Delivery of Cationic Platinum Prodrugs via Reduction Sensitive Polymer for Improved Chemotherapy

Abstract

A cationic monofunctional platinum anticancer drug, phenanthriplatin (PhenPt(II)), exhibits promising anticancer effect on various cancer cell lines. Unlike the conventional platinum(II) drugs, PhenPt(II) is more likely to bind the N7 adenosine base of DNA in situ, and consequently resulting in a unique cellular response profile and unusual potency. However, since this drug is positively charged, it can easily bind to plasma protein that leads to rapid systematic clearance and deleterious toxicities, which greatly limits its in vivo application. Herein, a lipophilic phenanthriplatin (PhenPt(IV)) prodrug is synthesized. To further reduce its toxicity, a negatively charged polymer P1 with reduction responsiveness is assembled with PhenPt(IV) to form PhenPt(IV) NPs. In comparison to cisplatin, PhenPt(IV) NPs exhibit up to 30 times greater in vitro potency against various cancer cell lines. Additionally, in vivo, no obvious side effect is found on PhenPt(IV) NPs. Significant enhancement in tumor accumulation and improvement of drug efficacy in 4T1 tumor model are demonstrated. Taken together, this study provides a promising strategy for the clinical translation of phenanthriplatin.

A Clinically Translatable Ternary Platinum(IV) Prodrug for Synergistically Reversing Drug Resistance

“…Tremendous progress has been made in the past several decades to develop novel nanodrug delivery systems to reverse cisplatin resistance by inhibiting GSH detoxification and reducing DNA self-repair. ,− Notable reported strategies using GSH-depleting nanomedicines for reversing cisplatin resistance include the introduction of reducible disulfide links, quinone methide, and NIR-light-triggered hyperthermia agents. , Alternatively, simultaneous transportation of cisplatin and DNA repair-inhibiting reagents such as hypoxia-activatable tirapazamine, toxic ONOO – -generating agents, and phosphoinositide 3-kinase (PI3K) inhibitors has been confirmed to be a useful means of overcoming drug resistance. Although both strategies have led to improved therapeutic efficiency against resistant tumor cells, successful clinical translation of those delivery systems still suffered from multistep synthesis and purification procedures, low drug loading efficiency, and utilization of any clinically unapproved materials.…”

Synthesis and DNA Interactions Study of Novel Fluorinated Pyridinium Platinum (IV) Complexes with Tumor Targeting Activity

“…In addition, the axial positions of Pt(IV) prodrugs allow the introduction of functionalized molecules as ligands to diversify the anti‐tumor effects and functions of Pt(IV) drugs, such as enhanced redox stability, cancer cell targeting, and/or synergistic anti‐tumor effects [2] . On the other hand, compared with classical platinum drugs, platinum drugs with different DNA binding mechanisms (such as intercalation, groove binding, or electrostatic interactions) are expected to overcome platinum drug resistance, so the design of this class of drugs is also a promising strategy to improve the therapeutic efficacy of platinum drugs [3] …”

“…[2] On the other hand, compared with classical platinum drugs, platinum drugs with different DNA binding mechanisms (such as intercalation, groove binding, or electrostatic interactions) are expected to overcome platinum drug resistance, so the design of this class of drugs is also a promising strategy to improve the therapeutic efficacy of platinum drugs. [3] Picoplatin, with the formula cis-[PtCl 2 (NH 3 )(C 6 H 7 N)], is a new generation of Pt(II) complex after cisplatin, carboplatin and oxaliplatin. The 2-methylpyridine ligand has a "steric hindrance effect", which reduces the hydrolysis rate of picoplatin and can spatially hinder the reaction of picoplatin with glutathione (GSH), thereby improving drug resistance mediated by glutathione.…”

Fluorescence‐Guided Spatial Drug Screening in 3D Colorectal Cancer Spheroids

“…Of note, several Pt(IV) compounds were designed with specific ligands to enhance apoptosis and demonstrated improvements over Pt(II) drugs in terms of antitumor efficacy. [31,32,61] Our previous work reported on a library of mitochondriatargeting Pt(IV) compounds for ovarian cancer. [55] These Pt(IV) compounds, based on either a cisplatin or oxaliplatin scaffold, were further modified with the inclusion of a chemosensitizer, 4phenylbutyrate (PhB) or dichloroacetic acid, and a mitochondriatargeting ligand, triphenylphosphonium (TPP) (Figure 1).…”