Effect of Tyrosine-Derived Triblock Copolymer Compositions on Nanosphere Self-Assembly and Drug Delivery

Abstract

We have obtained structure-activity relations for nanosphere drug delivery as a function of the chemical properties of a tunable family of self-assembling triblock copolymers. These block copolymers are synthesized with hydrophobic oligomers of a desaminotyrosyl tyrosine ester and diacid and hydrophilic poly(ethylene glycol). We have calculated the thermodynamic interaction parameters for the copolymers with anti-tumor drugs to provide an understanding of the drug binding by the nanospheres. We find that there is an optimum ester chain length, C8, for nanospheres in terms of their drug loading capacities. The nanospheres release the drugs under dialysis conditions, with release rates strongly influenced by solution pH. The nanospheres, which are themselves non-cytotoxic, deliver the hydrophobic drugs very effectively to tumor cells as measured by cell killing activity in vitro and thus offer the potential for effective parentarel in vivo delivery of many hydrophobic therapeutic agents.

Nanospheric Chemotherapeutic and Chemoprotective Agents

“…(21)(22)(23) In vivo efficacy of nanosphere-paclitaxel formulation exhibited anti-tumor activity in a breast cancer xenograft model that is similar to that of an equivalent dose of clinically used formulation of Cremophorpaclitaxel. (23,24) It is our believe, that this novel technology can potentially address the key military and civilian requirements for effective breast cancer chemotherapy: nontoxic administration, increased bioavailability, prolonged circulation and targeting cancer cells, leading to substantially greater drug efficacy and lower toxicity. Further exploration of the proposed multidisciplinary research, while potentially high risk, may result in the introduction of innovative, high impact treatments for breast cancer.…”

“…The synthesis of desaminotyrosyl-tyrosine esters, DTR,(28) and triblock copolymers has been previously described. (22,23,29) Briefly, the triblock copolymers were synthesized in a one-pot reaction at 20 °C using in situ carbodiimide coupling of the PEG and oligo(DTR-XA) while reaction conditions such as monomer ratios, temperature and reaction time were kept constant for all compositions. We expect to identify an optimum ratio of triblock hydrophobicity/hydrophilicity, determined by the physical and chemical properties of the copolymer blocks, that provides for effective delivery of each selected drug.…”

“…Tyrosine-derived triblock copolymers self-assemble into spherical structures with hydrodynamic diameters between 50 nm and 100 nm, thus providing particle size and surface chemical properties superior to conventional drug delivery designs. (21)(22)(23) In addition to their biocompatibility, biodegradability and lack of cellular toxicity, these nanospheres strongly bind and retain in vitro anti-tumor cytotoxicity of the hydrophobic chemotherapeutic agent, paclitaxel. (21)(22)(23) In vivo efficacy of nanosphere-paclitaxel formulation exhibited anti-tumor activity in a breast cancer xenograft model that is similar to that of an equivalent dose of clinically used formulation of Cremophorpaclitaxel.…”

“…(21)(22)(23) In addition to their biocompatibility, biodegradability and lack of cellular toxicity, these nanospheres strongly bind and retain in vitro anti-tumor cytotoxicity of the hydrophobic chemotherapeutic agent, paclitaxel. (21)(22)(23) In vivo efficacy of nanosphere-paclitaxel formulation exhibited anti-tumor activity in a breast cancer xenograft model that is similar to that of an equivalent dose of clinically used formulation of Cremophorpaclitaxel. (23,24) It is our believe, that this novel technology can potentially address the key military and civilian requirements for effective breast cancer chemotherapy: nontoxic administration, increased bioavailability, prolonged circulation and targeting cancer cells, leading to substantially greater drug efficacy and lower toxicity.…”

Synthesis and characterization of new functionalized polymer-Fe3O4 nanocomposite particles

“…These comprise among others: small size, the ability to carry a wide variety of chemotherapeutic agents with sufficient drug space to meet the desired amount of biologically active drugs, the ability to release the drug at a predictable rate, biocompatibility, minimal antigenic properties, biodegradability , minimized toxicity of the breakdown products [6]. Liposomes, polysaccharides, nanocrystals, dendrimers, and polymeric, inorganic and modified nanoparticles meet all of these conditions [7][8][9][10][11][12][13][14][15][16]. Magnetic nanoparticles could be potentially used for drug delivery, as they can be easily handled by an external magnetic field and are preferentially taken up by the target tissue.…”