Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity

被引：123

作者：

Sengupta, Poulomi ^{[1
,2
,7
]}

Basu, Sudipta ^{[1
,2
,7
]}

Soni, Shivani ^{[1
,2
,7
]}

Pandey, Ambarish ^{[1
,2
,7
]}

Roy, Bhaskar ^{[1
,2
,7
]}

Oh, Michael S. ^{[1
,2
,7
]}

Chin, Kenneth T. ^{[5
]}

Paraskar, Abhimanyu S. ^{[1
,2
,7
]}

Sarangi, Sasmit ^{[1
,2
,7
]}

Connor, Yamicia ^{[1
,2
,7
,8
]}

Sabbisetti, Venkata S. ^{[3
,4
,7
]}

Kopparam, Jawahar ^{[1
,2
,7
]}

Kulkarni, Ashish ^{[1
,2
,7
]}

Muto, Katherine ^{[5
]}

Amarasiriwardena, Chitra ^{[6
,10
]}

Jayawardene, Innocent ^{[6
,10
]}

Lupoli, Nicola ^{[6
,10
]}

Dinulescu, Daniela M. ^{[5
,7
]}

Bonventre, Joseph V. ^{[3
,4
,7
]}

Mashelkar, Raghunath A. ^{[1
,2
,9
]}

Sengupta, Shiladitya ^{[1
,2
,7
,8
,11
,12
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Lab Nanomed, Div Biomed Engn, Cambridge, MA 02139 USA

[2] Brigham & Womens Hosp, Ctr Regenerat Therapeut, Cambridge, MA 02139 USA

[3] Brigham & Womens Hosp, Div Renal, Cambridge, MA 02139 USA

[4] Brigham & Womens Hosp, Div Biomed Engn, Cambridge, MA 02139 USA

[5] Brigham & Womens Hosp, Dept Pathol, Cambridge, MA 02139 USA

[6] Brigham & Womens Hosp, Channing Lab, Cambridge, MA 02139 USA

[7] Harvard Univ, Sch Med, Boston, MA 02115 USA

[8] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[9] Natl Chem Labs, Pune 411021, Maharashtra, India

[10] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA

[11] Indo US Joint Ctr Nanobiotechnol, Cambridge, MA 02139 USA

[12] Dana Farber Canc Inst, Brookline, MA 02445 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 28期

基金：

美国国家卫生研究院;

关键词：

chemotherapy; nanomedicine; LIPOSOMAL-CISPLATIN; ANTICANCER AGENTS; K-RAS; CANCER; PHARMACOKINETICS; FORMULATIONS; TRANSPORT; DELIVERY; CARRIERS; TUMORS;

D O I：

10.1073/pnas.1203129109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O -> Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+/)Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a nextgeneration platinum-based agent in the clinics.

引用

页码：11294 / 11299

页数：6

共 39 条

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