Glutathione-Responsive Prodrug Nanoparticles for Effective Drug Delivery and Cancer Therapy.

Abstract

Spurred by recent progress in medicinal chemistry, numerous lead compounds have sprung up in the past few years, although the majority are hindered by hydrophobicity, which greatly challenges druggability. In an effort to assess the potential of platinum (Pt) candidates, the nanosizing approach to alter the pharmacology of hydrophobic Pt(IV) prodrugs in discovery and development settings is described. The construction of a self-assembled nanoparticle (NP) platform, composed of amphiphilic lipid-polyethylene glycol (PEG) for effective delivery of Pt(IV) prodrugs capable of resisting thiol-mediated detoxification through a glutathione (GSH)-exhausting effect, offers a promising route to synergistically improving safety and efficacy. After a systematic screening, the optimized NPs (referred to as P6 NPs) exhibited small particle size (99.3 nm), high Pt loading (11.24%), reliable dynamic stability (∼7 days), and rapid redox-triggered release (∼80% in 3 days). Subsequent experiments on cells support the emergence of P6 NPs as a highly effective means of transporting a lethal dose of cargo across cytomembranes through macropinocytosis. Upon reduction by cytoplasmic reductants, particularly GSH, P6 NPs under disintegration released sufficient active Pt(II) metabolites, which covalently bound to target DNA and induced significant apoptosis. The PEGylation endowed P6 NPs with in vivo longevity and tumor specificity, which were essential to successfully inhibiting the growth of cisplatin-sensitive and -resistant xenograft tumors, while effectively alleviating toxic side-effects associated with cisplatin. P6 NPs are, therefore, promising for overcoming the bottleneck in the development of Pt drugs for oncotherapy.

• Authors: Xiang Ling, Jiasheng Tu, Junqing Wang, Aram Shajii, Na Kong, Chan Feng, Ye Zhang, Mikyung Yu, Tian Xie, Zameer Bharwani, Bader M Aljaeid, Bingyang Shi, Wei Tao, Omid C Farokhzad
• Journal: ACS nano (ACS Nano) Vol. 13 Issue 1 Pg. 357-370 (01 22 2019) ISSN: 1936-086X [Electronic] United States
• PMID: 30485068 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Prodrugs
• Polyethylene Glycols
• Glutathione

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics)
• Cell Line, Tumor
• Female
• Glutathione (metabolism)
• Humans
• Mice
• Mice, Nude
• Nanoparticles (chemistry, metabolism)
• Organoplatinum Compounds (chemistry)
• Pinocytosis
• Polyethylene Glycols (chemistry)
• Prodrugs (administration & dosage, chemistry, pharmacokinetics)