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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.

SUBMITTER: Ling X

PROVIDER: S-EPMC7049173 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Ling Xiang X Tu Jiasheng J Wang Junqing J Shajii Aram A Kong Na N Feng Chan C Zhang Ye Y Yu Mikyung M Xie Tian T Bharwani Zameer Z Aljaeid Bader M BM Shi Bingyang B Tao Wei W Farokhzad Omid C OC

ACS nano 20181204 1

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- ...[more]

PMID: 30485068

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Project description:The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2 to release CB and Ce6. Ce6 can effectively generate abundant 1O2 under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2 and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment. Graphical abstract Schematic diagram of the H2O2-responsive P(EG-a-CPBE) prodrug with GSH-scavenger to encapsulate Ce6 for enhanced chemo-photodynamic synergistic cancer therapy.Image 1 Highlights • Polymer prodrug P(EG-a-CPBE) was synthesized by conjugating the chemodrug CB to the hydrophilic alternating copolymer P(EG-a-PD) via a H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA).• H2O2-responsive P(EG-a-CPBE) prodrug with GSH-scavenger was used to encapsulate photosensitizer Ce6 to form the Ce6@P(EG-a-CPBE) NPs for chemo-photodynamic synergistic cancer therapy.• Upon irradiation by 660 nm laser, the Ce6@P(EG-a-CPBE) NPs showed superior synergistic therapeutic effect and excellent biosafety.

Dataset Information

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

Publications

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

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