By combining the recent developments in engineering of multifunctional pharmaceutical nanocarriers and in preparing novel types of polymeric coatings using the layer-by-layer (LbL) technology, we expect to obtain new dosage forms of poorly soluble drugs and meet the unmet need for stable nanocolloids of such drugs suitable for parental administration. There exist serious problems with currently used micellar carriers for poorly soluble drugs: (a) low loading efficacy of the drug (usually below 5% wt);(b) impossibility to apply the same protocol for different drugs;(c) difficulties in controlling the drug release rate;(d) scaling up the technology;(e) insufficient stability. On the other hand, there exists an approach to assemble polyelectrolyte multilayer shells on various particles through the LbL process based on an alternate adsorption of oppositely charged polyelectrolytes. We plan LbL coatings to make stable aqueous colloids of poorly soluble drugs with high stability, controllable release rate, and very high content (up to 90% wt) of the active drug. For this, aqueous suspensions of poorly soluble drugs with micron range particles are subjected to ultrasonication to bring their size to the nano level, and stabilized drug nanoparticles in solution are formed by applying the LbL coating. We hypothesize that the formation of LbL shell around drug nanoparticles will result in stable drug preparations with high content of an active drug. By varying the charge density on polymers and/or the number of coating cycles, particles with a different surface charge and different composition of the coat can be prepared to control drug release rate. The use of a reactive polymer to form the "outer" surface layer will allow for the attachment of specific ligands or reporter groups and other moieties of interest to drug nanoparticles. The proposal pursues the following specific aims: (1) To prepare stable nanocolloids of poorly soluble drugs - paclitaxel (PCT), and camptothecin (CPT) - with a size of 100-to-200 nm, drug content of above 75% wt, and controllable drug release rate by using the LbL technology;(2) To prepare drug LbL nanocolloids with attached polyethylene glycol (for increased longevity), cancer-specific monoclonal antibody 2C5 or TAT peptide (TATp), for cancer targeting or intracellular penetration;(3) To investigate the properties, cytoxicity, interaction with cells, and cellular uptake and intracellular distribution of non-targeted and targeted LbL nanocolloids of PCT, and CPT in cancer cells in vitro;(4) To investigate the properties of non-targeted and targeted LbL drug nanocolloids in vivo in mice with experimental tumors;and (5) To prepare TATp-modified LbL nanocolloids of PCT, and CPT and study the effect of TATp-mediated intracellular delivery of drug nanocolloids on drug efficiency both in vitro and in vivo. This proposal will develop a novel platform for making stable targeted and non-targeted nanocolloids of poorly soluble drugs with high drug content and enhanced drug bioavailability.
We plan to obtain new dosage forms of poorly soluble drugs suitable for parenteral administration by applying the layer-by-layer (LbL) technology by assembling polyelectrolyte multilayer shells on various particles through the process of an alternate adsorption of oppositely charged polyelectrolytes. This will result in stable aqueous colloids of poorly soluble drugs with high stability, controllable release rate, and very high content (up to 90% wt) of the active drug. By varying the charge density on polymers and/or the number of coating cycles, particles with a controlled surface charge and different composition of the coat can be prepared to control drug release rate. The use of a reactive polymer to form the "outer" surface layer will allow for the attachment of specific ligands or reporter groups and other moieties of interest to drug nanoparticles. The approach will be applied to several poorly soluble anticancer drugs, and the nanocolloids obtained will be additionally modified by various ligands to make them long-circulating, targeted, and capable of intracellular penetration.
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