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Nirupama Sabnis1, Maya Nair1, Mervyn Israel2, Walter J McConathy3, Andras G Lacko11University of North Texas Health Science Center, Fort Worth, TX, 2University of Tennessee Health Science Center, Memphis, TN, 3Texas Tech University Health Sciences Center–Permian Basin, Odessa, TX, USAAbstract: Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs. In this study, we have investigated the enhancement of the therapeutic impact of valrubicin (AD-32), an antineoplastic agent that has been limited to intravesicular application against bladder cancer, despite the encouraging original preclinical data. Earlier studies validated the superior therapeutic efficacy of AD-32 over doxorubicin. In the present study, rHDL/AD-32 nanoparticles were formulated and characterized with regard to encapsulation efficiency, physicochemical properties, selective toxicity, and receptor-mediated uptake. The half maximal inhibitory concentration values (IC50) for rHDL/AD-32 nanoparticles were 1.8 and 2.6 times lower than the free AD-32 for prostate (PC-3) and ovarian (SKOV-3) cancer cell lines, respectively, whereas nonmalignant cell lines demonstrated 5 and 1.48 times higher IC50 doses with rHDL/AD-32 formulations. The data obtained demonstrated effective receptor-mediated uptake of AD-32 from the rHDL nanocarriers by PC-3 and SKOV-3 cancer cells via a targeted drug-delivery process. The rHDL/AD-32 formulation was stable for 6 months when stored at 4°C or at –20°C, as 92% of the AD-32 was retained in the nanoparticles. The findings from this study show that the rHDL/AD-32 formulation can overcome the solubility barriers of AD-32 and thus serve as an effective systemically administered chemotherapeutic agent.Keywords: AD-32, rHDL, nanoparticles, targeted drug delivery, selective drug delivery

A platform technology has been established, based on reconstituted high density lipoprotein (rHDL) nanoparticles, to facilitate the delivery of intravenously administered drugs (including cancer chemotherapeutic agents). We have prepared rHDL/Taxol complexes with a consistent composition and molecular weight that exhibited exceptional stability upon repeated gel chromatography and ultracentrifugation. Studies in mice led to the observation that about ten times as much HDL encapsulated Taxol remained in the circulation, 1 hr post injection, compared to free Taxol. We have examined a number of cancer cell lines for their ability to incorporate cholesterol esters and Taxol% from rHDL complexes. The delivery of cholesteryl esters and paclitaxel was nearly as efficient to cancer cells as it was to a normal control (ovarian granulosa cells). We also showed that the uptake efficiency of cholesteryl esters and pacliataxel by cancer cells were closely correlated (r2=O.89; p

Reconstituted high density lipoprotein (rHDL) particles have been developed to incorporate water insoluble drugs to serve as drug delivery agents. Specifically, we have prepared taxol (TX) containing rHDL particles that am stable on rechromatography and preparative ultracentrifugation as no losses of TX from the complexes were seen during these studies. The rHDL/TX complexes were as toxic to breast cancer cells as the commercial cremophor/taxol preparations. Taxol was avidly taken up by cancer cells from the rHDL/TX complexes, apparently by an SRB1 type receptor mediated mechanism. The uptake of core components from the rHDL complexes by a receptor mediated mechanism is supported by the observed expression of the SRB1 type receptors (demonstrated by immunoblotting) and by competition studies. Cancer cells were shown to exhibit considerably higher SRB1 receptor expression than fibroblasts, suggesting that the rHDL drug delivery system may be specifically targeting malignant cells.

Reconstituted high density lipoprotein (rHDL) particles have been developed to incorporate water insoluble drugs to serve as drug delivery agents. Specifically, we have prepared taxol (TX) containing rHDL particles that are stable on rechromatography and preparative ultracentrifugation as no losses of TX from the complexes were seen during these studies. The rHDL/ TX complexes were as toxic to breast cancer cells as the commercial cremophor/taxol preparations. Taxol was avidly taken up by cancer cells from the rHDL/TX complexes, apparently by an SRB1 type receptor mediated mechanism. The uptake of core components from the rHDL complexes by a receptor mediated mechanism is supported by the observed expression of the SRB1 type receptors (demonstrated by immunoblotting) and by competition studies. Cancer cells were shown to exhibit considerably higher SRB1 receptor expression than fibroblasts, suggesting that the rHDL drug delivery system may be specifically targeting malignant cells.