System for targeted delivery of therapeutic agents

#Cancer is the second leading cause of death in the United States. Over one million people develop cancer each year, and approximately half of all men and one third of all women in the United States will develop cancer during their lifetimes.

#Prostate cancer is the second most common type of cancer found in American men (after skin cancer), and the second-leading cause of cancer death (after lung cancer). The American Cancer Society (ACS) estimates that 1 in 6 men will develop prostate cancer in his lifetime and 1 in 34 men will die of the disease. The ACS further estimates that there will be about 218,890 new cases of prostate cancer and about 27,050 deaths attributable to prostate cancer in the United States in 2007.

#Most cancers, including prostate cancer, are frequently treated by a combination of approaches, including surgical removal of a tumor, chemotherapy, and/or radiation therapy. Surgical procedures are usually not sufficient to remove a tumor in its entirety, so surgery is frequently accompanied by chemotherapy and/or radiation therapy. Chemotherapy involves the use of drugs to kill tumor cells, and radiation therapy involves treatment with high-energy rays (e.g. x-rays) to kill or shrink tumor cells.

#FIG. 1: Synthesis of PLGA-b-PEG-COOH nanoparticles (NP), and association of aptamer to nanoparticles. Docetaxel was encapsulated within PLGA-b-PEG-COOH NP using the nanoprecipitation method. PLGA-PEG NP/Docetaxel was covalently associated with amine-terminated A10 prostate-specific membrane antigen (PSMA) aptamer (Apt) in the presence of EDC.

#FIG. 2: Effect of varying formulation parameters on nanoparticle size. (A) Varying solvent:water ratio (1:1, 1:2, 1:5, 1:10) while keeping PLGA-b-PEG polymer constant at 10 mg/ml. (B) Varying polymer concentrations in organic phase (5, 10, 20, or 50 mg/ml) while keeping solvent:water ratio constant at 1:2.

#FIG. 3: Correlation of nanoparticle volumetric sizes with polymer concentrations at constant solvent:water ratio.

#Amino acid: As used herein, term “amino acid,” in its broadest sense, refers to any compound and/or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N—C(H)(R)—COOH. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” or “natural amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. As used herein, “non-natural amino acid” encompasses chemically produced or modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and/or substitutions. Amino acids, including carboxy- and/or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, and/or substitution with other chemical groups that can change the peptide's circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond. The term “amino acid” is used interchangeably with “amino acid residue,” and may refer to a free amino acid and/or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide.

#Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone.

#Antibody: As used herein, the term “antibody” refers to any immunoglobulin, whether natural or wholly or partially synthetically produced. All derivatives thereof which maintain specific binding ability are also included in the term. The term also covers any protein having a binding domain which is homologous or largely homologous to an immunoglobulin binding domain. Such proteins may be derived from natural sources, or partly or wholly synthetically produced. An antibody may be monoclonal or polyclonal. An antibody may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE. As used herein, the terms “antibody fragment” or “characteristic portion of an antibody” are used interchangeably and refer to any derivative of an antibody which is less than full-length. In general, an antibody fragment retains at least a significant portion of the full-length antibody's specific binding ability. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, scFv, Fv, dsFv diabody, and Fd fragments. An antibody fragment may be produced by any means. For example, an antibody fragment may be enzymatically or chemically produced by fragmentation of an intact antibody and/or it may be recombinantly produced from a gene encoding the partial antibody sequence. Alternatively or additionally, an antibody fragment may be wholly or partially synthetically produced. An antibody fragment may optionally comprise a single chain antibody fragment. Alternatively or additionally, an antibody fragment may comprise multiple chains which are linked together, for example, by disulfide linkages. An antibody fragment may optionally comprise a multimolecular complex. A functional antibody fragment will typically comprise at least about 50 amino acids and more typically will comprise at least about 200 amino acids.