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United States Patent 6,759,431
Hunter ,   et al. July 6, 2004
Compositions and methods for treating or preventing diseases of body passageways


Abstract

The present invention provides methods for treating or preventing diseases associated with body passageways, comprising the step of delivering to an external portion of the body passageway a therapeutic agent. Representative examples of therapeutic agents include anti-angiogenic factors, anti-proliferative agents, anti-inflammatory agents, and antibiotics.

Inventors: Hunter; William L. (Vancouver, CA); Machan; Lindsay S. (Vancouver, CA)
Assignee: Angiotech Pharmaceuticals, Inc. (Vancouver, CA)
The University of British Columbia (Vancouver, CA)
Appl. No.: 09/933,652
Filed: August 20, 2001

Current U.S. Class: 514/449 ; 424/403; 424/426; 424/501
Field of Search: 514/449,824 424/501,426,423

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Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Seed Intellectual Property Law Group, PLLC
Parent Case Text


CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No. 08/653,207, filed May 24, 1996, now abandoned, which application is incorporated herein by reference in its entirety.
Claims


We claim:

1. A method for treating or preventing vascular diseases associated with body passageways, comprising delivering to an external portion of the body passageway paclitaxel, or an analogue or derivative thereof.

2. A method for treating or preventing vascular diseases associated with body passageways, comprising delivering to smooth muscle cells via the adventia of the body passageway a composition comprising paclitaxel, or an analogue or derivative thereof.

3. The method according to claim 1 or 2 wherein the paclitaxel, or analogue or derivative thereof further comprises a polymer.

4. The method according to claim 3 wherein the polymer comprises microspheres having an average size ranging from about 0.5 mm to 200 mm.

5. The method according to claim 3 wherein the polymer is a copolymer of lactic acid and glycolic acid.

6. The method according to claim 3 wherein the polymer is poly (caprolactone).

7. The method according to claim 3 wherein the polymer is poly (lactic acid).

8. The method according to claim 3 wherein the polymer is a copolymer of poly (lactic acid) and poly (caprolactone).

9. The method according to claim 3 wherein the polymer is poly(ethylene-vinyl acetate).

10. The method according to claim 3 wherein the polymer is gelatin.

11. The method according to claim 1 or 2 wherein the body passageway is an artery.

12. The method according to claim 1 or 2 wherein the paclitaxel, or analogue or derivative thereof is delivered to an artery via an outer wall of the artery into an adventia.

13. The method according to claim 1 or 2 wherein the vascular disease is stenosis.

14. The method according to claim 1 or 2 wherein the vascular disease is restenosis.

15. The method according to claim 1 or 2 wherein the vascular disease is atherosclerosis.

16. The method according to claim 1 or 2 wherein the body passageway is a vein.

17. The method according to claim 1 or 2 wherein the body passageway is a capillary.

18. The method according to claim 1 wherein the body passageway is an artery.

19. The method according to claim 11 wherein the artery is a coronary artery.

20. The method according to claim 11 wherein the artery is a carotid artery or an aorta.

21. A method for treating or preventing disease associated with graft anastomosis, comprising delivering to an external portion of the site of graft anastomosis paclitaxel, or an analogue or derivative thereof.

22. The method according to claim 21 wherein said paclitaxel, or analogue or derivative thereof further comprises a polymer.

23. The method according to claim 22 wherein the polymer is a copolymer of lactic acid and glycolic acid.

24. The method according to claim 22 wherein the polymer is poly (caprolactone).

25. The method according to claim 22 wherein the polymer is poly (lactic acid).

26. The method according to claim 22 wherein the polymer is a copolymer of poly (lactic acid) and poly (caprolactone).

27. The method according to claim 22 wherein the polymer is poly(ethylene-vinyl acetate).

28. The method according to claim 22 wherein the polymer comprises microspheres having an average size ranging from about 0.5 mm to 200 mm.

29. The method according to claim 22 wherein the polymer is in the form of a paste, film, or spray.

30. The method according to claim 21 or 22 wherein the graft is a PTFE graft.

31. The method according to claims 1, 2, or 21 wherein the paclitaxel, or an analogue or derivative thereof is paclitaxel.
Description


TECHNICAL FIELD

The present invention relates generally to compositions and methods for treating or preventing diseases of body passageways, and more specifically, to compositions comprising therapeutic agents which may be delivered to the external walls of body passageways.

BACKGROUND OF THE INVENTION

There are many passageways within the body which allow the flow of essential materials. These include, for example, arteries and veins, the esophagus, stomach, small and large intestine, biliary tract, ureter, bladder, urethra, nasal passageways, trachea and other airways, and the male and female reproductive tract. Injury, various surgical procedures, or disease can result in the narrowing, weakening and/or obstruction of such body passageways, resulting in serious complications and/or even death.

For example, many types of tumors (both benign and malignant) can result in damage to the wall of a body passageway or obstruction of the lumen, thereby slowing or preventing the flow of materials through the passageway. In 1996 alone, it has been estimated that over 11,200 deaths will occur due to esophageal cancer, over 51,000 deaths due to large and small intestine cancer and nearly 17,000 deaths due to rectal cancer in the United States. Obstruction in body passageways that are affected by cancer are not only in and of themselves life-threatening, they also limit the quality of a patient's life.

The primary treatment for the majority of tumors which cause neoplastic obstruction is surgical removal and/or chemotherapy, radiation therapy or laser therapy. Unfortunately, by the time a tumor causes an obstruction in a body passageway it is frequently inoperable and generally will not responded to traditional therapies. One approach to this problem has been the insertion of endoluminal stents. Briefly, stents are devices placed into the lumen of a body passageway to physically hold open a passageway that has been blocked by a tumor or other tissues/substances. Representative examples of commonly deployed stents include the Wallstent, Stecker stent, Gianturco stent and Palmaz stent (see e.g., U.S. Pat. Nos. 5,102,417, 5,195,984, 5,176,626, 5,147,370, 5,141,516, 4,776,337). A significant drawback however to the use of stents in neoplastic obstruction is that the tumor is often able to grow into the lumen through the interstices of the stent. In addition, the presence of a stent in the lumen can induce the ingrowth of reactive or inflammatory tissue (e.g., blood vessels, fibroblasts and white blood cells) onto the surface of the stent. If this ingrowth (composed of tumor cells and/or inflammatory cells) reaches the inner surface of the stent and compromises the lumen, the result is re-blockage of the body passageway which the stent was inserted to correct.

Other diseases, which although not neoplastic nevertheless involve proliferation, can likewise obstruct body passageways. For example, narrowing of the prostatic urethra due to benign prostatic hyperplasia is a serious problem affecting 60% of all men over the age of 60 years of age and 100% of all men over the age of 80 years of age. Present pharmacological treatments, such as 5-alphareductase inhibitors (e.g., Finasteride), or alpha-adrenergic blockers (e.g., Terazozan) are generally only effective in a limited population of patients.

Moreover, of the surgical procedures that can be performed (e.g., trans-urethral resection of the prostate (TURPs); open prostatectomy, or endo-urologic procedures such as laser prostatectomy, use of microwaves, hypothermia, cryosurgery or stenting), numerous complications such as bleeding, infection, incontinence, impotence, and recurrent disease, typically result.

In addition to neoplastic or proliferative diseases, other diseases such vascular disease can result in the narrowing, weakening and/or obstruction of body passageways. According to 1993 estimates (source-U.S. Heart and Stroke Foundation homepage), over 60 million Americans have one or more forms of cardiovascular disease. These diseases claimed 954,138 lives in the same year (41% of all deaths in the United States).

Balloon angioplasty (with or without stenting) is one of the most widely used treatments for vascular disease; other options such as laser angioplasty are also available. While this is the treatment of choice in many cases of severe narrowing of the vasculature, about one-third of patients undergoing balloon angioplasty (source Heart and Stoke Foundation homepage) have renewed narrowing of the treated arteries (restenosis) within 6 months of the initial procedure; often serious enough to necessitate further interventions.

Such vascular diseases (including for example, restenosis) are due at least in part to intimal thickening secondary to vascular smooth muscle cell (VSMC) migration, VSMC proliferation, and extra-cellular matrix deposition. Briefly, vascular endothelium acts as a nonthrombogenic surface over which blood can flow smoothly and as a barrier which separates the blood components from the tissues comprising the vessel wall. Endothelial cells also release heparin sulphate, prostacyclin, EDRF and other factors that inhibit platelet and white cell adhesion,VSMC contraction, VSMC migration and VSMC proliferation. Any loss or damage to the endothelium, such as occurs during balloon angioplasty, atherectomy, or stent insertion, can result in platelet adhesion, platelet aggregation and thrombus formation. Activated platelets can release substances that produce vasoconstriction (serotonin and thromboxane) and/or promote VSMC migration and proliferation (PDGF, epidermal growth factor, TGF-.beta., and heparinase). Tissue factors released by the arteries stimulates clot formation resulting in a fibrin matrix into which smooth muscle cells can migrate and proliferate.

This cascade of events leads to the transformation of vascular smooth muscle cells from a contractile to a secretory phenotype. Angioplasty induced cell lysis and matrix destruction results in local release of basic fibroblast growth factor (bFGF) which in turn stimulates VSMC proliferation directly and indirectly through the induction of PDGF production. In addition to PDGF and bFGF, VSMC proliferation is also stimulated by platelet released EGF and insulin growth factor -1.

Vascular smooth muscle cells are also induced to migrate into the media and intima of the vessel. This is enabled by release and activation of matrix metalloproteases which degrade a pathway for the VSMC through the extra-cellular matrix and internal elastic lamina of the vessel wall. After migration and proliferation the vascular smooth muscle cells then deposit an extra-cellular matrix consisting of gylcosaminoglycans, elastin and collagen which comprises the largest part of intimal thickening. A significant portion of the restenosis process may be due to remodeling of the vascular wall leading to changes in the overall size of the artery; at least some of which is secondary to proliferation within the adventitia (in addition to the media). The net result of these processes is a recurrence of the narrowing of the vascular wall which is often severe enough to require a repeat intervention.

In summary, virtually any forceful manipulation within the lumen of a blood vessel will damage or denude its endothelial lining. Thus, treatment options for vascular diseases themselves and for restenosis following therapeutic interventions continue to be major problems with respect to longterm outcomes for such conditions.

In addition to neoplastic obstructions and vascular disease, there are also a number of acute and chronic inflammatory diseases which result in obstructions of body passages. These include, for example, vasculitis, gastrointestinal tract diseases (e.g. Crohn's disease, ulcerative colitis) and respiratory tract diseases (e.g. asthma, chronic obstructive pulmonary disease).

Each of these diseases can be treated, to varying degrees of success, with medications such as anti-inflammatories or immunosuppressants. Current regimens however are often ineffective at slowing the progression of disease, and can result in systemic toxicity and undesirable side effects. Surgcal procedures can also be utilized instead of or in addition to medication regimens. Such surgical procedures however have a high rate of local recurrence to due to scar formation, and can under certain conditions (e.g., through the use of balloon catheters), result in benign reactive overgrowth.

Other diseases that can also obstruct body passageways include infectious diseases. Briefly, there are a number of acute and chronic infectious processes that can result in the obstruction of body passageways including for example, urethritis, prostatitis and other diseases of the male reproductive tract, various diseases of the female reproductive tract, cystitis and urethritis (diseases of the urinary tract), chronic bronchitis, tuberculosis and other mycobacteria infections and other respiratory problems and certain cardiovascular diseases.

Such diseases are presently treated either by a variety of different therapeutic regimens and/or by surgical procedures. As above however, such therapeutic regimens have the difficulty of associated systemic toxicity that can result in undesired side effects. In addition, as discussed above surgical procedures can result in local recurrence due to scar formation, and in certain procedures (e.g., insertion of commercially available stents), may result in benign reactive overgrowth.

The existing treatments for the above diseases and conditions for the most part share the same limitations. The use of therapeutic agents have not resulted in the reversal of these conditions and whenever an intervention is used to treat the conditions, there is a risk to the patient as a result of the body's response to the intervention. The present invention provides compositions and methods suitable for treating the conditions and diseases which are generally discussed above. These compositions and methods address the problems associated with the existing procedures, offer significant advantages when compared to existing procedures, and in addition, provide other, related advantages.

SUMMARY OF THE INVENTION

Briefly stated, the present invention provides methods for treating or preventing diseases associated with body passageways, comprising the step of delivering to an external portion of the body passageway a therapeutic agent. Within a related aspect, methods for treating or preventing diseases associated with body passageways are provided comprising the step of delivering to smooth muscle cells of said body passageway, via the adventia, a therapeutic agent. By delivering the therapeutic compound locally to the site of disease, systemic and unwanted side effects can be avoided and total dosages can potentially be reduced. Delivery quadrantically or circumferentially around diseased passageway also avoids many of the disadvantages of endoluminal manipulation, including damage to the epithelial lining of the tissue. For example damage to the endothelium can result in thrombosis, changes to laminar flow patterns, and/or a foreign body reaction to an endoluminal device, any of which can initiate the restenosis cascade. In the case of prostatic disease, avoiding instrumentation of the urethra can reduce the likelihood of strictures and preserve continence and potency.

A wide variety of therapeutic agents may be utilized within the scope of the present invention, including for example anti-angiogenic agents, anti-proliferative agents, anti-inflammatory agents, and antibiotics.

Within certain embodiments of the invention, the therapeutic agents may further comprise a carrier (either polymeric or non-polymeric), such as, for example, poly(ethylene-vinyl acetate) (40% crosslinked), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (lactic acid), copolymers of poly (lactic acid) and poly (caprolactone), gelatin, hyaluronic acid, collagen matrices, and albumen.

The therapeutic agents may be utilized to treat or prevent a wide variety of diseases, including for example, vascular diseases, neoplastic obstructions, inflammatory diseases and infectious diseases. Representative body passageways which may be treated include, for example, arteries, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, lacrimal ducts, the trachea, bronchi, bronchioles, nasal airways, eustachian tubes, the external auditory canal, uterus and fallopian tubes.

Within one particularly preferred embodiment of the invention, the therapeutic agent is delivered to an artery by direct injection via an outer wall of the artery into the adventia.

These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth below which describe in more detail certain procedures, devices or compositions, and are therefore incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which shows the effect of plasma opsonization of polymeric microspheres on the chemiluminescence response of neutrophils (20 mg/ml microspheres in 0.5 ml of cells (conc. 5.times.10.sup.6 cells/ml) to PCL microspheres.

FIG. 2 is a graph which shows the effect of precoating plasma +/-2% pluronic F127 on the chemiluminescence response of neutrophils (5.times.10.sup.6 cells/ml) to PCL microspheres

FIG. 3 is a graph which shows the effect of precoating plasma +/-2% pluronic F127 on the chemiluminescence response of neutrophils (5.times.10.sup.6 cells/ml) to PMMA microspheres

FIG. 4 is a graph which shows the effect of precoating plasma +/-2% pluronic F127 on the chemiluminescence response of neutrophils (5.times.10.sup.6 cells/ml) to PLA microspheres

FIG. 5 is a graph which shows the effect of precoating plasma +/-2% pluronic F127 on the chemiluminescence response of neutrophils (5.times.10.sup.6 cells/ml) to EVA:PLA microspheres

FIG. 6 is a graph which shows the effect of precoating IgG (2 mg/ml), or 2% pluronic F127 then IgG (2 mg/ml) on the chemiluminescence response of neutrophils to PCL microspheres.

FIG. 7 is a graph which shows the effect of precoating IgG (2 mg/ml), or 2% pluronic F127 then IgG (2 mg/ml) on the chemiluminescence response of neutrophils to PMMA microspheres.

FIG. 8 is a graph which shows the effect of precoating IgG (2 mg/ml), or 2% pluronic F127 then IgG (2 mg/ml) on the chemiluminescence response of neutrophils to PVA microspheres.

FIG. 9 is a graph which shows the effect of precoating IgG (2 mg/ml), or 2% pluronic F127 then IgG (2 mg/ml) on the chemiluminescence response of neutrophils to EVA:PLA microspheres.

FIG. 10A is a graph which shows the effect of the EVA:PLA polymer blend ratio upon aggregation of microspheres. FIG. 10B is a scanning electron micrograph which shows the size of "small" microspheres. FIG. 10C (which includes a magnified inset--labelled "10C-inset") is a scanning electron micrograph which shows the size of "large" microspheres. FIG. 10D is a graph which depicts the time course of in vitro paclitaxel release from 0.6% w/v paclitaxel-loaded 50:50 EVA:PLA polymer blend microspheres into phosphate buffered saline (pH 7.4) at 37.degree. C. Open circles are "small" sized microspheres, and closed circles are "large" sized microspheres. FIG. 10E is a photograph of a CAM which shows the results of paclitaxel release by microspheres ("MS"). FIG. 10F is a photograph similar to that of 10E at increased magnification.

FIG. 11A is a graph which shows release rate profiles from polycaprolactone microspheres containing 1%, 2%, 5% or 10% paclitaxel into phosphate buffered saline at 37.degree. C. FIG. 11B is a photograph which shows a CAM treated with control microspheres. FIG. 11C is a photograph which shows a CAM treated with 5% paclitaxel loaded microspheres.

FIGS. 12A and 12B, respectively, are two graphs which show the release of paclitaxel from EVA films, and the percent paclitaxel remaining in those same films over time. FIG. 12C is a graph which shows the swelling of EVA/F127 films with no paclitaxel over time. FIG. 12D is a graph which shows the swelling of EVA/Span 80 films with no paclitaxel over time. FIG. 12E is a graph which depicts a stress vs. strain curve for various EVA/F127 blends.

FIGS. 13A and 13B are two graphs which show the melting point of PCL/MePEG polymer blends as a function of % MePEG in the formulation (13A), and the percent increase in time needed for PCL paste at 60.degree. C. to being to solidify as a function of the amount of MePEG in the formulation (13B). FIG. 13C is a graph which depicts the softness of varying PCL/MePEG polymer blends. FIG. 13D is a graph which shows the percent weight change over time for polymer blends of various MePEG concentrations. FIG. 13E is a graph which depicts the rate of paclitaxel release over time from various polymer blends loaded with 1% paclitaxel. FIGS. 13F and 13G are graphs which depict the effect of varying quantities of paclitaxel on the total amount of paclitaxel released from a 20% MePEG/PCL blend. FIG. 13H is a graph which depicts the effect of MePEG on the tensile strength of a MePEG/PCL polymer.

FIG. 14 is a graph which shows paclitaxel release from various polymeric formulations.

FIG. 15 is a graph which depicts, over a time course the release of paclitaxel from PCL pastes into PBS at 37.degree. C. The PCL pastes contain microparticles of paclitaxel and various additives prepared using mesh #140. The error bars represent the standard deviation of 3 samples.

FIG. 16 is a graph which depicts time courses of paclitaxel release from paclitaxel-gelatin-PCL pastes into PBS at 37.degree. C. This graph shows the effects of gelatin concentration (mesh #140) and the size of paclitaxel-gelatin (1:1) microparticles prepared using mesh #140 or mesh #60. The error bars represent the standard deviation of 3 samples.

FIGS. 17A and 17B are graphs which depict the effect of additives (17A; mesh #140) and the size of microparticles (17B; mesh #140 or #60) and the proportion of the additive (mesh #140) on the swelling behavior of PCL pastes containing 20% paclitaxel following suspension in distilled water at 37.degree. C. Measurements for the paste prepared with 270 .mu.m microparticles in paclitaxel-gelatin and paste containing 30% gelatin were discontinued after 4 hours due to disintegration of the matrix. The error bars represent the standard deviation of 3 samples.

FIGS. 18A, 18B, 18C and 18D are representative scanning electron micrographs of paclitaxel-gelatin-PCL (20:20:60) pastes before (18A) and after (18B) suspending in distilled water at 37.degree. C. for 6 hours. Micrographs 18C and 18D are higher magnifications of 18B, showing intimate association of paclitaxel (rod shaped) and gelatin matrix.

FIGS. 19A and 19B are representative photomicrographs of CAMs treated with gelatin-PCL (19A) and paclitaxel-gelatin-PCL (20:20:60; 19B) pastes showing zones of avascularity in the paclitaxel treated CAM.

FIG. 20 is a table which shows the effect of peri-tumoral injection of paclitaxel-gelatin-PCL paste into mice with established tumors.

FIG. 21 is a table which shows the melting temperature, enthalpy, molecular weight, polydispersity and intrinsic viscosity of PDLLA-PEG-PDLLA compositions.

FIG. 22 is a graph which depicts DSC thermograms of PDLLA-PEG-PDLLA and PEG. The heating rate was 10.degree. C./min. See FIG. 21 for melting temperatures and enthalpies.

FIG. 23 is a graph which depicts the cumulative release of paclitaxel from 20% paclitaxel loaded PDLLA-PEG-PDLLA cylinders into PBS albumin buffer at 37.degree. C. The error bars represent the standard deviation of 4 samples. Cylinders of 40% PEG were discontinued at 4 days due to disintegration.

FIGS. 24A, 24B and 24C are graphs which depict the change in dimensions, length (A), diameter (B) and wet weight (C) of 20% paclitaxel laded PDLLA-PEG-PDLLA cylinders during the in vitro release of paclitaxel at 37.degree. C.

FIG. 25 is a graph which shows gel permeation chromatograms of PDLLA-PEG-PDLLA cylinders (20% PEG, 1 mm diameter) loaded with 20% paclitaxel during the release in PBS albumin buffer at 37.degree. C.

FIG. 26 is a table which shows the mass loss and polymer composition change of PDLLA-PEG-PDLLA cylinders (loaded with 20% paclitaxel) during the release into PBS albumin buffer at 37.degree. C.

FIGS. 27A, 27B, 27C and 27D are SEMs of dried PDLLA-PEG-PDLLA cylinders (loaded with 20% paclitaxel, 1 mm in diameter) before and during paclitaxel release. A: 20% PEG, day 0; B: 30% PEG, day 0; C: 20% PEG, day 69; D: 30% PEG, day 69.

FIG. 28 is a graph which depicts the cumulative release of paclitaxel from 20% paclitaxel loaded PDLLA:PCL blends and PCL into PBS albumin buffer at 37.degree. C. The error bars represent the standard deviations of 4 samples.

FIG. 29 is a table which shows the efficacy of paclitaxel loaded surgicalpaste formulations applied locally tosubcutaneous tumor in mice.

FIG. 30A is a graph which depicts the time course of paclitaxel release from 2.5 mg pellets of PCL. FIG. 30B is a graph which shows the percent paclitaxel remaining in the pellet, over time.

FIG. 31A is a graph which shows the effect of MePEG on paclitaxel release from PCL paste leaded with 20% paclitaxel. FIG. 31B is a graph which shows the percent paclitaxel remaining in the pellet, over time.

FIGS. 32A and 32B are graphs which show the effect of various concentrations of MePEG in PCL in terms of melting point (32A) and time to solidify (32B).

FIG. 33 is a graph which shows the effect of MePEG incorporation into PCL on the tensile strength and time to fail of the polymer.

FIG. 34 is a graph which shows the effect of irradiation on paclitaxel release.

FIG. 35 is a graph which depicts the range of particle sizes for control microspheres (PLLA:GA-85:15).

FIG. 36 is a graph which depicts the range of particle sizes for 20% paclitaxel loaded microspheres (PLLA:GA-85-15).

FIG. 37 is a graph which depicts the range of particle sizes for control microspheres (PLLA:GA-85-15).

FIG. 38 is a graph which depicts the range of particle sizes for 20% paclitaxel loaded microspheres (PLLA:GA-85-15).

FIGS. 39A, 39B and 39C are graphs which depict the range of particle sizes for various ratios of PLLA and GA.

FIGS. 40A and 40B are graphs which depict the range of particle sizes for various ratios of PLLA and GA

FIGS. 41A, 41B and 41C are graphs which depict the range of particle sizes for various ratios of PLLA and GA.

FIGS. 42A and 42B are graphs which depict the range of particle sizes for various ratios of PLLA and GA

FIG. 43 is a table which shows the molecular weights, CMCs and maximum paclitaxel loadings of selected diblock copolymers.

FIGS. 44A and 44B are graphs which depict the solubilization of paclitaxel crystals in water (37.degree. C.) by the copolymers and Cremophor EL. 44A; effect of the concentration of copolymer on Cremophor (20 hours incubation); 44B: effect of time (copolymer or Cremophor concentration 0.5%).

FIGS. 45A and 45B are graphs which depict the turbidity (uv-vis absorbance at 450 .mu.m) of micellar paclitaxel solutions at room temperature (22.degree. C.). Paclitaxel concentration was 2 mg/ml in water. Paclitaxel loading was 10% except MePEG 5000-30/70 where the loading was 5%.

FIG. 46 is a graph which depicts paclitaxel release from paclitaxel-nylon microcapsules.

FIG. 47 is a graph which plots the observed pseudo first order kinetic degradation of paclitaxel (20 .mu.g ml.sup.-1 in 10% HP.beta.CD and 10% HP.gamma.CD solutions at 37.degree. C. and pH of 3.7 and 4.9, respectively.

FIG. 48 is a graph which shows the phase solubility for cyclodextrins and paclitaxel in water at 37.degree. C.

FIG. 49 is a graph which shows second order plots of the complexation of paclitaxel and .gamma.CD, HP.beta.CD or HP.gamma.CD at 37.degree. C.

FIG. 50 is a graph which shows the phase solubility for paclitaxel at 37.degree. C. and hydroxypropyl-.beta.-cyclodextrin in 50:50 water:ethanol solutions.

FIG. 51 is a graph which shows dissolution rate profiles of paclitaxel in 0, 5, 10 or 20% HP.gamma.CD solutions at 37.degree. C.

FIGS. 51A and 51B are two photographs of a CAM having a tumor treated with control (unloaded) thermopaste. Briefly, in FIG. 51A the central white mass is the tumor tissue. Note the abundance of blood vessels entering the tumor from the CAM in all directions. The tumor induces the ingrowth of the host vasculature through the production of "angiogenic factors." The tumor tissue expands distally along the blood vessels which supply it. FIG. 51B is an underside view of the CAM shown in 51A. Briefly, this view demonstrates the radial appearance of the blood vessels which enter the tumor like the spokes of a wheel. Note that the blood vessel density is greater in the vicinity of the tumor than it is in the surrounding normal CAM tissue. FIGS. 51C and 51D are two photographs of a CAM having a tumor treated with 20% paclitaxel-loaded thermopaste. Briefly, in FIG. 51C the central white mass is the tumor tissue. Note the paucity of blood vessels in the vicinity of the tumor tissue. The sustained release of the angiogenesis inhibitor is capable of overcoming the angiogenic stimulus produced by the tumor. The tumor itself is poorly vascularized and is progressively decreasing in size. FIG. 51D is taken from the underside of the CAM shown in 51C, and demonstrates the disruption of blood flow into the tumor when compared to control tumor tissue. Note that the blood vessel density is reduced in the vicinity of the tumor and is sparser than that of the normal surrounding CAM tissue.

FIG. 52A is a graph which shows the effect of paclitaxel/PCL on tumor growth. FIGS. 52B and 52C are two photographs which show the effect of control, 10%, and 20% paclitaxel-loaded thermopaste on tumor growth.

FIG. 53 is a bar graph which depicts the size distribution of microspheres by number (5% poly (ethylene-vinyl acetate) with 10 mg sodium suramin into 5% PVA).

FIG. 54 is a bar graph which depicts the size distribution of microspheres by weight (5% poly (ethylene-vinyl acetate) with 10 mg sodium suramin into 5% PVA).

FIG. 55 is a graph which depicts the weight of encapsulation of Sodium Suramin in 50 mg poly (ethylene-vinyl acetate).

FIG. 56 is a graph which depicts the percent of encapsulation of Sodium Suramin in 50 mg poly (ethylene-vinyl acetate).

FIG. 57 is a bar graph which depicts the size distribution by weight of 5% ELVAX microspheres containing 10 mg sodium suramin made in 5% PVA containing 10% NaCl.

FIG. 58 is a bar graph which depicts the size distribution by weight of 5% microspheres containing 10 mg sodium suramin made in 5% PVA containing 10% NaCl.

FIG. 59 is a bar graph which depicts the size distribution by number of 5% microspheres containing 10 mg sodium suramin made in 5% PVA containing 10% NaCl.

FIG. 60A is a photograph of Suramin and Cortisone Acetate on a CAM (Mag=8.times.). Briefly, this image shows an avascular zone treated with 20 .mu.g of suramin and 70 .mu.g of cortisone acetate in 0.5% methylcellulose. Note the blood vessels located at the periphery of the avascular zone which are being redirected away from the drug source. FIG. 60B is a photograph which shows the vascular detail of the effected region at a higher magnification (Mag=20.times.). Note the avascular regions and the typical "elbowing" effect of the blood vessels bordering the avascular zone.

FIGS. 61A, B, C, D and E show the effect of MTX release from PCL over time.

FIG. 62 is a photograph of 10% methotrexate-loaded microspheres made from PLA:GA (50:50); Inherent Viscosity "IV"=0.78.

FIG. 63 is a graph which depicts the release of 10% loaded vanadyl sulfate from PCL.

FIG. 64 is a photograph of hyaluronic acid microspheres containing vanadium sulfate.

FIG. 65A is a graph which depicts the release of organic vanadate from PCL. FIG. 65B depicts the percentage of organic vanadate remaining over a time course.

FIG. 66 is a photograph showing poly D,L, lactic acid microspheres containing organic vanadate.

FIGS. 67A and 67B are graphs which show the time course of BMOV release from PCL (150 mg slabs). (A) .mu.g drug released or (B) % of drug remaining in slab. Initial loading of BMOV in PCL given by (.largecircle.), 5%; (.circle-solid.), 10%; (.DELTA.), 15%; (.sigma.), 20%; ( ), 30% and (.gradient.), 35%.

FIGS. 68A and 68B are graphs which show the time course of BMOV release from 150 mg slabs of PCL:MEPEG (80:20, w:w) expressed as (A) .mu.g drug released or (B) % drug remaining in slab. Initial loading of BMOV in PCL:MEPEG given by (.largecircle.), 5%; (.circle-solid.), 10%; (.DELTA.), 15%; (.sigma.), 20%.

FIGS. 69A, 69B and 69C are Scanning electron micrographs of (69A: top), BMOV crystals; (69B: middle) surface morphology of the PCL slab containing 20% BMOV at the start of the drug release experiment and (69C: bottom), surface morphology of the PCL slab containing 20% BMOV at the end of the drug release experiment (72 days in PBS).

FIGS. 70A and 70B are two graphs which show the effect of increasing concentration of BMOV on cell survival using 1 hour exposure of cells to BMOV (70A), or, continuous exposure to BMOV (70B). Cells described by (.largecircle.), HT-29 colon cells; (.circle-solid.), MCF-7 breast cells; (.DELTA.), Skmes-1 non-small lung cells and (.sigma.) normal bone marrow cells.

FIG. 71 is a table which shows the effect of BMOV loaded paste on the weights of MDAY-D2 tumors grown in mice. Briefly, PCL paste (150 mg) containing either 25%, 30%, or 35% BMOV was injected subcutaneously into mice bearing MDAY-2 tumors. Tumor weights were determined after 10 days treatment. This table shows the results from 2 separate experiments using (top table) 25% BMOV and (bottom table) 30% or 35% BMOV. Control data describes mice treated with PCL containing no BMOV.

FIG. 72 is a table which sets forth the effects of BMOV loaded PCL:MePEG paste on the weights of RIF-1 tumors grown in mice. Briefly, RIF-1 tumors were grown in mice for 5 days at which time 90% of the tumor was surgically removed and the resection site treated with 150 mg of PCL:MePEG (80:20, w:w) paste containing either no BMOV (control) or 5% BMOV. Tumor regrowth was determined on days 4, 5 and 6 following this treatment.

FIGS. 73A and 73B are two graphs. FIG. 73A shows the effect of increased loading of BEMOV in PCL thermopaste (150 mg pellet) on the time course of BEMOV released into 15 mL PBS/ALB. FIG. 73B also shows the effect of increase loading of BEMOV in PCL thermopaste (150 mg pellet) on the time course of BEMOV released into 15 mL PBS/ALB. Drug release is expressed as the % of BEMOV remaining in the pellet.

FIGS. 74A and 74B are two graphs. FIG. 74A shows the effect of increased loading of V5 in PCL thermopaste (150 mg pellet) on the time course of V5 released into 15 mL PBS/ALB. FIG. 74B also shows the effect of increase loading of V5 in PCL thermopaste (150 mg pellet) on the time course of V5 released into 15 mL PBS/ALB. Drug release is expressed as the % of V5 remaining in the pellet.

FIGS. 75A and 75B are two graphs. FIG. 75A shows the effect of increased loading of PRC-V in PCL thermopaste (150 mg pellet) on the time course of PRC-V released into 15 mL PBS/ALB. FIG. 75B also shows the effect of increase loading of PRC-V in PCL thermopaste (150 mg pellet) on the time course of PRC-V released into 15 mL PBS/ALB. Drug release is expressed as the % of PRC-V remaining in the pellet.

FIGS. 76A, 76B, 76C and 76D are a series of graphs which show the effect of loading different concentrations of MePEG in PCL thermopaste (150 mg pellet) with 5% BMOV (76A), 10% BMOV (76B), 15% BMOV (76C), and 20% BMOV (76D) on the time course of BMOV released into 15 mL PBS/ALB.

FIGS. 77A, 77B, 77C and 77D are a series of graphs which show the effect of loading different concentrations of MePEG in PCL thermopaste (150 mg pellet) with 0% MePEG (77A), 5% MePEG (77B), 10% MePEG (77C), and 15% MePEG (77D) on the time course of BMOV released into 15 mL PBS/ALB. Drug release is expressed as the % of BMOV remaining in the pellet.

FIGS. 78A and 78B are photographs of fibronectin coated PLLA microspheres on bladder tissue (78A), and poly (L-lysine) microspheres on bladder tissue.

DETAILED DESCRIPTION OF THE INVENTION

Prior to setting forth the invention, it may be helpful to an understanding thereof to set forth definitions of certain terms that will be used hereinafter.

"Body passageway" as used herein refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body. Representative examples of body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord.

"Therapeutic agent" as used herein refers to those agents which can mitigate, treat, cure, or prevent a given disease or condition. Representative examples of therapeutic agents are discussed in more detail below, and include, for example, anti-angiogenic agents, anti-proliferative agents, anti-inflammatory agents, and antibiotics.

As noted above, the present invention provides methods for treating or preventing diseases associated with body passageways, comprising the step of delivering to an external portion of the body passageway (i.e., a non-luminal surface), a composition comprising a therapeutic agent, and within preferred embodiments, a compositions comprising a therapeutic agent and a polymeric carrier. Briefly, delivery of a therapeutic agent to an external portion of a body passageway (e.g., quadrantically or circumferentially) avoids many of the disadvantages of traditional approaches which involve endoluminal manipulation. In addition, delivery of a therapeutic agent as described herein allows the administration of greater quantities of the therapeutic agent with less constraint upon the volume to be delivered.

As discussed in more detail below, a wide variety of therapeutic agents may be delivered to external portions of body passageways, either with or without a carrier (e.g., polymeric), in order to treat or prevent a disease associated with the body passageway. Each of these aspects is discussed in more detail below.

Therapeutic Agents

As noted above, the present invention provides methods and compositions which utilize a wide variety of therapeutic agents. Within one aspect of the invention, the therapeutic agent is an anti-angiogenic factor. Briefly, within the context of the present invention anti-angiogenic factors should be understood to include any protein, peptide, chemical, or other molecule which acts to inhibit vascular growth. A variety of methods may be readily utilized to determine the anti-angiogenic activity of a given factor, including for example, chick chorioallantoic membrane ("CAM") assays. Briefly, a portion of the shell from a freshly fertilized chicken egg is removed, and a methyl cellulose disk containing a sample of the anti-angiogenic factor to be tested is placed on the membrane. After several days (e.g., 48 hours), inhibition of vascular growth by the sample to be tested may be readily determined by visualization of the chick chorioallantoic membrane in the region surrounding the methyl cellulose disk. Inhibition of vascular growth may also be determined quantitatively, for example, by determining the number and size of blood vessels surrounding the methyl cellulose disk, as compared to a control methyl cellulose disk. Although anti-angiogenic factors as described herein are considered to inhibit the formation of new blood vessels if they do so in merely a statistically significant manner, as compared to a control, within preferred aspects such anti-angiogenic factors completely inhibits the formation of new blood vessels, as well as reduce the size and number of previously existing vessels.

In addition to the CAM assay described above, a variety of other assays may also be utilized to determine the efficacy of anti-angiogenic factors in vivo, including for example, mouse models which have been developed for this purpose (see Roberston et al., Cancer. Res. 51:1339-1344, 1991).

A wide variety of anti-angiogenic factors may be readily utilized within the context of the present invention. Representative examples include Anti-Invasive Factor, retinoic acid and derivatives thereof, Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, compounds which disrupt microtubule function, and various forms of the lighter "d group" transition metals. These and other anti-angiogenic factors will be discussed in more detail below.

Briefly, Anti-Invasive Factor, or "AIF" which is prepared from extracts of cartilage, contains constituents which are responsible for inhibiting the growth of new blood vessels. These constituents comprise a family of 7 low molecular weight proteins (<50,000 daltons) (Kuettner and Pauli, "Inhibition of neovascularization by a cartilage factor" in Development of the Vascular System, Pitman Books (CIBA Foundation Symposium 100), pp. 163-173, 1983), including a variety of proteins which have inhibitory effects against a variety of proteases (Eisentein et al, Am. J. Pathol. 81:337-346, 1975; Langer et al., Science 193:70-72, 1976; and Horton et al., Science 199:1342-1345, 1978). AIF suitable for use within the present invention may be readily prepared utilizing techniques known in the art (e.g., Eisentein et al, supra; Kuettner and Pauli, supra; and Langer et al., supra). Purified constituents of AIF such as Cartilage-Derived Inhibitor ("CDI") (see Moses et al., Science 248:1408-1410, 1990) may also be readily prepared and utilized within the context of the present invention.

Retinoic acids alter the metabolism of extracellular matrix components, resulting in the inhibition of angiogenesis. Addition of proline analogs, angiostatic steroids, or heparin may be utilized in order to synergistically increase the anti-angiogenic effect of transretinoic acid. Retinoic acid, as well as derivatives thereof which may also be utilized in the context of the present invention, may be readily obtained from commercial sources, including for example, Sigma Chemical Co. (# R2625).

Suramin is a polysulfonated naphthylurea compound that is typically used as a trypanocidal agent. Briefly, Suramin blocks the specific cell surface binding of various growth factors such as platelet derived growth factor ("PDGF"), epidermal growth factor ("EGF"), transforming growth factor ("TGF-.beta."), insulin-like growth factor ("IGF-1"), and fibroblast growth factor (".beta.FGF"). Suramin may be prepared in accordance with known techniques, or readily obtained from a variety of commercial sources, including for example Mobay Chemical Co., New York. (see Gagliardi et al., Cancer Res. 52:5073-5075, 1992; and Coffey, Jr., et al., J. of Cell. Phys. 132:143-148, 1987).

Tissue Inhibitor of Metalloproteinases-1 ("TIMP") is secreted by endothelial cells which also secrete MMPases. TIMP is glycosylated and has a molecular weight of 28.5 kDa. TIMP-1 regulates angiogenesis by binding to activated metalloproteinases, thereby suppressing the invasion of blood vessels into the extracellular matrix. Tissue Inhibitor of Metalloproteinases-2 ("TIMP-2") may also be utilized to inhibit angiogenesis. Briefly, TIMP-2 is a 21 kDa nonglycosylated protein which binds to metalloproteinases in both the active and latent, proenzyme forms. Both TIMP-1 and TIMP-2 may be obtained from commercial sources such as Synergen, Boulder, Colo.

Plasminogen Activator Inhibitor-1 (PA) is a 50 kDa glycoprotein which is present in blood platelets, and can also be synthesized by endothelial cells and muscle cells. PAI-1 inhibits t-PA and urokinase plasminogen activator at the basolateral site of the endothelium, and additionally regulates the fibrinolysis process. Plasminogen Activator Inhibitor-2 (PAI-2) is generally found only in the blood under certain circumstances such as in pregnancy, and in the presence of tumors. Briefly, PAI-2 is a 56 kDa protein which is secreted by monocytes and macrophages. It is believed to regulate fibrinolytic activity, and in particular inhibits urokinase plasminogen activator and tissue plasminogen activator, thereby preventing fibrinolysis.

Therapeutic agents of the present invention also include compounds which disrupt microtubule function. Representative examples of such compounds include estramustine (available from Sigma; Wang and Stearns Cancer Res. 48:6262-6271, 1988), epothilone, curacin-A, colchicine, methotrexate, and paclitaxel, vinblastine, vincristine, D.sub.2 0 and 4-tert-butyl-[3-(2-chloroethyl)ureido]benzene ("tBCEU"). Briefly, such compounds can act in several different manners. For example, compounds such as colchicine and vinblastine act by depolymerizing microtubules.

Within one preferred embodiment of the invention, the therapeutic agent is paclitaxel, a compound which disrupts microtubule formation by binding to tubulin to form abnormal mitotic spindles. Briefly, paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325, 1971) which has been obtained from the harvested and dried bark of Taxus brevifolia (Pacific Yew.) and Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew (Stierle et al., Science 60:214-216, 1993). "Paclitaxel" (which should be understood herein to include prodrugs, analogues and derivatives such as, for example, TAXOL.RTM., TAXOTERE.RTM., 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, W094/00156, WO 93/24476, EP 590267, WO 94/20089; U.S. Pat. Nos. 5,294,637, 5,283,253, 5,279,949, 5,274,137, 5,202,448, 5,200,534, 5,229,529, 5,254,580, 5,412,092, 5,395,850, 5,380,751, 5,350,866, 4,857,653, 5,272,171, 5,411,984, 5,248,796, 5,248,796, 5,422,364, 5,300,638, 5,294,637, 5,362,831, 5,440,056, 4,814,470, 5,278,324, 5,352,805, 5,411,984, 5,059,699, 4,942,184; Tetrahedron Letters 35(52):9709-9712, 1994; J. Med. Chem. 35:4230-4237, 1992; J. Med. Chem. 34:992-998, 1991; J. Natural Prod. 57(10):1404-1410, 1994; J. Natural Prod. 57(11):1580-1583, 1994; J. Am. Chem. Soc. 110:6558-6560, 1988), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Mo. (T7402--from Taxus brevifolia).

Representative examples of such paclitaxel derivatives or analogues include 7-deoxy-docetaxol, 7,8-Cyclopropataxanes, N-Substituted 2-Azetidones, 6,7-Epoxy Paclitaxels, 6,7-Modified Paclitaxels, 10-Desacetoxytaxol, 10-Deacetyltaxol (from 10-deacetylbaccatin III), Phosphonooxy and Carbonate Derivatives of Taxol, Taxol 2',7-di(sodium 1,2-benzenedicarboxylate, 10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives, 10-desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives), (2'-and/or 7-O-carbonate derivatives), Asymmetric Synthesis of Taxol Side Chain, Fluoro Taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III, 9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol, Derivatives containing hydrogen or acetyl group and a hydroxy and tert-butoxycarbonylamino, sulfonated 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol derivatives, succinyltaxol,2'-.gamma.-aminobutyryltaxol formate, 2'-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol, 2'-OH-7-PEG(5000)carbamate taxol, 2'-benzoyl and 2',7-dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol; 2',7-diacetyltaxol; 2'succinyltaxol; 2'-(beta-alanyl)-taxol); 2'gamma-aminobutyryltaxol formate; ethylene glycol derivatives of 2'-succinyltaxol; 2'-glutaryltaxol; 2'-(N,N-dimethylglycyl)taxol; 2'-[2-(N,N-dimethylamino)propionyl]taxol; 2'orthocarboxybenzoyl taxol; 2'aliphatic carboxylic acid derivatives of taxol, Prodrugs {2'(N,N-diethylaminopropionyl)taxol, 2'(N,N-dimethylglycyl)taxol, 7(N,N-dimethylglycyl)taxol, 2',7-di-(N,N-dimethylglycyl)taxol, 7(N,N-diethylaminopropionyl)taxol, 2',7-di(N,N-diethylaminopropionyl)taxol, 2'-(L-glycyl)taxol, 7-(L-glycyl)taxol, 2',7-di(L-glycyl)taxol, 2'-(L-alanyl)taxol, 7-(L-alanyl)taxol, 2',7-di(L-alanyl)taxol, 2'-(L-leucyl)taxol, 7-(L-leucyl)taxol, 2',7-di(L-leucyl)taxol, 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol, 2',7-di(L-isoleucyl)taxol, 2'-(L-valyl)taxol, 7-(L-valyl)taxol, 2',7-di(L-valyl)taxol, 2'-(L-phenylalanyl)taxol, 7-(L-phenylalanyl)taxol, 2',7-di(L-phenylalanyl)taxol, 2'-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2',7-di(L-prolyl)taxol, 2'-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2',7-di(L-lysyl)taxol, 2'-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2',7-di(L-glutamyl)taxol, 2'-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2',7-di(L-arginyl)taxol}, Taxol analogs with modified phenylisoserine side chains, taxotere, (N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyltaxol, and taxanes (e.g., baccatin III, cephalomannine, 10-deacetylbaccatin III, brevifoliol, yunantaxusin and taxusin)

Other therapeutic agents which may be utilized within the present invention include lighter "d group" transition metals, such as, for example, vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species. Such transition metal species may form transition metal complexes. Suitable complexes of the above-mentioned transition metal species include oxo transition metal complexes.

Representative examples of vanadium complexes include oxo vanadium complexes such as vanadate and vanadyl complexes. Suitable vanadate complexes include metavanadate (i.e., VO.sub.3.sup.-) and orthovanadate (i.e., VO.sub.4.sup.3-) complexes such as, for example, ammonium metavanadate (i.e., NH.sub.4 VO.sub.3), sodium metavanadate (i.e., NaVO.sub.3), and sodium orthovanadate (i.e., Na.sub.3 VO.sub.4). Suitable vanadyl (i.e., VO.sup.2+) complexes include, for example, vanadyl acetylacetonate and vanadyl sulfate including vanadyl sulfate hydrates such as vanadyl sulfate mono- and trihydrates, Bis[maltolato(oxovanadium)] (IV)] ("BMOV"), Bis[(ethylmaltolato)oxovanadium] (IV) ("BEOV"), and Bis(cysteine, amide N-octyl)oxovanadium (IV) ("naglivan").

Representative examples of tungsten and molybdenum complexes also include oxo complexes. Suitable oxo tungsten complexes include tungstate and tungsten oxide complexes. Suitable tungstate (i.e., WO.sub.4.sup.2-) complexes include ammonium tungstate (ie., (NH.sub.4).sub.2 WO.sub.4), calcium tungstate (i.e., CaWO.sub.4), sodium tungstate dihydrate (i.e., Na.sub.2 WO.sub.4.2H.sub.2 O), and tungstic acid (i.e., H.sub.2 WO.sub.4). Suitable tungsten oxides include tungsten (IV) oxide (i.e., WO.sub.2) and tungsten (VI) oxide (i.e., WO.sub.3). Suitable oxo molybdenum complexes include molybdate, molybdenum oxide, and molybdenyl complexes. Suitable molybdate (i.e., MoO.sub.4.sup.2-) complexes include ammonium molybdate (i.e., (NH.sub.4).sub.2 MoO.sub.4) and its hydrates, sodium molybdate (i.e., Na.sub.2 MoO.sub.4) and its hydrates, and potassium molybdate (i.e., K.sub.2 MoO.sub.4) and its hydrates. Suitable molybdenum oxides include molybdenum (VI) oxide (i.e., MoO.sub.2), molybdenum (VI) oxide (i.e., MoO.sub.3), and molybdic acid. Suitable molybdenyl (i.e., MoO.sub.2.sup.2+) complexes include, for example, molybdenyl acetylacetonate. Other suitable tungsten and molybdenum complexes include hydroxo derivatives derived from, for example, glycerol, tartaric acid, and sugars.

A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include Platelet Factor 4 (Sigma Chemical Co., #F1385); Protamine Sulphate (Clupeine) (Sigma Chemical Co., #P4505); Sulphated Chitin Derivatives (prepared from queen crab shells), (Sigma Chemical Co., #C3641; Murata et al., Cancer Res. 51:22-26, 1991); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine (Sigma Chemical Co., #S4400); Modulators of Matrix Metabolism, including for example, proline analogs {[(L-azetidine-2-carboxylic acid (LACA) (Sigma Chemical Co., #A0760)), cishydroxyproline, d,L-3,4-dehydroproline (Sigma Chemical Co., #D0265), Thiaproline (Sigma Chemical Co., #T0631)], .alpha.,.alpha.-dipyridyl (Sigma Chemical Co., #D7505), .beta.-aminopropionitrile fumarate (Sigma Chemical Co., #A3134)]}; MDL 27032 (4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Merion Merrel Dow Research Institute); Methotrexate (Sigma Chemical Co., #A6770; Hirata et al., Arthritis and Rheumatism 32:1065-1073, 1989); Mitoxantrone (Polverini and Novak, Biochem. Biophys. Res. Comm. 140:901-907); Heparin (Folkman, Bio. Phar. 34:905-909, 1985; Sigma Chemical Co., #P8754); Interferons (e.g., Sigma Chemical Co., #13265); 2 Macroglobulin-serum (Sigma Chemical Co., #M7151); ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, 1992); Chymostatin (Sigma Chemical Co., #C7268; Tomkinson et al., Biochem J. 286:475-480, 1992); .beta.-Cyclodextrin Tetradecasulfate (Sigma Chemical Co., #C4767); Eponemycin; Camptothecin; Fumagillin and derivatives (Sigma Chemical Co., #F6771; Canadian Patent No. 2,024,306; Ingber et al., Nature 348:555-557, 1990); Gold Sodium Thiomalate ("GST"; Sigma:G4022; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, 1987); (D-Penicillamine ("CDPT"; Sigma Chemical Co., #P4875 or P5000(HCl)); .beta.-1-anticollagenase-serum; .alpha.2-antipl