Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-12-10
2001-07-03
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S491000, C424S501000, C435S455000, C435S456000, C435S459000, C435S320100
Reexamination Certificate
active
06254890
ABSTRACT:
BACKGROUND OF THE INVENTION
The recent advances in drug discovery and molecular and pharmaceutical biology have created a need for the development of effective mechanisms for delivering therapeutic agents into cells. In but one example, researchers have particularly struggled to develop efficient means for introducing nucleic acids into cells. For example, in recent years, gene therapy has become a widely-publicized new method of ameliorating disease. However, very few, if any, attempts have successfully proceeded through clinical trials. The main reason lies in the lack of an efficient, targetable in vivo delivery vehicle despite much effort expended in developing viral and non-viral vectors. The development of a method to efficiently introduce nucleic acids into cells would be useful, for example, in gene therapy, antisense therapy, research purposes (e.g., to study cell differentiation, growth and carcinogenic transformation or for the creation of animal models for human disease; see, for example, Abdallah,
Biol. Cell,
1995, 85, 1, and references therein).
One potential in vivo delivery vehicle is a biodegradable polymer. Specifically, the advantages of a biodegradable polymer gene carrier over existing vectors are the stability and ease of handling of polymer systems, the ease with which one can add different characteristics to the carrier either by polymer design, and the protection they can provide the nucleic acids which they are carrying. Polymers are, relatively speaking, newcomers in this field (see, for example, Felgner,
Adv. Drug Del. Rev.
1990, 5, 163). There are two ways polymers have been explored as potential vectors: 1) as a capsule or mesh which houses genetically modified cells, or 2) as a nucleic acid carrier itself.
The ability of certain polymer microspheres and nanospheres to release drugs such as small molecules, peptides and proteins, has been previously described in the literature (see, for example, Niwa et al.,
J. Controlled Release
1993, 25, 89; Cho et al.,
Macromol. Rapid Commun.,
1997, 18, 361). In addition to the encapsulation of drugs such as small molecules, peptides and proteins, the formulation of microspheres encapsulating DNA has been described (see, for example, Mathiowitz et al.,
Nature,
1997, 386, 410; and Mathiowitz et al., WO97/03702), and also the preparation of nanospheres small enough to be used in injectable formulations has also been described (see, for example, Gref et al.,
Science,
1994, 1600; Bazile et al.,
J. Pharmaceut. Sci.
1995, 84, 493.). To date, however, there has been no description of the development of a system whereby 1) nanospheres encapsulating nucleic acids are formed and 2) the nucleic acids are subsequently released.
Clearly, however, there remains a need to develop a system in which nucleic acids can be encapsulated in nanospheres, and can also subsequently be released from these nanospheres. Additionally, it would also be desirable to encapsulate nucleic acids in nanospheres having targeting or masking moieties so that nucleic acids could be directly delivered and subsequently released into a specific cellular target.
The present invention for the first time demonstrates that nucleic acids, specifically DNA, can be encapsulated into nanospheres and can also be subsequently released from them. As a result, the present invention accomplishes the first step of development for an injectable system for eventual development into a fully functioning gene delivery vehicle. Clearly, this invention has wide implications for commercial applications such as gene replacement therapy, gene augmentation, or oligonucleotide delivery for antisense applications.
SUMMARY OF THE INVENTION
The present invention discloses a biodegradable polymer nanosphere capable of 1) encapsulating nucleic acids, and 2) releasing nucleic acids over a period of time. Specifically, in one aspect, the invention provides a system for delivering biologically agents, such as nucleic acids, from biodegradable polymer nanospheres, including forming a nanosphere encapsulating the desired agent, and subsequently releasing the agent from the nanosphere over a period of time. In another aspect, the present invention provides a method for delivering and releasing nucleic acids to cells including 1) encapsulating the desired agent within the nanosphere, 2) contacting the desired cells with the nanosphere encapsulating the nucleic acids, whereby release of the nucleic acids into the desired target is effected over a period of time. In a preferred embodiment, to effect the delivery of nucleic acids to specific cells, a targeting moiety is attached to the surface of the nanospheres. In another preferred embodiment, to effect the intravenous delivery of nucleic acids, a masking moiety is attached to the surface of the nanospheres. In yet another preferred embodiment, a system is provided for the intravenous delivery of nucleic acids by attaching both a masking and targeting moiety to the surface of the nanospheres.
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Abdallah et al.,Biol. Cell., 1995, 85, 1.
Bazile et al.,Journal of Pharmaceutical Sciences, 1995, 84, 493.
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Langer et al., “New Methods of Drug Delivery”,Science, 1990, 249, 1527.
Mao et al., “DNA-Chitosan Nanospheres for Gene Delivery” Proceedings of the International Symposium on Controlled Release Bioactive Materials, Jul. 7, 1996, p. 401.
Mathiowitz et al., “Biologically Erodable Microspheres as Potential Oral Drug Delivery Systems”,Nature, 1997, 386, 410.
Mulligan et al., “The Basic Science of Gene Therapy”,Science, 1993, 260, 926.
Niwa et al.,Journal of Controlled Release, 1993, 25, 89.
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Troung et al., “A Target-Specific Microspheres Drug Delivery System made of Enzymatically Degradable Gelatin and Chondroitin Sulfate Coacervates”Proceedings of the International Symposium on Controlled Release Biomaterials, vol. 20, Jul. 25, 1993, p. 474.
Hirosue Sachiko
Langer Robert S.
Mueller Bernhard G.
Mulligan Richard C.
Choate Hall & Stewart
Guzo David
Massachusetts Institute of Technology
Shair Karoline K. M.
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