Design and development of multi-targeted anticancer agents for anti-angiogenic therapy or tumor tissue-selective delivery
혈관신생억제 및 종양선택적 전달을 위한 다중표적형 항암제의 설계와 개발
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2015. 2. 변영로.
- Despite the rapid advances of cancer research, cancer is still one of the leading causes of mortality worldwide. During the past decades, research of anticancer agents mostly focused on selective targeting of tumor-specific antigens in the context of molecular targeted therapy as well as targeted drug delivery to improve the therapeutic index of the traditional chemotherapy. However, due to the intrinsic genetic diversity and complexity of tumors, the targeted therapeutics showed only limited improvements. Therefore, a breakthrough of the fundamental concept in cancer treatment has been deemed necessary. In this dissertation, novel therapeutic alternatives are proposed and evaluated that could contribute to the further advance in the cancer therapeutics.
Part one concerns development of a heparin-based anti-angiogenic agent LHT7 ? a sodium taurocholate conjugated LMWH ? that inhibits multiple stages of angiogenesis, and investigation of its mode of action. This study showed that the conjugation of sodium taurocholates abolished the intrinsic capability of LMWH to interact with ATIII while enhancing the binding property on VEGF, resulting in decreased anticoagulant activity and enhanced anti-angiogenic activity. The differential effects of sodium taurocholate conjugation to LMWH on its interaction between ATIII and VEGF were attributable to the unique structure of sodium taurocholate: the bulky and rigid sterane core of taurocholate sterically concealed the ATIII-binding pentasaccharide unit of LMWH, while the terminal sulfate group generated additional interactions with VEGF leading to a stronger binding.
The major advantage of exploiting heparin as a lead compound for the development of novel anti-angiogenic agents comes from the intrinsic capability of interacting and regulating wide array of pro-angiogenic factors. LHT7 was speculated to block FGF2 and PDGF-B in addition to VEGF. Since these three pro-angiogenic factors play key roles in multiple stages of angiogenesis, simultaneous blockade of these factors resulted in potent suppression of tumor angiogenesis as well as tumor growth. The results of this study suggested that LHT7 would potentially overcome the resistance issue shown in the conventional anti-angiogenic agents.
Part two discusses development of doxorubicin prodrugs that target induced-apoptosis for effective delivery of chemotherapeutics to the tumor regardless of its genomic property. The first doxorubicin prodrug involves two distinct features for an effective tumor targeting: EPR effect-mediated tumor accumulation with extended plasma half-life, and radiation-induced apoptosis targeting. This prodrug ? EMC-DEVD-S-DOX ? comprises a maleimide group, which binds to the circulating albumin after intravenous administration, and a DEVD motif, which is cleaved by caspase-3 upregulated in the tumor cells that are exposed to radiation. The EMC-DEVD-S-DOX showed a prolonged plasma half-life with selective accumulation within tumor tissue, and released free doxorubicin only when combined with radiotherapy.
The second doxorubicin prodrug ? RGDEVD-DOX ? comprises an integrin αvβ3 recognizing RGD sequence and a DEVD sequence. The RGD moiety selectively delivers the prodrug to the tumor during the initial phase of administration and induces apoptosis in certain subclone of tumor cells as well as tumor endothelial cells that overexpress integrin αvβ3. The caspase-3 from the apoptotic cells further activates other molecules of the prodrug, forcing those to release hydrophobic active compound with facilitated cell penetration regardless of integrin αvβ3 expression. Therefore, it could affect broader range of tumor cells within the tumor tissue, thereby providing more effective therapeutic outcomes. Since the upregulation of the caspase-3, which is the key event of the proposed drug delivery strategy, is common during the apoptosis, the genomic diversity of tumor cells hardly influences the efficacy of the currently developed prodrugs.