BIODEGRADABLE NANOCAPULES FOR DELIVERY OF MONENSIN AS POTENTIATOR OF IMMUNOTOXINS

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Immunotoxins have been used as tumor-specific cytotoxic agents by various investigators in academics and industry. One of the major limitations has been their low potency in vivo. Potentiators like monensin have been used with great success in vitro but their lipophillic nature has precluded their use in vivo. Liposomes (with long circulating times) containing monensin are being currently investigated as potentiators of immunotoxins in vitro and in vivo. The main objective of this research is to prepare nanocapsules of a carboxylic ionophore, monensin which can bypass the reticuloendothelial system (to be termed as 'stealth nanocapsules'). These nanocapsules will be used as potentiators of the anti My9 immunotoxin conjugate (IT) which is presently in Phase III clinical trials. The nanocapsules will be fully characterized for their entrapment efficiency, size, stability and pharmacokinetics profile. Stealth monensin nanocapsules will be incubated with the IT conjugate and different human tumor cell lines to see the in vitro potentiation. All in vitro qualitative and quantitative parameters of monensin nanocapsules will be compared to 'stealth' monensin liposomes. Monensin nanocapsules will be further tested for their potentiation of IT in vivo using human tumor xenografts in a i.p/i.v. and i.v./i.v. tumor model (using nude mice) with stealth monensin liposomes as controls. Two different human tumors, H- mesothelioma and HL-60 cells will be used as tumor xenografts. The results emanating from the above studies will allow us to decide what drug delivery system to use, polymer based or lipid based. The completion of the above studies will allow us to choose one formulation for Phase I studies to be used in combination with the IT conjugate as a potentiator.