Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity.
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 IC(50) 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 next-generation platinum-based agent in the clinics.
Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine and Center for Regenerative Therapeutics, Brigham and Women's Hospital, Cambridge, MA 02139, USA. ssengupta2@partners.org
Poulomi
P
Sengupta
Sudipta
S
Basu
Shivani
S
Soni
Ambarish
A
Pandey
Bhaskar
B
Roy
Michael S
MS
Oh
Kenneth T
KT
Chin
Abhimanyu S
AS
Paraskar
Sasmit
S
Sarangi
Yamicia
Y
Connor
Venkata S
VS
Sabbisetti
Jawahar
J
Kopparam
Ashish
A
Kulkarni
Katherine
K
Muto
Chitra
C
Amarasiriwardena
Innocent
I
Jayawardene
Nicola
N
Lupoli
Daniela M
DM
Dinulescu
Joseph V
JV
Bonventre
Raghunath A
RA
Mashelkar
Shiladitya
S
Sengupta
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D002470:Cell Survival; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods; D010984:Platinum / Q000008:administration & dosage*; D019802:Succinic Acid / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D010984:Platinum; D002784:Cholesterol; D019802:Succinic Acid; D002945:Cisplatin