I. A) Introduction to CCT PHARMA INC. (a division of Cav-Con, Inc.):
Our ongoing R&D program concerns targeted lipid nanoemulsion (microbubble/particle) technology, utilized to produce low-cost targeted supergenerics. CCT Pharma's worldwide licensing-out activities have traditionally involved mainly long-patented intellectual property. CCT Pharma also has always relied, both in the past and currently, on trade secrets and contracts to protect know-how and other non-patented, proprietary technical information.
In recent years, however, CCT Pharma has increasingly participated in an open-source drug discovery business model [e.g., Peplow (2019) Chem. Engin. News, vol. 97 (Feb. 4 issue):16-19], especially as concerns the immense (both nationally and worldwide) unmet medical need of treating cognitive impairment and late-onset dementias [D'Arrigo (2017) Medical Sciences 5(4):29; (2018a) Adv. Colloid Interface Sci. 251:44-54; (2018b) Biomimetics 3(1):4; (2018c) Geriatr. Med. Care 1(2):1-7; (2019) MDPI Preprints.org, doi: 10.20944/preprints201808.0204.v1]. CCT Pharma will rely on regulatory exclusivity, rather than patents, to ensure there is enough financial incentive for a manufacturer to make and distribute a supergeneric drug. Some drug regulators may grant companies several years of market exclusivity when they approve supergeneric drugs -- including the U.S. FDA. Note that whereas patents can be invalidated in court [and frequently are], regulatory exclusivity is rock solid; you cannot overturn it. In addition, potential competitors are more likely to work with CCT Pharma than try to scoop the firm; much of our key data is now in the public domain, so rivals cannot patent these results anyway [cf. (2019) Chem. Engin. News., vol. 97 (Feb. 4 issue), pp. 16-19].
The corporation's "active targeting" nanoemulsion formulations are produced by a proprietary method which is:
-- low-cost;
-- brief, with utter simplicity of manufacture;
-- scalable;
-- and reliable.
In addition, these parenteral lipid nanoemulsions, especially useful for "actively targeted" drug delivery, comprise several simple, nonionic,
self-assembling, lipid components that can be adjusted for specific applications.
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 and/or dyes) with them into the target cells. This LCM drug-delivery vehicle is constructed entirely of self-assembling nonionic lipids, which causes the LCM to display marked tumor-targeting abilities.
The low-cost, biobased, 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; accordingly, the LCM uptake 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 this stable, colloidal lipid population 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. Hence, the stable lipid nanoemulsion produced contains both submicron-sized "lipid-coated microbubbles" (LCM) and predominantly (LCM-related) "liquid-crystalline [micro/nano]particles".
Further concerning the physicochemical properties of the low-cost lipid components in this LCM (microbubble/nanoparticle) drug-delivery vehicle (a/k/a "Filmix®" nanoemulsion), biological lipids are known to form a variety of (lamellar and nonlamellar) liquid-crystalline structures in mixtures with water, and some of these nonlamellar lipid nanostructures tend to persist in excess water [e.g., Tanford (1973) The Hydrophobic Effect, Wiley, NY]. Moreover, as reported by various researchers in the chemical literature, such liquid-crystal phases have often been shown to form spontaneously (i.e., can represent self-assembling lipid nanoemulsions) when particular amphiphilic glycerides are placed in an aqueous environment. For example, cubic (liquid-crystal) phases are formed spontaneously when certain amphiphilic lipids, commonly monoglycerides, are placed in water. Such aqueous dispersions of these nanometer-scale cubic phases have already been investigated by various researchers as drug delivery systems [e.g., D'Arrigo (2010) Proc. of 2010 International Chemical Congress of Pacific Basin Societies (Pacifichem), sponsored jointly with American Chemical Society, Honolulu]. This particular aspect of monoglycerides is noteworthy, in the present context, since monoglycerides form the largest single-lipid fraction (by weight %) of the powdered solid lipid mixture used to produce the Filmix® nanoemulsion [cf. D'Arrigo (1993) U.S. Patent No. 5,215,680; D'Arrigo (1987) U.S. Patent No. 4,684,479]. In addition, as concerns the non-glyceride components of this "LCM/nanoparticle-derived" nanoemulsion, cholesterol and its esters change the packing structure of lipids [cf. D'Arrigo (2003) reference above] -- and in high local concentrations these cholesterol compounds have also been reported (in the literature by other investigators) to induce the formation of a liquid-crystal phase. Accordingly, the substantial proportion of cholesterol esters and cholesterol, in the "LCM/nanoparticle-derived" nanoemulsion formulation, likely further supports the known long-term stability of the liquid-crystalline lipid particles in such nanoemulsions [D'Arrigo, J.S. (2011) Stable Nanoemulsions: Self-Assembly in Nature and Nanomedicine, 436 pp.; Elsevier, Amsterdam and Oxford].
II. Research PUBLICATIONS (bibliography, with ABSTRACTS and sample illustrations) describing CCT Pharma's LCM technology for "targeted SUPERGENERICS" development, 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 low-cost stable (protein-free, non-phospholipid) biomolecular composition. This self-assembling 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; moreover, the targeting 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]. In other words, using this particular LCM/nanoparticle drug-delivery approach, the self-organizing "lipid particle" structure itself (upon injection of the Filmix nanoemulsion vehicle into the bloodstream) is apparently successfully utilized as the "active" targeting ligand -- which is directed via adsorbed plasma lipoproteins toward the appropriate receptors on the target-cell surface.
In addition, approximately 70% of the total measured LCM (including agglomerations of the far more numerous and smallest submicron, dispersed, liquid-crystalline lipid particles [previously undetected]) internalized by C6-tumor cells were found to be associated with acidic compartments -- which comprise endosomes and/or lysosomes. The rapid uptake of LCM by target cells displays both temperature dependence and energy dependence. These cell-culture data, similar to the in vivo data (see above), further confirmed that C6-tumor cells take up LCM via an endocytic pathway [cf. D'Arrigo (2003) reference above; and Barbarese et al. (1995) J. Neuro-Oncology 26:25-34].
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, e.g., atherosclerosis. Such hyperproliferative-disease sites commonly display overexpression of cell-surface lipoprotein receptors -- and particularly scavenger receptors. In accord with all the above findings, recent publications by several research groups have indicated that scavenger receptors represent an attractive molecular target for anti-atherosclerosis therapy. Therefore, the scope of potential clinical trials, which are applicable to the pharmaceutical category referred to as "LCM/nanoparticle-derived" lipid nanoemulsions, can now include the "actively targeted" chemotherapy of hyperproliferative diseases, for example, atherosclerosis and CNS-injury sites [cf. D'Arrigo (2009) AAPS Journal 11(S1):000246; see also D'Arrigo (2011) reference above].
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
F. Latest Studies: Filmix® lipid nanoemulsion agent
III. The "LCM/nanoparticle-derived" nanoemulsion drug-delivery system: Early stage details of therapeutic approach for
targeted-delivery of Taxol* to tumors
(via "active uptake", i.e.,"receptor-mediated endocytosis").
[*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.).]
IV.
V. TOXICOLOGICAL studies (conducted earlier) of the "LCM/nanoparticle" agent (Filmix® nanoemulsion).
VI. Mechanism (i.e., prototypical) of the markedly rapid and highly selective uptake of Filmix nanoemulsion by TUMOR cells: Indirect evidence for targeted drug-delivery (by "receptor-mediated endocytosis") via certain "lipoprotein receptor"-mediated endocytic pathways.
VII. Mechanism (synopsis) of selective identification, treating, and monitoring of NEUROINFLAMMATION and BRAIN INJURIES using Filmix nanoemulsion agent.
VIII. Targeting ALZHEIMER'S Therapy in Human Brain (under study) using lipid nanoemulsion vehicle.
E-mail - CAVCON@ntplx.net
Business Development contact person at CCT Pharma, Inc.:
Joseph D'Arrigo, Ph.D.
As a privately-held biotechnology company, Cav-Con Inc. (which includes it's main division, CCT Pharma) neither has nor is offering any
publicly-traded stock for sale to the general public. Also, Cav-Con Inc. is not a nonprofit entity and cannot accept any such donations.
Instead, Cav-Con Inc. is an R&D corporation, originally organized (1988) and continuously registered in State of Connecticut (USA), that conducts
worldwide licensing-out activities concerning its own R&D-related intellectual property.
LCM-technology (Filmix®) applications currently available for new business development:
A) Licensing-out of CCT Pharma's confidential intellectual property concerning DRUG-DELIVERY technology [available worldwide in fields other than cancer chemotherapy] TARGETING locations of certain hyperproliferative and/or inflammatory diseases, such as neuro-injury and neuroinflammation sites and/or cardiovascular injury/disease sites, using "LCM/nanoparticle-derived" nanoemulsions;
B) Licensing-out of CCT Pharma's confidential intellectual property concerning targeted IMAGING, of solid tumors and selected hyperproliferative-disease and/or neuroinflammation sites, using Filmix nanoemulsion agent.
Copyright © 2009-2020 by CCT Pharma (a division of Cav-Con, Inc.).
All rights reserved.