Unagglomerated core/shell nanocomposite particles - Patents

Unagglomerated core/shell nanocomposite particles

Agent: The Webb Law Firm, P.C. - Pittsburgh, PA, US
Inventors: James H. Adair, Sarah M. Rouse, Jun Wang, Mark Kester, Christopher Siedlecki, William B. White, Erwin Vogler, Alan Snyder, Carlo G. Pantano, Victor Ruiz-Velasco, Lawrence Sinoway
Class: 424489000 (USPTO), A61K009/14 (Intl Class)
#20050281884
12/22/05
The present invention provides a method for the synthesis of unagglomerated, highly dispersed, stable core/shell nanocomposite particles comprised of preparing a reverse micelle microemulsion that contains nanocomposite particles, treating the microemulsion with a silane coupling agent, breaking the microemulsion to form a suspension of the nanocomposite particles by adding an acid/alcohol solution to the microemulsion that maintains the suspension of nanocomposite particles at a pH of between about 6 and 7, and simultaneously washing and dispersing the suspension of nanocomposite particles, preferably with a size exclusion HPLC system modified to ensure unagglomeration of the nanocomposite particles. The primary particle size of the nanocomposite particles can range in diameter from between about 1 to 100 nm, preferably from between about 10 to 50 nm, more preferably about 10 to 20 nm, and most preferably about 20 nm.
[0002] 1. Field of the Invention
[0003] The present invention relates to nanocomposite particles. More particularly, the present invention provides a method for synthesizing stable, well dispersed, unagglomerated core/shell nanocomposite particles of varying sizes that may be used for a wide variety of applications.
SUMMARY OF THE INVENTION
[0013] The present invention provides methods for the preparation of stable, unagglomerated, well dispersed, active-medical-agent core/shell nanocomposite particles having silane coupling agents such as but not limited to alkylamine or alkylcarboxylic acid silane coupling agents attached. A detailed discussion of the graft mechanism has been described elsewhere (Plueddemann, E. P., "Silane coupling agent," pp 29-48, Plenum Press, NY, 1982; Ung, T. et al., Langmuir, 14:3740-3748, 1998; Chiang, C. H., et al., J. Colloid Interface Sci., 74(2):396-403, 1980; Chiang, C. H. et al., J. Colloid Interface Sci., 86(1):26-34, 1982). The dispersion of the nanocomposites is achieved preferably by using high performance liquid chromatography (HPLC) to simultaneously wash and disperse the nanocomposite particles, in place of other techniques that involve sequential washing and dispersal steps.
[0014] The present invention also provides for the preparation of stable, dispersed nanocomposite particles to be used in vivo under physiological conditions, i.e. isotonic environment, by surface modification such as a carbodiimide-mediated polyethylene glycol (PEG) coupling agent to the silane coupling agent, which maintains their dispersed state. Other surface modification methods include dendrimers, amphiphilic agents, and charged adsorbates such as citrate as is known in the art. The present invention further provides for the attachment of binders, such as antibodies, thus enabling the nanocomposite particles to target specific sites for intracellular drug delivery.
[0015] The nanocomposite particles can include a variety of medically-active substances, such as organic fluorophores and therapeutic drugs, doped inside silica, titania, calcium phosphate or calcium phospho-silicate matrices. The synthesis techniques also can be modified to produce nanoparticles containing combinations of fluorophores and therapeutic medicinal agents. The intended biomedical application for the colloid of nanocomposite particles dictates the selection of core and shell-matrix materials.
[0016] The stable, well dispersed and unagglomerated active-medical-agent nanoparticles can be used for a variety of applications, such as, without limitation, pigments, fluorescent labeling, inks, slow release formulations, bioimaging, drug delivery, gene therapy and combinations thereof. For example, and within limitation, the nanoparticles of the present invention can be used as calcium deposition transporters, for medical diagnosis, and for medical therapeutics for cancer, infectious diseases, diabetes, cystic fibrosis and other diseases and disorders.
[0017] The fluorescent nanocomposite particles possess several qualities that make them particularly attractive for imaging and pigment applications, such as precise tunability of emission peaks, extended fluorescence lifetimes relative to traditional organic fluorophores, negligible photobleaching and self-quenching with the benefit of biocompatibility. Additionally, the nanoparticulate fluorescent emissions are not intermittent. Within the nanoparticle, direct contact between dye molecules and the environment is avoided, eliminating photodegradation of the fluorophore presumably because of absorption of the most energetic, and therefore, damaging of the excitation photons. As a result, the nanocomposite particles exhibit extended fluorescence lifetimes relative to traditional organic fluorophores or quantum dots as shown in FIGS. 3 through 5.
[0018] Nanocomposite particles can be used as a drug delivery system based on the encapsulation of a therapeutic agent in either a metal oxide shell with controlled porosity and/or a soluble outer shell/coating that on dissolution releases the therapeutic agent in the immediate vicinity of the afflicted area as shown in FIGS. 6 through 9. The protection of the therapeutic agent provided by the shell-matrix material allows for the delivery of drugs that are highly water-insoluble or unstable in physiological solutions. Furthermore, dissolution kinetics of the shell-matrix materials can be engineered to provide sustained release of therapeutic agents at target sites for extended periods of time.
[0019] The nanocomposite suspensions can also be used to deliver drugs including, but not limited to, ceramide, AZT, and dobutamine. Insulin can also be encapsulated in a soluble shell material such as calcium phosphate or calcium phospho-silicate. The surface can be modified to permit the nanocomposite particles to cross physiological membranes such as the gastro-intestinal tract, the blood-brain barrier, and cellular membranes. The targeted, time-controlled release can be used to deliver therapeutic agents such as insulin from the core-shell nanoparticles.
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