Cancer is the second leading cause of death in the United States. Next to surgery and radiation treatments, chemotherapy and combination therapies involving drugs are among the most successful in increasing patient survival rates. Paclitaxel (PTX) is one of the most successful taxoids in clinical use today. PTX is very effective in treatment of several cancers including: ovarian, breast, colon, head and neck, and non small cell lung cancer. Unfortunately, the currently used formulations which are intended to increase the solubility and thus bioavailability of PTX, are linked to adverse allergic reactions. Therefore several prodrugs, typically containing PTX conjugated with the hydrophilic and hydrolyzable groups such as polycarboxylic acids, sugars, polymers and peptides, were synthesized and tested. Despite these efforts there is a considerable interest in developing novel prodrugs for targeted drug delivery of PTX and other weakly soluble drugs to increase their therapeutic efficiency. The goal of this proposal is to develop a novel class of local drug delivery systems (nanocarriers) for low solubility drugs (such as PTX) based on collagen mimetic peptides assembled into triple helical peptide (THP) The conjugation of PTX with THP affords numerous potential advantages over currently used prodrugs: (1) it improves prodrug solubility, (2) it increases protease resistance due to rigid rod conformation (3) it allows incorporation of drug targeting sequence or cell penetrating vector, (4) it allows immobilization of the prodrug within a collagen matrix . Additionally, the THP nanocarrier unlike metallic nanocarriers biodegrades to biologically safe products. The proposal aims at developing peptide sequences to form water soluble model prodrugs based on PTX attached to the peptide's lysine group via succinylic link at C2'-OH position. By varying the peptide length and sequence the solubility of the prodrug will be adjusted. The proposed peptide sequences will form THP rigid-rod nanocarrier providing increased stability against in vivo biodegradation. Moreover, the THP carrier will open the possibility of delivering the hydrophobic drugs from hydrophilic collagen matrix. The release profile of a prodrug will be measured as a function of the nanocarrier structure. By synthesizing different length of THP and incorporating pre-heated (self-assembled) or non-preheated (blended) nanocarrier within collagen matrix we hope to effectively control the rates of the prodrug release. The feasibility of incorporating the cell-penetrating vectors into the prodrug wil be investigated. The incorporation of the polyarginine sequences into the prodrug sequence to study preferential nanocarrier cell uptake is also proposed. The cytotoxicity of the proposed Paclitaxel prodrug will also be studied. The developmental objective is to increase the PI's involvement in interdisciplinary research directly related to human health and to increase the productivity of the PI laboratory. The requested support will result in the development of new methodologies and protocols in the PI's laboratory and increased participation of graduate and undergraduate students, including students from traditionally underrepresented backgrounds. This SC-3 support, if awarded, will increase the PI's research output and improve competitiveness for major grant support such as NSF and NIH-RO1 type grants.
This proposal describes a novel class of local drug delivery nanocarriers for low solubility anti-cancer drugs, such as Paclitaxel, based on collagen mimetic peptides assembled into triple helical peptide (THP). Conjugation of Paclitaxel with THP, a rigid- rod nanocarrier, offers numerous potential advantages over currently used prodrugs by increasing solubility in water, improving stability, allowing incorporation of drug targeting sequence or cell penetrating vector, and allowing local delivery of hydrophobic drugs from hydrophilic collagen matrix.
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