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Journal of controlled release : official journal of the Controlled Release Society v.247, 2017년, pp.73 - 85   SCI SCIE
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Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

England, Richard M. (AstraZeneca, Pharmaceutical Sciences, Innovative Medicines, Silk Court Business Park, Macclesfield, Cheshire SK10 2NA, United Kingdom. ) ; Hare, Jennifer I. (AstraZeneca, IMED Oncology, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom ) ; Barnes, Jennifer (AstraZeneca, Pathological Sciences, Drug Safety and Metabolism, Cambridge, CB4 0WG, United Kingdom ) ; Wilson, Joanne (AstraZeneca, IMED Oncology, Li Ka Shing Centre, CRUK Cambridge Institute, Cambridge CB2 0RE, United Kingdom ) ; Smith, Aaron (AstraZeneca, IMED Oncology, Li Ka Shing Centre, CRUK Cambridge Institute, Cambridge CB2 0RE, United Kingdom ) ; Strittmatter, Nicole (AstraZeneca, Pathological Sciences, Drug Safety and Metabolism, Cambridge, CB4 0WG, United Kingdom ) ; Kemmitt, Paul D. (AstraZeneca, IMED Oncology, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom ) ; Waring, Michael J. (Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom ) ; Barry, Simon T. (AstraZeneca, IMED Oncology, Li Ka Shing Centre, CRUK Cambridge Institute, Cambridge CB2 0RE, United Kingdom ; ) ; Alexander, Cameron ; Ashford, Marianne B. ;
  • 초록  

    Abstract Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 L -lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial C max of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Nanomedicine .   Irinotecan .   SN-38 .   Dendrimer .   Colorectal cancer .   Drug delivery .   Therapeutic index.  

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