Novel Pt(IV) prodrug self-assembled nanoparticles with enhanced blood circulation stability and improved antitumor capacity of oxaliplatin for cancer therapy

Abstract

Pt(IV) compounds are regarded as prodrugs of active Pt(II) drugs (i.e. cisplatin, carboplatin, and oxaliplatin) and burgeoned as the most ideal candidates to substitute Pt(II) anticancer drugs with severe side effects. Nanoparticle drug delivery systems have been widely introduced to deliver Pt(IV) prodrugs more effectively and safely to tumors, but clinical outcomes were unpredictable owing to limited in vivo pharmacokinetics understanding. Herein, a novel Pt(IV) prodrug of oxaliplatin(OXA) was synthesized and prepared as self-assembled micellar nanoparticles(PEG-OXA NPs). In vitro, PEG-OXA NPs rapidly released biologically active OXA within 5 min in tumor cells while remaining extremely stable in whole blood or plasma. Importantly, the pharmacokinetic results showed that the AUC 0-∞ , and t 1/2 values of PEG-OXA NPs were 1994 ± 117 h·µg/mL and 3.28 ± 0.28 h, respectively, which were much higher than that of free OXA solution (2.03 ± 0.55 h·µg/mL and 0.16 ± 0.07 h), indicating the longer drug circulation of PEG-OXA NPs in vivo. The altered pharmacokinetic behavior of PEG-OXA NPs remarkably contributed to improve antitumor efficacy, decrease systemic toxicity and increase tumor growth inhibition compared to free OXA. These findings establish that PEG-OXA NPs have the potential to offer a desirable self-delivery platform of platinum drugs for anticancer therapeutics.

Metallodrugs in the battle against non-small cell lung cancer: unlocking the potential for improved therapeutic outcomes

“…These are the most extensively studied and clinically utilized metallodrugs in cancer therapy. This group includes first-generation cisplatin ( Johnstone et al, 2016 ), second-generation carboplatin ( Devanabanda and Kasi, 2023a ), third-generation oxaliplatin ( Devanabanda and Kasi, 2023b ), and novel platinum nanoparticled complexes ( Fu et al, 2023 ). By forming DNA adducts induced apoptosis, these platinum-based drugs exert their anti-cancer effects with varying pharmacokinetics, toxicity profiles, resistance mechanisms, and therapeutic indications.…”

Pt(iv) anticancer prodrugs bearing an oxaliplatin scaffold: what do we know about their bioactivity?

“…41) to form self-assembled micellar nanoparticles (PEG-OXA NPs). 144 The cytotoxicity in HT29 cells was found to be 1.7-fold lower than oxaliplatin alone (6.12 μM) at 48 h. In vitro , PEG-OXA NPs remained stable in plasma but rapidly released oxaliplatin in HT29 tumor cells. In vivo , pharmacokinetic studies demonstrated a long circulation of the nanoparticles with a low concentration of oxaliplatin in plasma upon PEG-OXA NPs administration.…”

“…41) to form selfassembled micellar nanoparticles (PEG-OXA NPs). 144 The cytotoxicity in HT29 cells was found to be 1.7-fold lower than oxaliplatin alone (6.12 μM) at 48 h. In vitro, PEG-OXA NPs remained In another example, a prodrug vesicle (NP2) for ICD-based cancer chemoimmunotherapy was reported. 145 The vesicles comprised an oxaliplatin prodrug HODAan hexadecyl-oxaliplatin diethylene amine modified with the acid-sensitive 2,3dimethylmaleic anhydride (compound 106, Fig.…”

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

“…Pt(IV), the oxidized state of divalent platinum, is a focal point in the research and development of novel platinum-based drugs. Pt(IV) compounds offer several advantages: (1) Improved drug stability: Pt(IV) compounds exhibit good stability, reducing drug degradation and inactivation in the body, thus prolonging the drug's half-life [13,[15][16][17].…”

“…Pt(IV), the oxidized state of divalent platinum, is a focal point in the research and development of novel platinum-based drugs. Pt(IV) compounds offer several advantages: (1) Improved drug stability: Pt(IV) compounds exhibit good stability, reducing drug degradation and inactivation in the body, thus prolonging the drug’s half-life [ 13 , 15 , 16 , 17 ]. (2) Increased selectivity: Pt(IV) compounds can selectively target specific tumors by tailoring their ligand structure and chemical properties, minimizing toxicity to normal cells [ 18 ].…”