I. A) Introduction to CCT PHARMA INC. (a division of Cav-Con, Inc.), and its ongoing R&D program: Targeted lipid nanoemulsion (microbubble/particle) technology, and worldwide licensing-out activities involving related intellectual property.
B) Background:
Early studies on lipid-coated microbubbles (LCM) reported on their use as an intravenous contrast agent. Later studies demonstrated that fluorescent-labeled LCM are rapidly internalized by various types of tumor cells both in vivo and in vitro. LCM are also capable of physically carrying other compounds (i.e., lipophilic drugs) with them into the target cells. This LCM drug-delivery vehicle is constructed entirely of nonionic lipids, which causes the LCM to display marked tumor-targeting abilities.
The lipid composition of LCM (i.e., glycerides and cholesterol compounds) is similar to lipids contained in several types of plasma lipoproteins. Accordingly, when LCM are injected into the bloodstream, they likely acquire (i.e., bind) plasma apolipoprotein(s). It has been proposed in several publications [e.g., D'Arrigo (2003) Stable Gas-in-Liquid Emulsions, 2nd edition, Elsevier] that such bound species of apolipoproteins A-E are recognized by the corresponding lipoprotein receptors (often found overexpressed on the surface membrane of tumor cells) -- since confocal laser microscopy clearly demonstrates tumor-selective endocytosis of LCM. The measured LCM uptake by target cells (e.g., tumor cells) displays both temperature dependence and energy dependence, and accordingly involves endocytic pathways -- i.e., those likely associated with certain lipoprotein receptors [cf. D'Arrigo (2008) Proc. of Joint 63rd Northwest/21st Rocky Mountain Regional Meeting, American Chemical Society, p. 71].
Recent multidisciplinary analyses on newer particle-sizing instruments uncovered evidence that LCM actually represent a colloidal "microbubble/particle" population, the vast majority of which exhibits diameters less than one micron (i.e., includes microparticles and nanoparticles). [In this discussion, the word "colloidal" is formally defined as: a state of subdivision in which the particles, droplets, or bubbles dispersed in another phase have at least one dimension between approximately 1 and 1,000 nm (-- cited from: The Language of Colloid and Interface Science, A Dictionary of Terms; by L.L. Schramm, 1993, American Chemical Soc., Wash. DC).] Based upon the above (and other related) physicochemical factors, these predominant submicron-sized LCM probably represent liquid-crystalline lipid particles, i.e., lipid mesophase nanostructures. [Note also that measurements of enthalpies and entropies associated with a transition from condensed to expanded (lipid) monolayers have been found consistent with the corresponding thermodynamic parameters associated with crystal to liquid-crystal phase (polymorphic) transitions in lamellar polymorphs, implying that the respective condensed and expanded states were analogous in the two (lipid-polymorph) structures (-- cited from: The Molecular Biology of Cell Membranes; by P.J. Quinn, 1976, Univ. Park Press, London).] Hence, the term LCM now carries an additional meaning: "liquid-crystalline microparticles", or the essentially equivalent definition "lipid-colloid mesophases".
II. Research PUBLICATIONS (bibliography, with ABSTRACTS and sample illustrations) describing CCT Pharma's LCM technology, international tradename "FilmixTM" (see added links below).
Filmix (nanoemulsion) agent, which was modeled primarily from (nanoscale and mesoscale) self-assembling film-stabilized microbubbles in natural waters, is a stable (protein-free, non-phospholipid) biomolecular composition; this lipid nanoemulsion contains specifically nonionic lipids exclusively throughout the coated microbubble's and/or related nanoparticle's (i.e., related lipid polymorphs') supramolecular structure(s). This apparently unique molecular composition of Filmix nanoemulsion agent resulted in both microbubble/nanoparticle stability and marked targeting abilities, potentially useful medically both in diagnosis and as a drug-delivery vehicle. The targeted drug delivery by such "LCM/nanoparticle-derived" nanoemulsions, to solid tumors and certain other lesions (see below), is very rapid and has been demonstrated to occur by an "active uptake" process, i.e., "endocytosis" -- which likely involves certain "lipoprotein receptor"-mediated endocytic pathways.
Specifically, animal studies utilizing confocal laser microscopy clearly demonstrate both tumor-selective [e.g., Ho et al. (1997) Neurosurgery 40:1260-1268] and brain injury-selective [e.g., Wakefield et al. (1998) Neurosurgery 42:592-598] endocytosis of "LCM/nanoparticle" agent (Filmix nanoemulsion). The measured uptake, of such targeted "LCM/nanoparticle-derived" nanoemulsions, by the above target cells can be observed as early as 2 minutes after intravenous injection [see Ho et al. (1997) and Wakefield et al. (1998) references above]. In addition, the similarity of lipid composition between LCM, LDL, oxidized LDL, acetylated LDL, HDL, and chylomicron remnant particles suggests that the Filmix nanoemulsion particles themselves can act as ligands for lipoprotein receptors (including scavenger receptors) [cf. D'Arrigo (2008) reference above; and D'Arrigo (2009) Proc. of 2009 A.A.P.S. National Biotechnology Conference, Amer. Assoc. Pharmaceutical Scientists, p. 106].
Besides many types of tumors, as well as neuro-injury sites (as cited above; [see also Kureshi et al. (1999) Neurosurgery 44:1047-1053, and Ho et al. (1997) Brain Res. Bull. 43:543-549]), there are a few other non-cancerous lesion/injury sites involving proliferative processes, such as atherosclerosis, which display overexpression of cell-surface lipoprotein receptors [D'Arrigo, 2009 (in press)].
LISTING of Research PUBLICATIONS: Categories as follows -
A) Targeted Imaging of Tumors
B) Targeted Cavitation-Therapy of Tumors
C) Targeted Drug-Delivery to Tumors
D) Targeted Drug-Delivery to Neuro-Injury Sites
E) Background Publications: Natural-Microbubble studies, and Patents
III. The "LCM/nanoparticle-derived" nanoemulsion drug-delivery system: Details of therapeutic approach for targeted-delivery of Taxol* to tumors (via "active uptake", i.e.,"receptor-mediated endocytosis").
IV.
V. Toxicological studies of the "LCM/nanoparticle" agent (Filmix® nanoemulsion).
VI. Mechanism of the markedly rapid and highly selective uptake of Filmix nanoemulsion by tumor cells (and/or neuro-injury sites): Indirect evidence for targeted drug-delivery (by "receptor-mediated endocytosis") via certain "lipoprotein receptor"-mediated endocytic pathways.
*Taxol is used in this work to refer to the drug that now has the generic name paclitaxel and the registered tradename Taxol® (Bristol-Myers Squibb Company, New York, N.Y.).
E-mail - CAVCON@ntplx.net
Business Development contact person at CCT Pharma, Inc.:
Joseph D'Arrigo, Ph.D.
LCM-technology (Filmix®) applications currently available for new business development:
A) Licensing-out of, or acquisition of, CCT Pharma's intellectual property concerning drug-delivery technology [available in fields other than cancer chemotherapy] targeting locations of certain proliferative diseases, i.e., neuro-injury sites, cardiovascular injury/disease sites, hepatitis B virus infection sites, and/or Alzheimer's lesions using "LCM/nanoparticle-derived" nanoemulsions;
B) Licensing-out of, or acquisition of, CCT Pharma's intellectual property concerning targeted cavitation-therapy and diagnostic imaging (monitoring) of solid tumors, using Filmix nanoemulsion agent.
Copyright © 2009 by CCT Pharma (a division of Cav-Con, Inc.).
All rights reserved.