Drug delivery formulations and targeting

Details Drug delivery formulations and targeting Drug delivery formulations and targeting

2001-07-03

2004-01-20

Nguyen, Dave T. (Department: 1635)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C514S001000, C514S002600, C514S04400A

Reexamination Certificate

active

06680068

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to drug delivery.
BACKGROUND OF THE INVENTION
The efficiency of drug transport to solid tumors can vary as a function of host microenvironment, tumor type, and growth. Several barriers have been shown to impede delivery of therapeutics to solid tumors in clinically relevant concentrations (Jain,
Scientific American,
271(1):58-65, 1994). These barriers include a heterogeneous blood supply, elevated tumor interstitial pressure (Jain,
Nature Medicine,
6:655-657, 1998), and a dynamic range of tumor blood vessel pore sizes (Hobbs et al.,
Proc. Natl. Acad. Sci. USA,
95:4607-4612, 1998). Delivery of drugs to solid tumors can thus present a formidable challenge.
Studies have shown anatomical and morphological differences between normal and tumor blood vessels (Baldwin et al.,
Microvascular Research,
42:160-178, 1991). Most tumors are angiogenesis-dependent (Folkman,
Journal of the National Cancer Institute,
82(1):4-6, 1989), requiring the development of new blood vessels. The glycoprotein layer of the vascular endothelium of angiogenic blood vessels is composed primarily of negatively charged functional groups (Baldwin et al.,
Microvascular Research,
42:160-178, 1991). These functional groups can facilitate molecular interactions with positively charged macromolecules (Dellian et al.,
British Journal of Cancer,
82:1513-1518, 2000). Accordingly, it was hypothesized that cationic liposomes could be used to target tumor vessels where established glycoprotein layers had formed. Indeed, it was found that cationic liposomes are taken up by tumor vessels to a greater extent than by the normal vascular endothelia. Cationic liposomes have thus been used to target anionic endothelial cells in tumors and chronic inflammation in mice, with some success (Thurston et al.,
Journal of Clinical Investigation
101:1401-1413, 1998; Roberts et al.,
Cancer Research
57:765-772, 1997).
In addition to tumor growth, numerous other disease states are associated with abnormal angiogenesis. Increased angiogenesis in the bones, joints, skin, liver, kidney, lung, ear, nerves, heart, skeletal muscles, adipose tissue, peritoneum pleura, endocrine organs, hematopoiesis, lymph, and other organs and systems, for example, is associated with tumors and chronic inflammation in those organs, as well as obesity, warts, uterine bleeding, and respiratory disease. On the other hand, vascular insufficiency is associated with diseases such as aseptic necrosis, impaired healing of fractures, decubitus or stasis ulcers, gastrointestinal ulcers, pulmonary and systemic hypertension, placental insufficiency, stroke, vascular dementia, Alzheimer's disease, CADASIL, ischemic heart and limb disease, and thyroid pseudocysts. Other vascular abnormalities have been implicated in psoriasis, diabetes, and hypertension.
SUMMARY OF THE INVENTION
The invention is based on the discovery that angiogenic vessels have heterogeneous surface charge and that cationic liposomes actually target human tumor blood vessels only in irregularly shaped patches. The invention thus features methods for delivering therapeutic compounds to angiogenic vascular endothelial surfaces using a mixture, or “cocktail”, of positively charged and neutral liposomes. The new methods can be used to target multiple regions on the same tumor vessel and/or clusters of vessels within the same tumor. Liposomes with different chemical and/or physical properties (e.g., charge, stability, solubility, diameter) can be delivered simultaneously, and can target tumor vessels and other angiogenic vessels with greater efficiency compared to cationic liposomes alone.
In general, the invention features a formulation that includes cationic liposomes, containing a first therapeutic agent, and electrostatically neutral liposomes, containing a second therapeutic agent, where the first and second therapeutic agents can be the same or different. Each therapeutic agent can include, for example, one or more compound that have, or are suspected to have, some biological activity, as well as other additives and excipients. Preferably, such additives or excipients are substantially non-toxic at the concentration and quantity employed. The cationic and neutral liposomes can be present in various ratios (e.g., between about 1:9 and 9:1, between about 1:3 and 3:1, or between about 2:3 and 3:2, such as about 1:1. Either or both of the first and second therapeutic agents can be, for example, an anti-tumor drug (e.g., a chemotherapeutic agent such as paclitaxel, doxorubicin, or other plant alkaloids, antibiotics, alkylating agents, antimetabolites, or miscellaneous agents), a nucleic acid, or another natural or synthetic therapeutic agent. The cationic lipids can include, for example, dioleoyltrimethyl-ammonium propane (DOTAP), N-[1-(2,3-dioleoyloxy)-propyl]-N,N,N-trimethylammonium chloride (DOTMA), dimethyldioctadecylammonium bromide (DDAB), 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl (DMRIE), dioleoyl-3-dimethylammonium propane (DODAP), N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), or N-(1-(2,3-dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethyl ammonium trifluoroacetate (DOSPA), or any other natural or synthetic cationic lipids. The neutral liposomes can include, for example, dioleoylphosphatidyl-choline (DOPC), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or 1,2-sn-dioleoylphosphatidylcholine (DOPE), or any other natural or synthetic electrostatically neutral lipids.
The invention also features several methods of administering a drug to a patient. One method includes the steps of providing a formulation as described above (i.e., where at least one of the first and second therapeutic agents includes the drug to be administered), and administering the formulation to the patient (e.g., intravenously or intraarterially or by any other suitable route). The patient can be, for example, a patient suspected of having a tumor. The patient can be, for example, a mammal such as a human, a mouse, a rat, a sheep, a goat, a dog, a cat, a pig, a cow, or other animal used for research, human companionship, agriculture, or consumption. Another method includes administering to the patient a formulation that includes a heterogeneously charged drug delivery system that can include liposomes or other drug carriers. A third method includes administering to the patient two differently charged therapeutic formulations, either or both of which can include the drug.
The invention provides several advantages. Liposome formulations can function as vascular targeting systems. Several reasons currently exist for applying vascular targeting strategies. First, damage to even a single vessel can leaves hundreds or thousands of neoplastic cells starving for nutrients, resulting in the death of a significant number of malignant cells. The blood vessels carry nutrients to the cells; without the nutrients, the cells cannot survive. Second, the physical barriers that impede delivery of drugs to solid tumors do not provide an obstacle to drug delivery to the vascular endothelium. The new methods are also not limited to delivery of therapeutics to tumor interstitial space where the majority of tumor cells reside. Additionally, the vascular targeting agent can target both the tumor vascular endothelium and a percentage of tumor cells in the tumor interstitium, resulting in additional gains in therapy. Third, endothelial cells are generally non-malignant, although they can in some cases mutate as a tumor progresses. As a result, mutant phenotypes are rare, and drug resistance is unlikely to arise.
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 pub

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