Cedars-sinai Medical Center

Arrogene Nanotechnology, Inc.

Other

Arrogene, Inc.

Julia Y Ljubimova

Keith L Black

Eggehard Holler

Hui Ding

Rameshwar Patil

Satoshi Inoue

Alexander Ljubimov

Achilles A Demetriou

Nanobiopolymeric conjugates based on biodegradable, non-toxic and non-immunogenic poly (&#x3b2;-L-malic acid) PMLA covalently linked to molecular modules that include morpholino antisense oligonucleotides (AONa), an siRNA or an antibody specific for an oncogenic protein in a cancer cell, and an antibody specific for a transferrin receptor protein, are provided. Methods for treating a cancer in subject with nanobiopolymeric conjugates are described.

Polymalic acid-based nanobiopolymer compositions

Nanoconjugates that include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold are provided. Methods of targeting a diseased cell or a diseased tissue in a subject by administering the nanoconjugate are described. Methods of synthesizing the nanoconjugate are also provided.

Polymalic acid based nanoconjugates for imaging

The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety. The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety.

Drug delivery of temozolomide for systemic based treatment of cancer

A drug delivery system for delivering a drug payload to a specific tissue or cell type is disclosed. The system includes a polymalic acid molecular scaffold which can be used for attaching a plurality of molecular modules. Molecular modules include targeting antibodies for promoting cellular uptake by a target cell, and pro-drugs for altering cellular metabolism, for example, a pro-drug that alters expression of protein kinase CK2.

Polymalic acid-based multifunctional drug delivery system

The invention relates to the use of Polycefin-LLL nanoconjugate as a means of cytoplasmic delivery of drugs. In one embodiment, the present invention provides a drug delivery molecule, comprising a polymerized carboxylic acid molecular scaffold covalently linked to L-leucylleucylleucine. In another embodiment, the Polycefin-LLL includes drug antisense morpholino oligos, targeting antibodies, and a pH-sensitive endosome escape unit. In addition, the drug could be siRNA, microRNA, and aptamer.

Poly(beta malic acid) with pendant Leu-Leu-Leu tripeptide for effective cytoplasmic drug delivery

A structured drug system that is useful for delivering a drug payload to a specific tissue or cell type is disclosed. The system is based on purified polymalic acid. This polymer isolated from natural sources is biocompatible, biodegradable and of very low toxicity. The polymer is extremely water soluble and contains a large number of free carboxyl groups which can used to attach a number of different active molecules. In the examples disclosed N-hydroxysuccinimide esters of the carboxyl groups are used to attach such molecules. The active molecules include monoclonal antibodies to promote specific cellular uptake and specific pro-drugs such as antisense nucleic acids designed to modify the cellular metabolism of a target cell. The pro-drugs are advantageously linked by a somewhat labile bond so that they will be released under specific conditions. In addition, the system contains amide-linked valine to encourage membrane disruption under lysosomal conditions. Polyethylene glycol groups are attached to extend the drug system's circulation half-life. In addition, fluorescent reported groups can be readily included to aid in visualizing and confirming drug system targeting. The drug system can deliver treatments for a wide range of diseases and is specially advantageous for treatment of neoplasms.

The invention relates to the use of Polycefin-LLL nanoconjugate as a means of cytoplasmic delivery of drugs. In one embodiment, the present invention provides a drug delivery molecule, comprising a polymerized carboxylic acid molecular scaffold covalently linked to L-leucylleucylleucine. In another embodiment, the Polycefin-LLL includes drug antisense morpholino oligos, targeting antibodies, and a pH-sensitive endosome escape unit. In addition, the drug could be siRNA, microRNA, and aptamer. 

Poly(beta malic acid) with pendant leu-leu-leu tripeptide for effective cytoplasmic drug delivery

Polymalic acid-based multi-functional drug delivery system

Using gene array technology, we observed that an increase of the &#x3b1;4 chain-containing Laminin-8 correlated with poor prognosis for patients with brain gliomas. We established that inhibition of Laminin-8 expression by a new generation of highly specific and stable antisense oligonucleotides (Morpholino&#x2122;) against chains of Laminin-8 could slow or stop the spread of glioma. This was demonstrated in an in vitro model using human glioblastoma multiforme cell lines M059K and U-87MG co-cultured with normal human brain microvascular endothelial cells (HBMVEC). Using Western blot analysis and immunohistochemistry, we con-firmed that antisense treatment effectively blocked laminin-8 protein synthesis. Antisense oligonucleotides against both &#x3b1;4 and &#x3b2;1 chains of laminin-8 blocked significantly the invasion of co-cultures through Matrigel. The results show that Laminin-8 may not only contribute to glioma progression and recurrence as part of the neovascularization process but also by directly increasing the invasive potential of tumor cells.

Antisense inhibition of laminin-8 expression to inhibit human gliomas

The present invention provides a gene that encodes proteins associated with liver neoplastic diseases, such as liver cirrhosis and hepatocellular carcinoma. Significantly, these proteins are not expressed in normal, non-neoplastic liver. In accordance with the present invention there also are provided antibodies that are capable of binding to the invention proteins, as well as methods and kits for screening for liver neoplastic diseases.

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Studio City, CA, United States of America

Julia Y Ljubimova