| From: donpat | 7/6/2005 8:09:23 PM | | | | | | United States Patent 6,521,736
Watterson, et al., February 18, 2003
From:
tinyurl.com
[Snips]
Amphiphilic polymeric materials
Abstract
The invention is based in part on the discovery of polymers that can complex with certain types of therapeutic drugs and transport those drugs across cell membranes in cell cultures with demonstrable therapeutic activity. The polymers are designed to overcome some of the known problems of liposomes as drug carriers. The polymers can be used in the development of physiologically stable, non-leaking, non-immunogenic, efficacious and safe targetable drug delivery systems (e.g., for delivery of anti-HIV or anticancer drugs).
Inventors: Watterson; Arthur C. (Nashua, NH); Danprasert; Kunya (Bangkapi, TH); Diwan; Anil (West Haven, CT)
Assignee: University of Massachusetts (Boston, MA)
Appl. No.: 952883
Filed: September 14, 2001
Description
FIELD OF THE INVENTION
This invention relates to new drug delivery vehicles, and more particularly to novel micellar amphiphilic polymers that include PEG esters.
BACKGROUND OF THE INVENTION
A large number of drugs are utilized in cancer treatment and other pharmaceutical applications. Drug delivery vehicles are needed to efficiently deliver these drugs to a variety of sites in the body, dependent on the specific disease to be treated. Given that many drugs used to treat cancer, bacterial and viral infections, and diseases such as AIDS are highly toxic and/or have other unfavorable properties such as low solubility in blood or other aqueous solutions, rapid metabolism, or uneven biodistribution, strategies aimed at reaching therapeutic levels of drugs into infected cells are needed. An ideal drug delivery system would: (i) be adaptable to a variety of therapeutic drugs to produce drug-specific vehicles, (ii) have low to zero immunogenicity, (iii) have low clearance by organismal defense mechanisms, (iv) have high stability, even when complexed with a drug, in a physiological milieu, (v) have good shelf life and stability in room temperature storage, (vi) yield only nontoxic byproducts upon metabolism, (vii) be delivered into non-lysosomal compartments, to minimize degradation of the drug, and (viii) have the potential to be targeted to a specific site.
Due to their natural uptake by various cells, the potential of liposomes to be used as drug delivery vehicles has been long recognized (see, e.g., Desormeaux et al., J. Drug Targeting, 6(1):1-15, 1998). However, the use of liposomes has also been limited by their immunogenicity, antigenicity, thrombogenicity, cell adherence, and protein absorption characteristics. Although a number of strategies have been devised to improve targeting of drugs to tumor and disease sites, a need still exists for better alternatives.
SUMMARY OF THE INVENTION
The invention is based in part on the discovery of polymers that can complex with certain types of therapeutic drugs and transport those drugs across cell membranes in cell cultures with demonstrable therapeutic activity. The polymers are designed to overcome some of the known problems of liposomes as drug carriers. The polymers can be used in the development of physiologically stable, non-leaking, non-immunogenic, efficacious and safe targetable drug delivery systems (e.g., for delivery of anti-HIV or anticancer drugs).
In general, the invention features a polymer having the structure: ##STR1##
where R is hydrogen, a linear or branched alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, or isomeric alkyl group, C8-C16 alkyls, or higher alkyl, or aralkyls such as benzyl), a linear or branched alkenyl group (e.g., ethenyl, propenyl, or higher alkenyls), or an aryl group (e.g., phenyl), where the alkyl, alkenyl, or aryl group can be either unsubstituted or substituted with one or more heteroatomic functional groups (e.g., a carboxylate group, a carboxylic acid group, an amino group, an ammonium group, an alkoxyl group, or a hydroxyl group, or other nitrogen, oxygen, or sulfur-containing groups); R' is hydrogen, folic acid, phosphatidylethanolamine, a glycolipid, an indole-containing compound, or other acyl group, antibody fragment, chemomimetic functional group, immunoconjugate, or ligand for a biological target, or ##STR2##
where R'" is a hydroxyl group, an alkoxyl group (e.g., OCH3, O-epitope), or a primary or secondary amino group (e.g., glucosamine, mannosamine, galactosamine); n is at least 1 (e.g., 1, 2, 3, 4, 5, 9, 13, 20, 34, 50, 100, 200, 500 or more); and m is at least 1 (e.g., 1, 2, 3, 4, 5, 10, 20, 50, 100, 200, 500 or more).
The invention also features a method for making the polymer. The method includes the step of reacting a dialkyl-5-hydroxy-isophthalate or a dialkyl-5-alkoxy-isophthalate with a polyethylene glycol.
Another embodiment of the invention features a polymer having the structure: ##STR3##
where R and R' are defined as above.
The invention also features a method for making this polymer. The method includes the step of reacting a dialkyl-2-hydroxymalate or a dialkyl-2-alkoxymalate with a polyethylene glycol.
The polymer can be a polymer of either of the above structures that forms micelles in aqueous or organic solutions. A solution that includes a solvent and such a polymer, wherein the polymer is present at a concentration at or above its critical micelle concentration, is also contemplated to be an aspect of the invention.
Another aspect of the invention is a method of enhancing the solubility of a compound, or of increasing the effectiveness or potency of a drug. The method includes the step of complexing the compound or drug with either of the above polymers to render the compound more soluble, effective, or potent. Where the polymer has a receptor ligand (e.g., an antibody or antigen fragment such as Fab or Fab2'; or RGD or an RGD-mimic) recognized by a particular cell type, covalently attached to it (e.g., at position R'), the invention also features a method of targeting a drug to a particular cell type.
The invention also features a composition that includes a complex of either of the above polymers and a drug. The composition can also include an aqueous or organic solution, in which the polymer/drug combination is soluble. The drug can be, for example, a steroid, an anticancer drug, an antibiotic drug, or an antiviral drug. Thus, for example, the drug can be camptothecin, etoposide, zidovudine (AZT), didanosine (ddl), nevirapine, delavirdine, nelfinavir, saquinavir, neomycin, kazugamycin, thorstrepton, erythromycin, taxol, betulinic acid, doxorubicin, or carmustine.
The invention also features a method of administering a drug to a patient (e.g., a patient having a disease such as cancer, cystic fibrosis, an HIV infection, or other bacterial or viral infection. The method includes the step of administering to the patient an effective amount of the composition, together with a suitable excipient.
Yet another aspect of the invention features a gene delivery vehicle that includes a gene or nucleic acid complexed with either of the above polymers. Optionally, an adjuvant can be added to the vehicle.
The invention provides several advantages. For example, the polyethylene glycol (PEG) grafted surfaces of the new polymers improve their long-term stability in plasma, and reduce their immunogenicity, antigenicity, thrombogenicity, cell adherence, and protein absorptivity. The new polymers have many of the advantages associated with liposomes, but share few of their disadvantages. Like liposomes, the new polymers have a spherical micellar structure that mimics the structure of cell membranes. The new polymers can also carry water- or lipid-soluble drugs at a higher drug-loading capacity than is generally possible by conjugation of the drug to a single polymer chain.
The new polymers can form conjugates with natural small molecules to target specific sites. The polymers' molecular structure can be systematically varied to produce a range of well-defined polymeric structures, for example, to result in a range of hydrophilic, hydrophobic, and complexing properties. Thus, numerous closely related structures can be prepared, each having properties optimized for individual drugs rather than having a general structure that would be useful for some drugs but not for others. The new drug delivery systems are, therefore, adaptable to particular drugs, avoiding the need for drugs to be adapted to a particular liposome preparation.
Preparations including the new polymers can provide high therapeutic efficacy at relatively low dosages, thereby reducing toxicity. The new polymers are particularly beneficial for delivery of highly toxic drugs such as anti-HIV drugs. Complexes of the new polymers with antiviral drugs, for example, can decrease the drugs' IC50 (i.e., the drug concentration required to produce 50% inhibition of virus production by a cell line) by 10- to 150-fold or more. Additionally, the long-lived micellar formulations can permit maintenance of therapeutic concentrations with less frequent dosing.
The new polymers also allow delivery of the multiple drug components of a multi-drug therapeutic system (e.g., highly active anti-retroviral therapy, "HAART") in a single delivery vehicle. Alternatively, the combinations of the new polymers can be used, each optimal for one or more components of a multi-drug regimen.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. |
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| From: archimedest | 7/12/2005 9:59:20 AM | | | | | | | Anyone have a target price? I am looking for a least a dollar but it may take a year or so. With this management team and advisory board, I am betting that they will have some deals with the big boys. |
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| To: archimedest who wrote (5) | 7/12/2005 12:41:30 PM | | From: jmhollen | | | | No target price, but I think I'll join you in the Long department today or tomorrow.
Nano is definitely where it's at. Also, suggest you look at NNGY soon.
John :-)
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| To: archimedest who wrote (5) | 7/12/2005 3:14:03 PM | | From: donpat | | | | Re 'the big boys'
I agree!
First they must do the heavy thinking to perfect this development. Once they iron out the wrinkles with a few proofs of concept, I expect we will be trading well north of $1 if not north of $100.
I'm optimistic.
Nano is the future in so many ways.
Bio will be the foremost user, IMHO. |
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| From: canbballtrader | 7/13/2005 11:05:47 AM | | | | | | | News on financing is out. Convertible debentures. Looks like the company is on its way to legitimacy with a pending IND filing after the preclinical work. Does anyone know the amount of the financing? I would like to figure out the dilution impact via interest payments on shares. |
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| To: canbballtrader who wrote (9) | 7/13/2005 11:07:49 AM | | From: jmhollen | | | | NanoViricides Announces Terms of Series A Convertible Debentures and Receives Partial Funding
NEW YORK, Jul 13, 2005 (BUSINESS WIRE) -- NanoViricides, Inc. (Pink
Sheets:NNVC)(the "Company"), announced today the terms of its Series A
Convertible Debenture offered to select Institutional and Accredited Investors.
The Debentures are to be repaid on the first anniversary, with interest at the
rate of nine percent, which shall be paid quarterly in shares of the Company's
common stock equal to the average closing price for the preceding fifteen
trading days prior to the close of the respective quarterly period. The
principal balance of the Debentures may be repaid, at the holders' option, in
cash or a number of shares of common stock equal to seventy percent of the
average closing price of fifteen trading days prior to maturity (not to exceed
$.50 per share). The Company will have the right, but not the obligation, to
redeem the Debentures, if at maturity, the holders' conversion price is less
than $0.25 at the time of conversion. Any Debentures redeemed by the Company
shall be paid in immediately available funds with interest at the rate of
fifteen percent. If the Company registers any securities for public resale,
holders who purchased Debentures will have the right to include any shares of
common stock in the offering in such registration.
This press release does not constitute an offer or solicitation to sell or
purchase any of the Company's securities. Any of the Company's securities
offered will not be registered under the Securities Act of 1933, as amended (the
"Securities Act"), and may not be offered or sold in the United States unless
registered under the Securities Act upon applicable exemptions from registration
under the Securities Act.
Eugene Seymour, MD, CEO, said, "The financing, when completed, is anticipated to
be sufficient to allow the Company to complete its HIV drug Hivicide 1(TM)
preclinical work, and bring it to the point of applying for an IND with the Food
and Drug Administration."
About NanoViricides - nanoviricides.com
NanoViricides, Inc. is a development stage company that is creating special
purpose nanomaterials for viral therapy. NanoViricides, Inc. has exclusive
license in perpetuity for technologies developed by Theracour Pharma for the
five virus types - HIV, HCV, Herpes, Asian (bird) flu and Influenza. A
NanoViricide(TM) is a nanoparticle that contains an encapsulated active
pharmaceutical ingredient and targets it to a specific type of virus. When a
NanoViricide(TM) drug particle enters the patient's blood stream, it attacks and
immobilizes circulating virus particles. Once this is done, the active
pharmaceutical ingredient is injected into the virus by the NanoViricide(TM)
particle, destroying it. The company plans to develop novel NanoViricide(TM)
drugs first against HIV, and anticipates that in 2006, it will license the
products to major pharmaceutical companies.
SOURCE: NanoViricides, Inc.
CONTACT: NanoViricides, Inc., New York
Leo Ehrlich, 917-853-6440
leo@nanoviricides.com
or
Anil R. Diwan, Ph.D.
adiwan@snet.net
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| To: jmhollen who wrote (10) | 7/13/2005 11:24:54 AM | | From: jmhollen | | | | I hate freakin' Debentures, but this one doesn't come across as one of the Pangia-tyyle Death-Spiral screw jobs; and they can pay it off in advance if revenues are strong.
If someone reads it differently, please let me know.
John :-)
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| From: donpat | 7/14/2005 11:47:35 AM | | | | | | Dr. John Rossi, Holder of 14 Key Patents, and Author of over 275 Scientific Articles, Joins NanoViricides, Inc. Scientific Advisory Board
Thursday July 14, 9:33 am ET
"Widely Regarded as a World Leader in Clinical Research for the Treatment of HIV/AIDS and in the Development of Therapeutic Applications of RNA Interference"
NEW YORK--(BUSINESS WIRE)--July 14, 2005-- NanoViricides, Inc. (Pink Sheets:NNVC - News), announced today that Dr. John Rossi, Chairman and Professor, Division of Molecular Biology, Beckman Research Institute and Dean, Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA
cityofhope.org
has joined the NanoViricides, Inc. Scientific Advisory Board.
City of Hope is a Comprehensive Cancer Center dedicated to the prevention and cure of cancer, HIV/AIDS, diabetes, and other life-threatening diseases.
"Dr. Rossi is a wonderful addition to our Scientific Advisory Board. He brings almost twenty five years of basic HIV research experience to our company. He is on the editorial boards of numerous science journals including Antisense Research and Development, Gene Therapy and Molecular Biology and Molecular Therapy, and has extensive experience in many critical areas that will help us develop true HIV killing nanomachines," said Eugene Seymour, MD, Chief Executive Officer of NanoViricides, Inc.
"Dr. Rossi has great expertise in the clinical aspects as well as in the HIV genome silencing aspects which are areas of special interest to NanoViricides. His active involvement as our scientific advisor will accelerate our development programs particularly for our second generation anti-HIV drugs and other nanoviricides," said Dr. Diwan, President of NanoViricides, Inc. and inventor of the underlying technology.
In addition to his responsibilities at the City of Hope, he is also Adjunct Professor, Division of Biomedical Sciences, University of California, Riverside, CA, as well as Adjunct Professor, Department of Biochemistry and Microbiology, Loma Linda University, CA.
Dr. Rossi received his PhD in microbial genetics from the University of Connecticut. His post-doctoral fellowship was at Brown University in Providence, RI.
About NanoViricides - nanoviricides.com
NanoViricides, Inc. is a development stage company that is creating special purpose nanomaterials for viral therapy. NanoViricides, Inc. has exclusive license in perpetuity for technologies developed by Theracour Pharma for the five virus types: HIV, HCV, Herpes, Asian (bird) flu and Influenza. A NanoViricide(TM) is a nanoparticle that contains an encapsulated active pharmaceutical ingredient and targets it to a specific type of virus. When a NanoViricide(TM) drug particle enters the patient's blood stream, it attacks and immobilizes circulating virus particles. Once this is done, the active pharmaceutical ingredient is injected into the virus by the NanoViricide(TM) particle, destroying it. The company plans to develop novel NanoViricide(TM) drugs first against HIV, and anticipates that it will license the products to major pharmaceutical companies.
Contact:
NanoViricides, Inc., New York
Leo Ehrlich, 917-853-6440
leo@nanoviricides.com
or
Anil R. Diwan, Ph.D.
adiwan@snet.net
Source: NanoViricides, Inc.
biz.yahoo.com |
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