Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile
| Autor: | Tina Van Geen Hoven, Daniel D. Von Hoff, Kevin McDonnell, Allen Horhota, James Wright, Erick Peeke, Jason Auer, Stephen E. Zale, Abhimanyu Sabnis, Jason Summa, Michael Figa, Young-Ho Song, Mir Mukkaram Ali, David De Witt, Greg Troiano, Edward Schnipper, Jeffrey J. Song, Susan Low, Omid C. Farokhzad, Beadle Retnarajan, Tarikh Christopher Campbell, Douglas Tompsett, Elizaveta Andrianova, Christopher Sweeney, Jeffrey S. Hrkach, Neil H. Bander, Philip W. Kantoff, Robert Langer, Maria Figueiredo, Patricia LoRusso |
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| Rok vydání: | 2012 |
| Předmět: |
Glutamate Carboxypeptidase II
Male Drug Polymers media_common.quotation_subject Docetaxel Mice Prostate cancer Pharmacokinetics Antigen Cell Line Tumor Glutamate carboxypeptidase II medicine Animals Humans media_common business.industry General Medicine medicine.disease Xenograft Model Antitumor Assays Controlled release Tumor antigen Rats Antigens Surface Cancer research Nanoparticles Taxoids business medicine.drug |
| Zdroj: | Science Translational Medicine. 4 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic. |
| Databáze: | OpenAIRE |
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