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Design and Evaluation of Novel Theranostic Polyphosphazene-Drug Conjugates

Title
Design and Evaluation of Novel Theranostic Polyphosphazene-Drug Conjugates
Authors
박정현
Issue Date
2016
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
이화정
Abstract
Docetaxel and oxaliplatin are anticancer agents widely used in cancer chemotherapy for various cancers such as non small cell lung cancer and colorectal cancer. In this study, a new biocompatible polyphosphazene drug delivery system as a drug carrier polymer was designed and conjugated to both drugs. A hydrophilic methoxy poly(ethylene glycol) with an average molecular weight of 550 (MPEG550) was introduced to the polyphosphazene backbone as a side group for long blood circulation. These polyphosphazene-drug conjugates were named “Polytaxel” and “Polyplatin”, respectively. The cryo-TEM image and DLS (dynamic light scattering) measurements of Polytaxel and Polyplatin showed typical polymeric micelles with a mean diameter of 123.7 nm and 55.1 nm, which are suitable sizes for passive tumor targeting by EPR effect. Several studies were performed to evaluate physicochemical properties, pharmacokinetics, in vivo efficacy and toxicity. The pharmacokinetics of Polytaxel and Polyplatin were remarkably improved with prolonged elimination half-life (t1/2, t1/2β) and enhanced AUClast compared with their references. They were accumulated in tumor tissue other than normal organs along with high value of TTR and cleared out from the major organs after approximately 5-6 weeks after injection. The xenograft trials using nude mouse against the human gastric tumor cell line MKN-28 have shown excellent tumor regression with low systemic toxicity. Therefore, Polytaxel and Polyplatin are promising candidates for clinical studies.;도세탁셀과 옥살리플라틴은 비소세포성 폐암과 대장암 등의 다양한 암의 치료에 널리 사용되는 항암제이다. 이 연구에서는, 고분자 약물전달 시스템으로 생체에 적합한 새로운 폴리포스파젠을 합성하고, 여기에 항암제인 도세탁셀과 옥살리플라틴을 도입하여 각각 “Polytaxel”과 “Polyplatin” 으로 명명하였다. Polytaxel과 Polyplatin은 고분자마이셀로 평균 지름이 123.7 nm 와 55.1 nm 이었으며, 이는 EPR 효과를 나타내기에 최적의 크기 범위에 해당한다. 물리화학적 성질과 약물동태, 항암효능과 독성 등을 평가하기 위하여 여러가지 시험이 시행되었다. Polytaxel과 Polyplatin 모두 대조군 약물에 비해 반감기가 현저하게 증가하였으며, AUC 또한 증가하였다. 이 약물들은 정상 조직보다 암 조직에 선택적으로 축적되는 결과를 보였으며, 체내에서 약 5-6주 후에 완전히 사라지는 것을 확인하였다. 사람 위암 세포를 사용한 항암효능 시험에서도 훌륭한 암성장 저해를 보였으며, 독성 또한 낮았다. 따라서, Polytaxel과 Polyplatin은 새로운 항암제로서 발전하기에 높은 가능성이 있다고 여겨진다.
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