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Targeting Bone Metastases with a Bispecific Anticancer and Antiangiogenic Polymer-Alendronate-Taxane Conjugate

Targeting Bone Metastases with a Bispecific Anticancer and Antiangiogenic Polymer-Alendronate-Taxane Conjugate,10.1002/anie.200805133,Angewandte Chemi

Targeting Bone Metastases with a Bispecific Anticancer and Antiangiogenic Polymer-Alendronate-Taxane Conjugate   (Citations: 14)
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Angiogenesis is a critical step in tumor development and metastasis formation. (3-5) Tumor endothelial cells are sensitive to drugs for long time periods of drug treatment and may be treated with cytotoxic agents in an "antiangiogenic dosing schedule". (6) This schedule involves the administration of chemotherapy in low doses, well below the maximum tolerated dose (MTD), at close intervals ("metronomic dosing"). (7, 8) As a result, the drugs may be administered for extended periods of time, (6, 8) and acute toxicity is avoided. The taxane paclitaxel (PTX) is a known potent cytotoxic agent approved as a first line of therapy for metastatic breast cancer. It is being tested in the clinic in combination with other chemotherapeutic agents for the treatment of meta- static prostate cancer. (9-11) Despite its potent anticancer activity, PTX exhibits serious dose-limiting toxicities owing to its lack of selectivity for the target tissue. Furthermore, because of the poor water solubility of PTX, it is formulated in cremophor EL, which causes hypersensitivity. (12) At low doses, PTX has antiangiogenic properties. (13, 14) For these reasons, we chose PTX as the model chemotherapeutic agent. We have now developed a new approach in an attempt to target bone metastases selectively with PTX and thus decrease the side effects caused by the drug. Our strategy rests upon the conjugation of the specific bone-targeting agent alendronate (ALN) and PTX with an N-(2-hydroxy- propyl)methacrylamide (HPMA) copolymer. ALN, which is generally used to treat osteoporosis and bone metastases as well as to prevent bone fractures, was chosen as the bone-targeting moiety and antiangiogenic model agent. Like all bisphosphonates, it exhibits an excep- tionally high affinity for the bone mineral hydroxyapatite (HA). (15, 16) This unique feature of bisphosphonates makes them good candidates for the bone targeting of antineoplastic compounds, radionucleotides, and nucleoside analogues. (16, 17) ALN should facilitate the delivery of PTX to the bones. Conjugation with the HPMA copolymer should cause PTX to mostly target the metastatic sites within the bones: Passive extravasation of the conjugate should occur through the leaky tumor vessels, whereas normal blood vessels in healthy bones should be poor targets owing to the size of the conjugate. The water-soluble HPMA copolymers are biocompatible, non- immunogenic, and nontoxic carriers that enable selective delivery into tumor tissue. (18) These macromolecules (diame- ter of 10-200 nm) do not diffuse through normal blood vessels but rather accumulate selectively in the tumor site because of the enhanced permeability and retention (EPR) effect. (19) Furthermore, conjugation with the HPMA copolymer should restrict the passage through the blood-brain barrier and thus eliminate the neurotoxicity associated with free PTX and prolong the circulation half-life of the free drugs ALN and PTX. Consequently, the inhibitory effect on the growth of tumor endothelial and epithelial cells should be enhanced by the exposure of the cells to the conjugated drugs in the circulation for a longer time. (20-22)
Journal: Angewandte Chemie-international Edition - ANGEW CHEM INT ED , vol. 48, no. 16, pp. 2949-2954, 2009
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