Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy

Abstract

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O → Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 AE 0.16 μM) comparable to that of free cisplatin (3.87 AE 0.37 μM), and superior to carboplatin (14.75 AE 0.38 μM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras LSL∕þ ∕Pten fl∕fl ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structureactivity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.chemotherapy | nanomedicine | cancer

Electrohydrodynamic fabrication of core–shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment

“…It has been suggested that internalization of CDDP-loaded carriers is a key factor in increasing the drug's efficacy. 35,36 Therefore, the enhanced cytotoxicity of the PLGA nanocarriers in comparison to free drug may also be explained by the effective endocytosis exhibited by both types of NPs. The CS-CDDP NPs demonstrated relatively similar cytotoxicity to the U-CDDP NPs, although they released ~10% less drug over the 72 h period, possibly, because they released less of the drug into the cell medium and more intracellularly.…”

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

“…Yet, no improvement in antitumor activity of ∼110 nm PEG-poly (N-amino acidyl)-aspartamidecisplatin micelles relative to free cisplatin was reported. Recent work by Paraskar et al 33 also utilized aggressive cancer models (subcutaneous Lewis lung carcinoma and 4T1 breast cancer xenografts) to evaluate the antitumor activity of 80-140 nm cisplatin-loaded poly-isobutylene-maleic acid nanoparticles. However, no improvement in antitumor activity relative to equidose free cisplatin was observed.…”

Reporter nanoparticle that monitors its anticancer efficacy in real time

“…PIMA contains reactive anhydride functional groups that can be easily conjugated to a wide range of drugs and other reactive moieties under mild reaction conditions and can be used for conjugating more than one agent for multiplexing studies. Recently, we reported that the coordination complex between platinum (II) and PIMA could enable the self-assembly into nanostructures that exhibited greater antitumor efficacy with reduced systemic toxicity compared with cisplatin (41,42).…”