Synthesis and Characterization of Novel Polyphosphazene-Docetaxel Conjugate

Abstract

Docetaxel(DTX) belongs to the taxane group and is a semi-synthetic analogue of paclitaxel. It is a useful chemotherapeutic agent for advanced or metastatic breast cancer, head and neck cancer, gastric cancer, hormone refractory prostate cancer and non-small-cell lung cancer. However, DTX has several side effects such as neutropenia, febrile neutropenia and neurosensory disturbances. These undesirable side effect are attribute to DTX itself and non-ionic surfactants (e.q., polysorbate 80) used to dissolve DTX. Beside that DTX is unsuitable to apply in clinical trial because of the characteristics of non-target toxicity and a short circulation time. In order to overcome such shortcomings and enhance its efficacy, a novel polyphosphazene drug delivery system [NP(MPEG550)1.5(LysEt)0.5]n (PP550) was first prepared as a carrier polymer, and DTX was conjugated to the newly synthesized polymer. This system was named as “Polytaxel” (PP550D). According to the biodistribution study, Polytaxel showed high tumor selectivity with the TTR value (tumor tissue to normal tissue ratio) of 3 to 5. This beneficial outcome originated from the enhanced permeability and retention (EPR) effect and extended systemic circulation of Polytaxel. The corresponding values of τ1/2 of Polytaxel and Taxotere were 6.115 and 0.615 h. Inaddition, AUC of Polytaxel amounted to 1.439 μg•h/ml, whereas that of Taxotere was only 0.678 μg•h/ml. On study demonstrated that Polytaxel satisfy most of the requirments to become a new targeting anticancer drug in the future.;탁센(taxane)계열인 도세탁셀(docetaxel) 항암제는 유방암, 위암, 호르몬 무반응성 전립선암 등 다양한 암에 대한 탁월한 효과들을 보여왔다. 하지만 항암제와 계면활성제인 폴리소베이트 80(polysorbate 80)으로 인해 호중구 감소증, 감각신경장애와 같은 부작용이 나타나고 임상적으로 비표적 장기에 대한 독성과 짧은 반감기로 인해 많은 환자군 에서의 폭 넓은 사용은 제한되어 왔다. 이번 연구에서 도세탁셀 항암제에 고분자요법을 적용하여 항암제 본래의 단점을 감소하고 항암제로써 필요한 요소들을 보강한 폴리포스파젠(polyphosphazene)을 기반으로한 [NP(MPEG550)1.5(LysEt)0.5]n (PP550) 약물 전달체를 만들어 도세탁셀과 컨쥬게이트(conjugate)하여 새로이 폴리탁셀(polytaxel)을 합성하였다. 생체분포 실험을 수행한 결과, EPR효과로 인한 암 선택성이 높게 나왔으며 랫트(rat)에게 5mg/kg의 농도로 정맥 투여하여 도출한 약동학적 지표에서, 현재 널리 사용되고 있는 도세탁셀 항암제인 탁소티어(taxotere)의 (τ1/2 = 0.651 h and AUC = 0.678 μg•h/ml) 보다 폴리탁셀(τ1/2 = 6.115 h and AUC = 1.439 μg•h/ml)이 우수하게 나왔다. 이러한 결과들로, 합성된 폴리탁셀이 다양한 면에서 조건이 갖춰졌으므로 새로운 항암제로 발전하기에 높은 가능성을 확인하였다.