Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-05-12
2002-06-25
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009100, C424S009300, C424S009351, C424S009400, C424S009430, C514S054000, C514S058000
Reexamination Certificate
active
06409990
ABSTRACT:
BACKGROUND OF THE INVENTION
The field of the invention relates to therapeutics and diagnostics that make use of macromolecules as delivery agents.
The use or hypothetical use of certain macromolecules as delivery agents to target appended drugs and diagnostic agents is known, but currently not without severe limitations. Attempts with therapeutics have yielded only limited clinical success due to a lack of inexpensive and nontoxic molecular backbones to which drugs and target substrates of sufficient load can be attached. Similar problems plague current cardiovascular and tumor imaging techniques, which make use of appended agents for magnetic resonance imaging (MRI) and computed tomography (CT).
Focus has thus centered on the delivery agent's molecular backbone, which function is to carry drugs, substrates, and imaging and other diagnostic molecules for delivery to specific cell tissues. The most commonly employed backbones to date are dextran, polylysine, synthetic copolymers, starburst dendrimers, and human serum albumin.
Dextran, a branched polymer of glucose, has an extensive human-use experience, and offers the highest ratio of attachment sites per molecular weight. It is also very hydrophilic, which permits a low injection volume. While dextran is relatively inexpensive, it has the disadvantage of having insufficient chemical flexibility in its usual attachment sites and a high incidence of unwanted cross-linking that results from standard means of attachment.
Polylysine, by contrast, is extremely expensive and has a very limited human-use experience. Despite this, polylysine has the advantage of being available in various chain lengths and the further advantage of its side chains being readily amenable to chemical attachment of drugs and receptor substrates. Consequently, polylysine is frequently employed to test prospective drug delivery systems in animals.
Synthetic copolymers, e.g., as described by Krinick et al., Makromol. Chem. 191:839-856 (1990), offer linearity and a net neutral charge which increases diffusion. Synthetic copolymers offer further advantage in that they may be synthesized in bulk. However, their synthesis requires multiple steps that, if not complex, are nevertheless time consuming, expensive, and therefore inefficient. Further, there is limited human-use experience with synthetic copolymer backgrounds.
Starburst dendrimers (see Tomalia et al. (1985) Polymer J. 17:117-132) are advantageous in that they provide less molecular weight heterogeneity, and therefore more reproducibility and predictability. However, they have the disadvantages that they (1) offer a low, inadequate number of attachment sites per backbone, and (2) have a limited human-use experience. Similar disadvantages characterize the use of human serum albumin.
In light of the foregoing, an inexpensive and nontoxic molecular backbone delivery vehicle replete with high density molecular attachment capabilities is sorely needed.
SUMMARY OF THE INVENTION
It is an object of the invention to remedy or ameliorate one or more of the above-noted problems in the field and to provide useful alternatives.
Specifically, it is an object of the invention to provide a new or improved macromolecule delivery system for agents of any type, diagnostic, therapeutic, or otherwise.
It is a further object of the invention to provide a relatively nontoxic macromolecule possessing a high density of attachment sites relative to what has previously been described in the art.
It is a further object of the invention to improve delivery success and reduce administration volumes in techniques employing macromolecular backbones as delivery vehicles.
It is yet a further object of the invention to provide a macromolecule that is highly available, relatively inexpensive, and of demonstrable value in scientific research and medicine.
It is a further object of the invention to describe the chemical synthesis and product of new chemical attachment leashes having suitable flexibility.
In accordance with one or more of these objectives, in a first aspect the invention features a carrier molecule comprising a backbone, the backbone having affixed thereto a plurality of leash groups having structure —O(CH
2
)
3
S(CH
2
)
2
NH
2
.
In preferred embodiments, the backbone is derived from a polysaccharide, preferably dextran, and the leash structures are accomplished through reaction of an allyl group with aminoethanethiol. When dextran is used, it may be selected from any molecular weight appropriate for the ultimate use of the molecule, its leashes, and conjugates. Different diagnostic and therapeutic applications will call for different MW dextrans, as the person of ordinary skill in the art is aware.
In most advantageous embodiments, it is preferred that at least one chemical group be conjugated to the backbone via the amino groups of the leashes. These chemical groups may be selected from any of a variety of compounds having useful therapeutic or diagnostic uses, including but not limited to: chelators, receptor ligands, lectins, enzymatic substrates, nucleic acids, peptides, polysaccharides, monosaccharides, radiosensitizers, radioprotectors, and dyes. The groups need not be directly useful, but may be indirectly useful by permitting targeting to a given cell or tissue type such that another functional moiety attached to the backbone may perform the affirmative or negative function desired.
The high load and density of leashes per nontoxic backbone is an important aspect of the invention due to the significant kinetic advantages that are obtained for attachment and delivery. Relatively more therapeutic or diagnostic molecules may be delivered to work their purpose. This may include the very simplistic case in which ligands of high density may be simply attached to the backbone molecule such that they more effectively block certain receptors when administered or contacted thereto or therewith. Receptors impart cellular biochemical function. Blockage of that function may have a useful therapeutic value for a given indication and context. Thus, antagonists capable of competitive or noncompetive inhibition with normal or abnormal biological agents are contemplated.
Agonists can also be used to obtain the desired effect in that they may signal or stimulate endocytosis of the backbone moiety and agents to which they are attached, or can signal an intracellular cascade. Those of skill in the art will recognize the broad range of applications and implications for the many embodiments of the invention.
In especially preferred embodiments, the backbone carries both a ligand having a specific affinity for a given tissue or cell type, and a chelator molecule. The chelator normally has nitrogen groups possessing free electrons that adhere tightly to positively charged metal atoms and ions. Preferred chelators for use with the invention include DOTA, MAG3, and DTPA. DOTA is especially preferred because its geometry conveniently and tightly accommodates the gadolinium atom, which can be used for both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). The MAG3 chelator is preferred for complexation with the radioelement Technetium-99m (Tc-99m), which has a relatively short half-life of 6 hours. This half-life is compatible with biologic processes and clinical protocols, which for sentinel node detection is of sufficient duration to permit a surgeon to evaluate the precise location and extent of, e.g., tumor growth or metastases and remove it. This particular combination thus has excellent application in nuclear medicine.
In other, not necessarily mutually exclusive embodiments, the chelator may be combined with a non-radioisotope or element, e.g., an absorbing element (high density), or paramagnetic atom, each having special application, respectively, in computed tomography and nuclear magnetic or magnetic resonance imaging procedures. These are diagnostic procedures that permit imaging of various physiological or anatomical structures using characteristics of the high density or paramagnetic atoms introduced. Such diagnos
Brown Martin Haller & McClain
Jones Dameron L.
The Regents of the University of California
Wells Lauren Q.
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