loading using ionizable cyclodextrin, mono-6-amino-6-deoxy-β-cyclodextrins (β-CD-NH2), into liposomes is demonstrated. This formulation (LP-β-lap-β-CD-NH2) showed sustained release of β-lapachone over extended period of time without showing an initial burst effect. The cytotoxicity of remotely loaded β-lapachone demonstrated an efficacious response to HeLa cells by providing similar potency to free drug. The targeted delivery system seeks to improve therapeutic response by peptide-guided liposome formulations by expressing the specificity towards a targeted marker. This peptide is derived from the key binding motif of the adhesion protein, fibronectin attachment protein (FAP), which is known to interact with exposed fibronectin (FBN) of bladder tumor cells. This study shows a positive cell association towards mouse model bladder tumor cells (MB49) when liposomes were fabricated with lipopeptides bearing targeting groups (RWFV). The utilization of a double PEGylation strategy in the liposome system further enhanced the binding events by providing favored ligand orientation. The in vivo data showed a greater mean radiance values for targeted liposomes towards MB49-bearing mice when the regions of interest (ROI) were assigned around both whole bladder or tumor only areas.
Degree
Ph.D.
Advisors
Thompson, Purdue University.
Subject Area
Chemistry|Organic chemistry|Biomedical engineering|Pharmaceutical sciences
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