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

Abstract

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 systemicand 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.chemotherapy | nanomedicine

Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

“…Conversely, genetically engineered models are particularly suited for testing nanocarriers as they promote stepwise molecular and cellular events resulting in malignancies with close interactions with immune cells, vascular and lymphatic networks, and the extracellular matrix (6,7). Moreover, whereas the therapeutic effect of nanocarriers on transgenic tumor models has been assessed by endpoint analysis (13) or indirectly measuring the tumor burden by computed tomography (14), in this study, we were able to match initial tumor burden between groups, monitor the progression of tumors, incidence of metastases and ascites, and the antitumor activity of micelles in real time by bioluminescence imaging due to the Fig. 4.…”

“…Genetically engineered tumor models arise in situ where immune function, angiogenesis, and inflammatory processes can all interact normally with a gradually developing tumor, closely relating to the clinical setting of the disease (6,7). Although these transgenic tumor models may be more appropriate for the evaluation of promising nanocarriers, only a few nanocarrier systems have been assessed on transgenic models so far (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), mainly for imaging purposes (15)(16)(17)(18)(19).…”

Engineering of lipid prodrug-based, hyaluronic acid-decorated nanostructured lipid carriers platform for 5-fluorouracil and cisplatin combination gastric cancer therapy

“…33 In order to reduce the toxicity, nanoparticles and liposomes have been used. [34][35][36] CDDP is poorly soluble in water and can be loaded into NLC.…”

Scope of Nanotechnology in Drug Delivery

“…[44][45][46][47][48][49][50]. Another targeting systems for cancer treatment was also investigated with microRNAdirected oncology approach using MRX34 (a liposome-containing miRNA carrier), for usefulness in metastatic liver cancer [51,52].…”