Browse

Pharmacokinetics and pharmacodynamics of novel nanoformulations for the proteasome inhibitor drug carfilzomib : Expanding its therapeutic utility against solid cancers
새로운 나노제형의 개발을 통한 프로테아좀 저해제약물 carfilzomib의 약동학 및 약력학적 특성 개선

DC Field Value Language
dc.contributor.advisor이우인-
dc.contributor.author박지은-
dc.date.accessioned2019-05-07T06:28:47Z-
dc.date.available2020-02-03T23:58:14Z-
dc.date.issued2019-02-
dc.identifier.other000000154454-
dc.identifier.urihttps://hdl.handle.net/10371/152526-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과, 2019. 2. 이우인.-
dc.description.abstractOver two decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today proteasome inhibitors (PIs) are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of three billion US dollars annually. More importantly, the availability of PIs has greatly improved the survival and quality of life for patients with MM. Carfilzomib (CFZ) is the second-in-class PI with much improved efficacy and safety profiles over bortezomib, the first-in-class PI, for MM therapy. Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. The potential for improvement remains and the development and optimal use of PIs for solid cancer therapy continues to be an active area of research. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites is considered to be major factors limiting its efficacy against solid cancers. To expand the utility of CFZ to solid cancer therapy, the aim was to overcome the pharmaceutical limitations of CFZ, and current findings may provide important insights in the development of next-generation PIs. As one of approaches to improve the pharmacokinetic profiles of CFZ, a novel polymer micelle-based formulation of CFZ was developed. In the previous report, polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol)-poly(caprolactone) (PEG-PCL) were shown to improve the metabolic stability of CFZ in vitro. In Chapter I, in vivo anticancer efficacy and pharmacokinetic profiles were assessed using CFZ-loaded PM composed of PEG-PCL-deoxycholic acid (CFZ-PM). Despite in vitro metabolic protection of CFZ, CFZ-PM displayed in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) comparable to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD. The residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, these results showed that despite its favorable in vitro performances, CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Thus, it seems to be necessary to consider potential confounding factors in translating in vitro results to in vivo settings and to develop another type of nanoformulation with an enhanced in vivo stability. In Chapter II, it was investigated whether a nanocrystal (NC) formulation enhances in vivo stability and anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake, and cytotoxic effects in breast cancer cells in vitro. CFZ-alb NC also showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than CFZ-CD. Overall, these results demonstrated the potential of CFZ-alb NC as a viable formulation for breast cancer therapy. These studies may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for breast cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.-
dc.description.abstract현재 임상에서 사용되고 있는 2세대 프로테아좀 저해제인 carfilzomib (CFZ)은1세대 프로테아좀 저해제인 bortezomib과 더불어 다발성 골수종 치료에 매우 획기적인 치료효과를 나타내고 있다. CFZ은 bortezomib 보다 향상된 항암 효과 뿐만 아니라, 구조적으로 epoxyketone pharmacophore를 가지고 있어 타겟인 프로테아좀에 보다 선택적으로 반응하여 개선된 안전성 프로파일을 나타낸다. 하지만 수용성이 매우 낮고 1시간 이내에 체내에서 대부분 소실되는 경향을 보인다는 제한점이 있다. 이는 CFZ의 펩타이드 backbone과 epoxyketone 구조가 대사 반응에 취약하여, 체내 대사가 빠른 시간 내에 일어나기 때문에 짧은 반감기의 약물동태학적 특성을 보이는 것으로 사료된다. 이러한 제한 점을 극복하기 위해 나노제형을 도입한다면 CFZ의 약물동태학적 문제점을 해결하고 더 나아가 약물동력학적 특성도 개선할 수 있어 고형암 환자에게 적용 가능성의 향상을 또한 예상하는 바, 본 연구에서는 CFZ의 새로운 나노제형을 개발하고 고형암 세포주와 실험 동물 모델을 사용하여 항암 효능을 평가 하였다.

이전의 연구에서는 생분해성 폴리머인 폴리에틸렌글리콜과 폴리카프로락톤으로 구성된 폴리머마이셀에 CFZ을 loading 하였을 경우 in vitro 실험계에서 대사 안정성이 향상되었음 이미 보고 한 바가 있다. 이에 본 논문연구에서는 선행 연구되었던 CFZ을 포함하는 폴리머마이셀 나노제형(CFZ-PM)의 항암 효능의 향상 여부를 인간 폐암 세포주 H460가 이식된 마우스 실험 동물 모델에서 평가하여 보았다. CFZ-PM를 투약한 마우스에서 종양 증식 억제효과가 나타나기는 하였지만, 임상적으로 사용되는 사이클로 덱스트린 기반의 CFZ 제제 (CFZ-CD)보다 우수한 효과를 나타내지는 않았다. 이는 CFZ-PM의 혈장 약물동태학 프로파일이 CFZ-CD과 유사하였고, CFZ-PM이 이종 이식 마우스에서 자란 폐암 조직에 대한 CFZ의 접근성이 증가하지 못하여 폐암 조직에 존재하는 프로테아좀을 일부만 억제하는 효과를 보였기 때문으로 사료된다. 이러한 결과를 바탕으로, 보다 제제 안정성이 높고 효과적으로 CFZ 을 암조직으로 전달 하기 위해 새로운 나노제형의 CFZ을 준비하였다.

친수성이 약한 CFZ은 쉽게 결정화되는 특징을 갖고 있어 체내 안정성이 높은 나노크리스탈 제제로 제형화가 가능하리라는 판단 하에 CFZ을 나노크리스탈 제제로 개발하였다. 그리고 CFZ 나노크리스탈 제형의 표면은 알부민으로 코팅하여 암세포 및 암세포 주변에 위치한 알부민 결합 단백질과의 상호 작용을 통해 종양에 대한 약물 전달을 향상시킬 전략을 세웠다. 알부민이 코팅 된 CFZ 의 나노크리스탈 제제 (CFZ-alb NC)는 280nm 크기로서 약 80%의 높은 약물 loading content를 나타내었다. CFZ-alb NC 은 in vitro 와 in vivo 실험계에서 향상된 대사 안정성을 보였을 뿐만 아니라, CFZ solution과 비교하였을 경우 사람의 여러 유방암 세포주에서 향상된 세포 침투 능력 및 세포 독성 효과를 나타냈다. 또한 CFZ-alb NC을 마우스의 유방암 세포주인 4T1가 이식된 BALB/C 마우스 orthotopic 유방암 실험 동물 모델에 투약 하였을 경우 부작용이 없이 CFZ-CD보다 더 향상된 항암 효과를 나타냈다. 이는CFZ-alb NC에 코팅된 알부민이 유방암 조직에 과발현 되어있는 알부민 결합 단백질인 SPARC가 관여하는 전달 메커니즘에 기반함을 검증하였다. 이 연구를 통해 유방암 치료에 적용 가능한 CFZ-alb NC 나노입자 제제화의 잠재력을 입증하였다.
-
dc.description.tableofcontentsABSTRACT.......................................................................................................................................................I

CONTENTS.....................................................................................................................................................III

LIST OF TABLES..............................................................................................................................................VI

LIST OF FIGURES............................................................................................................................................VII



INTRODUCTION: The review of next-generation proteasome inhibitors for cancer research..............................1

1. Proteasomes............................................................................................................................................2

2. Proteasome inhibitor drugs in clinical use for cancer therapy....................................................................4

2.1. Bortezomib (BTZ, PS-341, Velcade): Rise of proteasome inhibitors as an anticancer agent..............5

2.2. Carfilzomib (CFZ, PR-171, Kyprolis®): Novel mode of proteasome inhibition.....................................8

2.3. Ixazomib (IXZ, MLN9708, Ninlaro®): First oral proteasome inhibitor drug.......................................12

3. Drug resistance (acquired or de novo): Major hurdles in improving PI therapy.........................................13

4. Development strategies for next-generation proteasome inhibitors........................................................14

4.1. Immunoproteasome-selective inhibitors..........................................................................................15

4.2. Peptide-based proteasome inhibitors..............................................................................................15

4.3. Non-peptide-based proteasome inhibitors......................................................................................15

4.4. Application of drug delivery system on proteasome inhibitors.........................................................17



CHAPTER I. Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and

pharmacokinetic studies in mice...................................................................................................................19

1. Introduction..........................................................................................................................................20

2. Material and methods............................................................................................................................21

3. Results...................................................................................................................................................24

3.1. Physicochemical properties of CFZ-PM............................................................................................24

3.2. In vivo anticancer efficacy of CFZ-PM in H460 xenograft mice.........................................................25

3.3. Proteasome inhibition in post-treatment xenograft tumor tissues and whole blood samples collected

from mice that received CFZ-PM or CFZ-CD.....................................................................................25

3.4. Comparison of plasma PK profiles of CFZ-PM and CFZ-CD in ICR mice.............................................28

4. Discussion.............................................................................................................................................29



CHAPTER II. Expanding therapeutic utility of carfilzomib for breast cancer therapy by novel albumin-coated nanocrystal formulation................................................................................................................................32

1. Introduction..........................................................................................................................................33

2. Material and methods...........................................................................................................................35

3. Result and discussion............................................................................................................................43

3.1. Preparation and characterization of CFZ-alb NC..............................................................................43

3.2. Enhanced physical and metabolic stability of CFZ-alb NC.................................................................46

3.3. Enhanced cellular uptake and cytotoxic effects of CFZ-alb NC in breast cancer cell lines...................48

3.4. Enhanced in vivo anticancer efficacy of CFZ-alb NC in BALB/C bearing 4T1 breast cancer cell...........51

3.5. Comparison of PK and BD profiles of CFZ-alb NC with CFZ-CD........................................................53

3.6. SPARC-dependent uptake of CFZ-alb NC to cancer cells...................................................................57

4. Supporting information.........................................................................................................................60

4.1. Supporting experimental methods..................................................................................................60

4.2. Supporting table.............................................................................................................................63

4.3. Supporting figures..........................................................................................................................64



CONCLUSION................................................................................................................................................70

REFERENCES.................................................................................................................................................72

국문 초록.......................................................................................................................................................83



APPENDIX.....................................................................................................................................................85
-
dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subject.ddc615-
dc.titlePharmacokinetics and pharmacodynamics of novel nanoformulations for the proteasome inhibitor drug carfilzomib-
dc.title.alternative새로운 나노제형의 개발을 통한 프로테아좀 저해제약물 carfilzomib의 약동학 및 약력학적 특성 개선-
dc.typeThesis-
dc.typeDissertation-
dc.contributor.AlternativeAuthorJI EUN PARK-
dc.description.degreeDoctor-
dc.contributor.affiliation약학대학 약학과-
dc.date.awarded2019-02-
dc.title.subtitleExpanding its therapeutic utility against solid cancers-
dc.contributor.major약제과학-
dc.identifier.uciI804:11032-000000154454-
dc.identifier.holdings000000000026▲000000000039▲000000154454▲-
Appears in Collections:
College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
Files in This Item:
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse