Sustained delivery of a camptothecin prodrug – CZ48 by nanosuspensions with improved pharmacokinetics and enhanced anticancer activity
| Autor: | Beppino C Giovanella, Cheng-Hui Hsiao, Diana S.-L. Chow, Zhijie Li, Dong Dong, Yifei Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
Sustained delivery media_common.quotation_subject Biophysics Pharmaceutical Science Bioengineering 02 engineering and technology Pharmacology 010402 general chemistry 01 natural sciences Biomaterials Pharmacokinetics Drug Discovery Zeta potential medicine Clinical efficacy media_common Chemistry Organic Chemistry General Medicine Prodrug 021001 nanoscience & nanotechnology 0104 chemical sciences 0210 nano-technology Camptothecin Efficacy Study medicine.drug |
| Zdroj: | International Journal of Nanomedicine. 14:3799-3817 |
| ISSN: | 1178-2013 |
| Popis: | Background and aim: We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.) administration. Methods and materials: A three-factor, five-level central composite design (CCD) was employed to establish the impacts of the critical influencing factors (concentrations (wt%) of CZ48, polysorbate 80 (Tween-80), and Pluronic® F-108 (F-108)) on the responses (particle size and zeta potential). Based on the quantitative influencing factor-response relationships, two optimized CZ48 nanosuspensions of 197.22 ± 7.12 nm (NS-S) and 589.35 ± 23.27 nm (NS-L) were developed with the zeta potential values of -26.5 mV and -27.9 mV, respectively. Results: CZ48 released from the nanosuspensions in a sustained manner in contrast to the rapid release from cosolvent in both PBS and human plasma. Moreover, NS-S exhibited more favored pharmacokinetic properties than NS-L, with a 31-fold prolonged elimination half-life of CPT, and a 2.4-fold enhanced CPT exposure over cosolvent. In efficacy study, NS-S exhibited significant tumor suppression and an improved survival rate with a higher tolerable dose, compared to CZ48 cosolvent. Conclusion: We have successfully developed CZ48 nanosuspensions with significantly favorable pharmacokinetics and improved efficacy using CCD approach. The formulation offers potential merits as a preferred candidate for clinical trials with the prolonged CPT exposure, which is known to correlate with the clinical efficacy. |
| Databáze: | OpenAIRE |
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