A pharmaceutical carrier for poorly soluble drugs should ideally possess small size, biodegradability, good loading capacity, high drug content in a final preparation, prolonged circulation in the blood, and targetablity. The development of nanoparticulate drug carriers displaying these properties for the delivery of poorly soluble pharmaceuticals still represents a challenge, Micelles, nanoscopic particles with a highly hydrophobic core capable of solubilizing water insoluble substances, are carriers of choice for this purpose. Recently, we have proposed, prepared and investigated a new family of micellar drug carriers with controlled properties. These micelles are prepared from conjugates of soluble biocompatible polymers, such as polyethylene glycol (PEG), with highly hydrophobic diacyllipid-fragments, such as phosphatidylethanolamine (PE). They can be used for both non-specific and targeted drug delivery, increasing bioavailability and decreasing side effects of micelle-incorporated drugs. Based on our preliminary experiments, our hypothesis is that PEG.diacyllipid-based micelles loaded with poorly soluble anticancer drugs, such as taxol, camptothecin, and porphyrin derivatives (M-porphyrin), will provide an increased anticancer effect both in vitro and in vivo, in different treatment modalities (such as chemotherapy and photo-dynamic therapy). Their therapeutic potential will be further increased if micelles are additionally modified with specific Iigands allowing for their tumor accumulation (immunomicelles) and/or intracellular delivery (micelles modified with TAT peptide, TATp). The following specific aims will be pursued to test our hypothesis: 1. To prepare PEG-PE-based micelles loaded with camptothecin and taxol; determine the maximum tolerated dose (MTD) in C57BL and nude mice; and investigate their tumor accumulation and therapeutic effect in vivo in normal mice bearing either subcutaneous B16 melanoma or EL4 T lymphoma tumors and in nude mice bearing subcutaneous BT20 or MCF7 human breast adenocarcinomas; 2. To prepare PEG-PE-based immunomicelles with attached cancer-specific antinucleosome monoclonal antibodies 2C5 or 1G3, and investigate their anticancer effect in vivo in normal mice with subcutaneous B16 or EL4 tumors and in nude mice with BT20 or MCF7 tumors; 3. To prepare M-porphyrin-loaded PEG-PE-based plain micelles and immunomicelles, and investigate their anticancer effects under conditions of photodynamic therapy both in vitro and in vivo using B16, EL4, BT20, and MCF7 cell cultures and experimental tumors; 4. To prepare TATp-modified PEG-PE-based micelles loaded with camptothecin and taxol, and study the effect of TATp-mediated intracellular delivery of drug-loaded micelles on drug anticancer activity both in vitro and in vivo in B16, EL4, BT20, and MCF7 cell cultures and tumors; 5. To combine the targeting ability and the intracellular deliverability in one preparation of drug-loaded micelles by co-immobilizing TATp and cancer-specific antibody on the surface of the same micelles; and compare the therapeutic efficacy of such a combined preparation with that of drug-loaded TATpmicelles or immunomicelles. This study will bring to life a new set of micellar drug carriers with controlled stability, high loading efficiency, slower clearance rate, and enhanced targetability, suitable for the intratumoral and intracellular delivery of poorly soluble pharmaceuticals in a fashion that generates a highly effective treatment of a broad variety of experimental tumors in different therapeutic modalities. ? ?
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