Amphiphilic polymeric materials

Details Amphiphilic polymeric materials Amphiphilic polymeric materials

2001-09-14

2003-02-18

Boykin, Terressa M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

From carboxylic acid or derivative thereof

C424S423000, C424S448000, C424S449000, C424S499000, C424S501000

Reexamination Certificate

active

06521736

ABSTRACT:

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., Désormeaux 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:
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
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:
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

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