RESUMO
We have previously improved the bioactivity of PEG5k-FTS2 system by incorporating disulfide bond (PEG5k-S-S-FTS2) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG5k-FTS2 system (PEG5k-Fmoc-FTS2) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG5k-FTS2 to form a simple PEG5k-Fmoc-S-S-FTS2 micellar system. PEG5k-Fmoc-S-S-FTS2 conjugate formed filamentous micelles with a â¼10-fold decrease in critical micellar concentration (CMC). Compared with PEG5k-Fmoc-FTS2, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG5k-Fmoc-S-S-FTS2 in treated tumor cells compared to PEG5k-Fmoc-FTS2, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG5k-Fmoc-S-S-FTS2 micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG5k-Fmoc-FTS2. PTX release kinetics of PTX/PEG5k-Fmoc-S-S-FTS2 was much slower than that of Taxol and PTX/PEG5k-Fmoc-FTS2 in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG5k-Fmoc-S-S-FTS2 micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG5k-Fmoc-S-S-FTS2 system maintained PTX in circulation for a longer time and delivered more PTX to tumor sites with less accumulation in major organs. Finally, PTX-loaded PEG5k-Fmoc-S-S-FTS2 micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG5k-Fmoc-FTS2 micelles.
Assuntos
Paclitaxel/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Farneseno Álcool/análogos & derivados , Farneseno Álcool/química , Feminino , Glutationa/química , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Polietilenoglicóis/química , Salicilatos/química , Distribuição TecidualRESUMO
Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)-induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)-containing diet for bile acid depletion, or a 0.2% cholic acid (CA)-containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet-fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury.
Assuntos
Acetaminofen/efeitos adversos , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Overdose de Drogas/patologia , Overdose de Drogas/fisiopatologia , Regeneração Hepática , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Resina de Colestiramina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We have developed a dual-functional nanocarrier composed of a hydrophilic polyethylene glycol (PEG) and a hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist), which is effective in delivery of hydrophobic anticancer drug, paclitaxel (PTX). To facilitate the retention of the therapeutic activity of the carrier, FTS was coupled to PEG via a reduction-sensitive disulfide linkage (PEG5k-S-S-FTS2). PEG5k-S-S-FTS2 conjugate formed uniform micelles with very small size (â¼30 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG5k-FTS2 micellar system resulted in a 4-fold decrease in the critical micelle concentration (CMC). In addition, the PTX loading capacity and colloidal stability of PTX-loaded micelles were improved. HPLC-MS showed that parent FTS could be more effectively released from PEG5k-S-S-FTS2 conjugate in tumor cells/tissues compared to PEG5k-FTS2 conjugate in vitro and in vivo. PEG5k-S-S-FTS2 exhibited a higher level of cytotoxicity toward tumor cells than PEG5k-FTS2 without a disulfide linkage. Furthermore, PTX-loaded PEG5k-S-S-FTS2 micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG5k-FTS2 micelles. More importantly, PTX-loaded PEG5k-S-S-FTS2 micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG5k-FTS2 micelles in an aggressive murine breast cancer model (4T1.2).
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Micelas , Nanoestruturas/química , Paclitaxel/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Farneseno Álcool/análogos & derivados , Farneseno Álcool/química , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Oxirredução , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , Salicilatos/químicaRESUMO
Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumours as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-b-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed. POEG-b-PSAHA prodrug polymer was able to form spherical micelles with a diameter around 60 nm and well retained the pharmacological activity of SAHA in either inhibiting the proliferation of tumour cells or inducing histone acetylation. DOX formulated in POEG-b-PSAHA-based micelles showed a sustained release profile. DOX-loaded POEG-b-PSAHA exhibited more potent cytotoxicity towards tumour cells than free DOX and DOX loaded in a pharmacologically 'inert' nanocarrier, POEG-b-POM. Consistently, DOX/POEG-b-PSAHA formulation resulted in an improved therapeutic effect in vivo compared to free DOX, Doxil or DOX formulated in POEG-b-POM micelles. These results suggest that SAHA-based prodrug micelles may serve as a dual functional carrier for combination strategies in epigenetic-oriented anticancer therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias/tratamento farmacológico , Vorinostat/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Preparações de Ação Retardada , Portadores de Fármacos/química , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Neoplasias/patologia , Polímeros/química , Ácidos Polimetacrílicos/química , Pró-FármacosRESUMO
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42â¯days at 4⯰C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMPâ¯>â¯DOX/POEG-b-POMâ¯≥â¯Doxilâ¯>â¯POEG-b-PPPMPâ¯>â¯POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.
Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Portadores de Fármacos/administração & dosagem , Glucosiltransferases/antagonistas & inibidores , Nanopartículas/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/farmacocinética , Feminino , Glucosiltransferases/genética , Humanos , Camundongos , Micelas , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polímeros/administração & dosagemRESUMO
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.