Novel therapeutic nano-particles (lipocores): trapping poorly water soluble compounds

The development of stable spherical lipid-coated drug particles that are te rmed 'lipocores' is reported here. Unlike conventional lipid-based particle s (i.e, liposomes, emulsions, micelles), these particles are comprised sole ly of a core of a pool ly water soluble drug surrounded by polyethyleneglyc ol conjugated lipid (PEG-lipid) and are formed via a 'kinetic' trapping pro cess. These lipocore particles were made with the acyl chain of 16 carbon l ength (C16) acyl-chain derivatives of paclitaxel or vinblastine and with th e polyene antifungal hamycin. Formation of the particles occurred regardles s of the type of PEG-phospholipid used (i.e. acyl chain length, chain satur ation, and polymer length) and could also be formed with the negatively cha rged lipid N-glutaryl-dioleoyl-phosphatidylethanolamine (DOPE-GA). Images f rom both freeze-fracture electron microscopy and electron cryo-microscopy r evealed solid spherical structures with no internal lamellae for the PEG-li pid particles made with the C16 derivatives of paclitaxel (BrC16-T) or vinb lastine (C16-Vin). From a solute distribution study of lipocores made with BrC16-T and distearoyl-phosphatidylethanolamine-PEG(2000) (DSPE-PEG(2000)) the particles were found to have no measurable aqueous captured volume. Flu orescence anisotropy and order parameter measurements revealed the core mat erial of these particles to be highly immobilized. The mole ratio of BrC16- T:lipid in the lipocores was typically > 90: < 10 and as high as 98:2, and the refrigerated lipocores were stable for several months. BrC16-T/DSPE-PEG (2000) lipocores of 50-100 nm particle size were far less toxic than paclit axel (Taxol(R)) after intraperitoneally (i.p.) or intravenously (i.v.) admi nistration in mice and were active against i.p. and subcutaneously (s.c.) p lanted human (OvCar3) ovarian carcinoma grown in SCID mice. It is believed the high drug:lipid ratio, the stability, and therapeutic efficacy of these novel particles make them a paradigm for delivery of poorly water soluble drugs and/or their hydrophobic derivatives. (C) 2000 Elsevier Science B.V. All rights reserved.