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1.
Int J Nanomedicine ; 14: 6231-6247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496683

RESUMO

Purpose: A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution. Methods: A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC's chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated. Results: MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and -20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile. Conclusion: NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.


Assuntos
Composição de Medicamentos , Emtricitabina/farmacologia , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Antirretrovirais/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Emtricitabina/sangue , Emtricitabina/síntese química , Emtricitabina/química , Humanos , Cinética , Macrófagos/efeitos dos fármacos , Masculino , Nanopartículas/ultraestrutura , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley
2.
Chem Commun (Camb) ; 55(73): 10892-10895, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31436766

RESUMO

Bifunctional supramolecular prodrug vesicles have been successfully constructed based on the complexation between a glutathione (GSH)-responsive prodrug guest molecule (DNS-CPT) and a water-soluble pillar[5]arene (WP5) for cancer diagnosis and therapy. Under the microenvironment of cancer cells with high GSH concentration, 7-ethyl-10-hydroxycamptothecin (SN-38) with strong yellow fluorescence can be efficiently released from the prodrug DNS-CPT for drug location and cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Portadores de Fármacos/química , Compostos Macrocíclicos/química , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Camptotecina/toxicidade , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Feminino , Glutationa/química , Humanos , Compostos Macrocíclicos/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Solubilidade , Água , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Chem Commun (Camb) ; 55(68): 10142-10145, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31389424

RESUMO

Hydrogen sulfide, an endogenous signalling molecule, is central to several pathophysiological processes in mammalian systems. It scavenges reactive oxygen species and is known to ameliorate dopaminergic neuronal degeneration in neurotoxin-induced Parkinson's disease models. The rapid volatilization of H2S from spontaneously releasing sulfide salts being a challenge, we describe peptide conjugates which exhibit tris(2-carboxyethyl)phosphine mediated "slow and sustained" H2S release. These conjugates reduced hydrogen peroxide-induced oxidative stress and significantly increased dopamine levels in transgenic C. elegans.


Assuntos
Dopamina/metabolismo , Sulfeto de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/farmacologia , Tionas/farmacologia , Tiofenos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Liberação Controlada de Fármacos , Oxirredução , Peptídeos/síntese química , Peptídeos/química , Fosfinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tionas/síntese química , Tionas/química , Tiofenos/síntese química , Tiofenos/química , alfa-Sinucleína/genética
4.
Inorg Chem ; 58(16): 11076-11084, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31393117

RESUMO

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Receptores LHRH/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta à Radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores LHRH/metabolismo , Relação Estrutura-Atividade
5.
Chem Commun (Camb) ; 55(53): 7683-7686, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204739

RESUMO

An easy access to topical gels (both hydro- and organogels) derived from an anti-cancer prodrug namely 5-fluorouracil acetic acid (5-FuA) achieved by exploiting a simple salt formation strategy is reported for the first time. Nearly 85% of the salts synthesized were gelators. Single crystal structures of some of the gelator salts revealed an intriguing hydrogen bonding network including double stranded 1D chains stabilized through uracil-uracil complementary interactions and the crystal structures of the gelator salts corroborated well with the hypothesis based on which the gelators were designed. Studies indicated that both the hydrogel and the methyl salicylate gel of the gelator salt FuA-15 were suitable for self-drug-delivery application.


Assuntos
Ácido Acético/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Fluoruracila/farmacologia , Pró-Fármacos/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluoruracila/síntese química , Fluoruracila/química , Géis/síntese química , Géis/química , Géis/farmacologia , Humanos , Ligações de Hidrogênio , Estrutura Molecular , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Propriedades de Superfície
6.
Eur J Med Chem ; 177: 448-456, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174062

RESUMO

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 µM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.


Assuntos
Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Feminino , Células HCT116 , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica/efeitos dos fármacos , Solubilidade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Adv Mater ; 31(32): e1902672, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31206855

RESUMO

Cancer theranostics holds potential promise for precision medicine; however, most existing theranostic nanoagents are simply developed by doping both therapeutic agents and imaging agent into one particle entity, and thus have an "always-on" pharmaceutical effect and imaging signals regardless of their in vivo location. Herein, the development of an organic afterglow protheranostic nanoassembly (APtN) that specifically activates both the pharmaceutical effect and diagnostic signals in response to a tumor-associated chemical mediator (hydrogen peroxide, H2 O2 ) is reported. APtN comprises an amphiphilic macromolecule and a near-infrared (NIR) dye acting as the H2 O2 -responsive afterglow prodrug and the afterglow initiator, respectively. Such a molecular architecture allows APtN to passively target tumors in living mice, specifically release the anticancer drug in the tumor, and spontaneously generate the uncaged afterglow substrate. Upon NIR light preirradiation, the afterglow initiator generates singlet oxygen to react and subsequently transform the uncaged afterglow substrate into an active self-luminescent form. Thus, the intensity of generated afterglow luminescence is correlated with the drug release status, permitting real-time in vivo monitoring of prodrug activation. This study proposes a background-free design strategy toward activatable cancer theranostics.


Assuntos
Antineoplásicos/síntese química , Substâncias Luminescentes/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/síntese química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Dimerização , Sistemas de Liberação de Medicamentos , Floxuridina/química , Peróxido de Hidrogênio/metabolismo , Raios Infravermelhos , Camundongos , Polietilenoglicóis/química , Pró-Fármacos/farmacologia , Nanomedicina Teranóstica , Distribuição Tecidual , Microambiente Tumoral , Uridina/análogos & derivados , Uridina/química
8.
Eur J Med Chem ; 179: 84-99, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247375

RESUMO

The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 µM and EMAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells.


Assuntos
Antineoplásicos/farmacologia , Ciclofosfamida/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/síntese química , Ciclofosfamida/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Eur J Med Chem ; 178: 515-529, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207463

RESUMO

Carvacrol (CAR), a natural monoterpene particularly abundant in plants belonging to the Lamiaceae family, has recently attracted much attention for its many biological properties (antioxidant, anti-inflammatory, neuroprotective, antitumour, antibacterial, and several others). However, CAR has poor chemical-physical properties (low water solubility and high volatility), which hamper its potential pharmacological uses. In this paper, the synthesis and antimicrobial evaluation of 23 carvacrol derivatives (WSCP1-23) against a panel of selected gram-positive and gram-negative bacteria are reported. Using the prodrug approach, CAR hydrophilic (WSCP1-17) and lipophilic prodrugs (WSCP18-23) were prepared. Notably, CAR water solubility was increased by using polar neutral groups (such as natural amino acids) with the aim of improving oral drug delivery. On the other hand, CAR lipophilic prodrugs, obtained by prenylation of CAR hydroxyl group, were designed to promote membrane permeation and oral absorption. Our results revealed that WSCP1-3, showing the highest water solubility (>1700-fold compared to that of CAR), possessed good antibacterial activity against gram-negative bacteria with MIC values comparable to those of CAR and antifungal properties against different species of Candida. WSCP18-19 were the most promising prodrugs, showing good antibacterial profiles against gram-positive bacteria by interfering with the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis. Moreover, WSCP18-19 resulted more stable in simulated fluids and human plasma than WSCP1-3. Toxicity studies performed on human erythrocytes and HaCaT cells revealed that all WSCPs were not toxic at the tested concentrations.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Monoterpenos/farmacologia , Pró-Fármacos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade
10.
Chem Commun (Camb) ; 55(46): 6603-6606, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31119252
11.
Eur J Med Chem ; 176: 105-116, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31100648

RESUMO

Development of peptide-based conjugates for targeted tumour therapy is a current research topic providing new possibilities in cancer treatment. In this study, VHLGYAT heptapeptide selected by phage display technique for HT-29 human colon cancer was investigated as homing peptide for drug delivery. Daunomycin was conjugated to the N-terminus of the peptide directly or through Cathepsin B cleavable spacers. Conjugates showed moderate in vitro cytostatic effect. Therefore, sequence modifications were performed by Ala-scan and positional scanning resulting in conjugates with much higher bioactivity. Conjugates in which Gly was replaced by amino acids with bulky apolaric side chains provided the best efficacy. The influence of the cellular uptake, stability and drug release on the anti-tumour activity was investigated. It was found that mainly the difference in the cellular uptake of the conjugates generated the distinct effect on cell viability. One of the most efficient conjugate Dau = Aoa-LRRY-VHLFYAT-NH2 showed tumour growth inhibition on orthotopically developed HT-29 colon cancer in mice with negligible toxic side effect compared to the free drug. We also indicate that this sequence is not specific to HT-29 cells, but it has a remarkable effect on many other cancer cells. Nevertheless, the Phe-containing conjugate was more active in all cases compared to the conjugate with the parent sequence. The literature data suggested that this sequence is highly overlapped with peptides that recognize Hsp70 membrane bound protein overexpressed in many types of tumours.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Daunorrubicina/análogos & derivados , Daunorrubicina/uso terapêutico , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Catepsina B/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Visualização da Superfície Celular/métodos , Daunorrubicina/metabolismo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Células HT29 , Humanos , Camundongos SCID , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Proteólise , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Dalton Trans ; 48(21): 7388-7393, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30957798

RESUMO

Platinum(iv) carboxylate scaffolds have garnered considerable research interest because they can be engineered to function as prodrugs of clinical platinum(ii) anticancer drugs. These platinum(iv) prodrug complexes are stable and tunable, and activated by reduction to release their cytotoxic platinum(ii) cargo. Here we propose new platinum(iv) prodrug complexes designed to release cisplatin via photoreduction upon UV irradiation. The central strategy is to utilise aryl carboxylate ligands on the axial positions of that platinum(iv) scaffold that confer significant UV absorption and would stabilise carboxyl radical formation, thus favouring homolytic Pt-O bond cleavage. We isolated and identified aryl carboxyl radicals via spin-trapping and showed that the photoreduced platinum species mirror cisplatin reactivity toward DNA bases, thereby validating the efficacy of this approach.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Compostos Organoplatínicos/síntese química , Pró-Fármacos/síntese química , Cisplatino/química , Ligantes , Oxirredução , Relação Estrutura-Atividade , Raios Ultravioleta
13.
Eur J Med Chem ; 171: 383-400, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928710

RESUMO

The use of nitroreductases (NTR) that catalyze the reduction of nitro compounds by using NAD(P)H in GDEPT (Gene-directed enzyme prodrug therapy) studies which minimize toxicity at healthy cells and increases concentration of drugs at cancer cells is remarkable. Discovery of new prodrug/NTR combinations is necessary to be an alternative to known prodrug candidates such as CB1954, SN23862, PR-104A. For this aim, nitro containing aromatic amides (A1-A23)2 were designed, synthesized, performed in silico ADMET and molecular docking techniques in this study. Prodrug candidates were studied on reduction potentials with Ssap-NtrB by HPLC system. Also, cyototoxic properties and prodrug ability of these amides were investigated using different cancer cell lines such as Hep3B and PC3. As a result of theoretical and biological studies, combinations of A5, A6 and A20 with Ssap-NtrB can be suggested as potential prodrugs/enzyme combinations at NTR based cancer therapy compared with CB1954/NfsB.


Assuntos
Amidas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Nitrorredutases/metabolismo , Pró-Fármacos/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Nitrorredutases/química , Células PC-3 , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
14.
Nano Lett ; 19(4): 2731-2738, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30919635

RESUMO

Nitric oxide (NO) induces a multitude of antitumor activities, encompassing the induction of apoptosis, sensitization to chemo-, radio-, or immune-therapy, and inhibition of metastasis, drug resistance, angiogenesis, and hypoxia, thus attracting much attention in the area of cancer intervention. To improve the precise targeting and treatment efficacy of NO, a glutathione (GSH)-sensitive NO donor (1,5-bis[(l-proline-1-yl)diazen-1-ium-1,2-diol- O2-yl]-2,4-dinitrobenzene, BPDB) coordinates with iron ions to form the nanoscale coordination polymer (NCP) via a simple precipitation and then partial ion exchange process. The obtained Fe(II)-BNCP shows desirable solubility, biocompatibility, and circulation stability. Quick NO release triggered by high concentrations of GSH in tumor cells improves the specificity of NO release in situ, thus avoiding side effects in other tissues. Meanwhile, under high concentrations of H2O2 in tumors, Fe2+ ions in BPDB-based NCP, named Fe(II)-BNCP, exert Fenton activity to generate hydroxyl radicals (·OH), which is the main contribution for chemodynamic therapy (CDT). In addition, ·O2- generated by the Haber-Weiss reaction of Fe2+ ions with H2O2 can quickly react with NO to produce peroxynitrite anion (ONOO-) that is more cytotoxic than ·O2- or NO only. This synergistic NO-CDT effect has been proved to retard the tumor growth in Heps xenograft ICR mouse models. This work not only implements a synergistic effect of NO-CDT therapy but also offers a simple and efficient strategy to construct a coordination polymer nanomedicine via rationally designed prodrug molecules such as NO donors.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Nanomedicina/métodos , Doadores de Óxido Nítrico/química , Óxido Nítrico/química , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dinitrobenzenos/química , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Neoplasias Hepáticas/patologia , Óxido Nítrico/biossíntese , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos
15.
Nano Lett ; 19(5): 2968-2978, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30924343

RESUMO

Cisplatin-based chemotherapy is a widely used first-line strategy for numerous cancers. However, drug resistances are often inevitable accompanied by the long-term use of cisplatin in vivo, significantly hampering its therapeutic efficacy and clinical outcomes. Among others, autophagy induction is one of the most common causes of tumor resistance to cisplatin. Herein, a self-assembled nanoprodrug platform was developed with the synergistic effect of cisplatin and RNAi to fight against cisplatin-resistant lung cancer. The nanoprodrug platform consists of three molecular modules, including prodrug complex of Pt(IV)-peptide-bis(pyrene), DSPE-PEG, and cRGD-modified DSPE-PEG. The Pt(IV) is immobilized with peptide via amide bonds, allowing the Pt(IV) to be loaded with a loading efficiency of >95% and rapid-release active platinum ions (Pt(II)) in the presence of glutathione (GSH). Meanwhile, the peptide of the prodrug complex could efficiently deliver Beclin1 siRNA ( Beclin1 is an autophagy initiation factor) to the cytoplasm, thereby leading to autophagy inhibition. In addition, incorporation of DSPE-PEG and cRGD-modified DSPE-PEG molecules improves the biocompatibility and cellular uptake of the nanoprodrug platform. In vivo results also indicate that the nanoprodrug platform significantly inhibits the growth of a cisplatin-resistant tumor on xenograft mice models with a remarkable inhibition rate, up to 84% after intravenous injection.


Assuntos
Cisplatino/farmacologia , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia , Pró-Fármacos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/química , Proteína Beclina-1/genética , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Neoplasias/genética , Peptídeos/síntese química , Peptídeos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur J Pharm Sci ; 132: 125-131, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30878380

RESUMO

Two types of haloperidol prodrugs in which a chemical modification was carried out on the hydroxyl group or carbonyl group were synthesized, and their metabolic activation abilities were evaluated in a human liver microsome (HLM) solution, a human small intestine microsome (HIM) solution and solutions of human recombinant carboxylesterases (hCESs). The metabolic activation rates of alcohol ester prodrugs in HLM solution were similar to those in hCES2 solution, and haloperidol pentanoate and haloperidol hexanoate showed high metabolic activation rates in the synthesized alcohol ester prodrugs. In addition, haloperidol acetate and haloperidol 2-methylbutanoate were hydrolyzed as slowly as haloperidol decanoate. The results suggested that haloperidol prodrugs with a small chain or a branched chain are useful as prodrugs for sustained release. The metabolic activation rate of the enol ester prodrug in HLM solution was similar to that in hCES1 solution, and the enol ester prodrug was found to behave differently from alcohol ester prodrugs, which were metabolically activated by hCES2.


Assuntos
Carboxilesterase/metabolismo , Haloperidol/análogos & derivados , Haloperidol/síntese química , Microssomos/enzimologia , Pró-Fármacos/síntese química , Estabilidade de Medicamentos , Ésteres , Haloperidol/metabolismo , Humanos , Técnicas In Vitro , Inativação Metabólica , Intestino Delgado/enzimologia , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Pró-Fármacos/metabolismo
17.
Biomed Pharmacother ; 112: 108614, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798129

RESUMO

Lung cancer is the leading cause of cancer death worldwide. To overcome the toxic side effects and multidrug resistance (MDR) during doxorubicin (DOX) chemotherapy, a urokinase plasminogen activator receptor (uPAR) targeting U11 peptide decorated, pH-sensitive, dual drugs co-encapsulated nanoparticles (NPs) system is employed in this study. A U11 peptide conjugated, pH-sensitive DOX prodrug (U11-DOX) was synthesized and used as materials to produce NPs. A curcumin (CUR) and U11-DOX co-encapsulated NPs system (U11-DOX/CUR NPs) was constructed to treat lung cancer. After the characterization of biophysical properties of this NPs system, synergistic chemotherapeutic efficacy was evaluated in both cultured cancer cells and tumor-bearing animal model. U11-DOX/CUR NPs had a uniformly spherical shape with a core-shell structure. The mean particle size and zeta potential of the U11-DOX/CUR NPs was 121.3 nm and -33.5 mV, with a DOX and CUR EE of 81.7 and 90.5%, respectively. The DOX release from U11-DOX/CUR NPs was 83.5, 55.2, and 32.8% correspondence to the pH of 5.0, 6.0 and 7.4. Cellular uptake efficiency of U11-DOX/CUR NPs was significantly higher than non U11 peptide decorated DOX/CUR NPs. U11-DOX/CUR NPs displayed a pronounced synergy effects in vitro and an obvious tumor tissue accumulation efficiency in vivo. In vivo antitumor experiment showed that U11-DOX/CUR NPs could inhibit the tumor growth to a level of 85%.In vitro and in vivo studies demonstrated that U11-DOX/CUR NPs is a sustained released, pH responsive, synergistic antitumor system. This study suggests that the U11-DOX/CUR NPs have promising potential for combination treatment of lung cancer.


Assuntos
Curcumina/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Nanomedicina/métodos , Pró-Fármacos/administração & dosagem , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Curcumina/síntese química , Doxorrubicina/síntese química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Pró-Fármacos/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Chem Asian J ; 14(8): 1238-1248, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30615821

RESUMO

Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on-mechanism normal tissue toxicity. Hypoxia presents a target for tumour-selective drug delivery using hypoxia-activated prodrugs. We designed and prepared hypoxia-activated prodrugs of modified PERK inhibitors using a 2-nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2-substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia-selective manner.


Assuntos
Hipóxia/metabolismo , Nitroimidazóis/metabolismo , Nitroimidazóis/farmacologia , Pró-Fármacos/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Desenho de Drogas , Células HCT116 , Humanos , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , eIF-2 Quinase/metabolismo
19.
Drug Des Devel Ther ; 13: 231-242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30643389

RESUMO

Background: We examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis. Methods: MCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}- 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated. Results: Our results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses. Conclusion: Thus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite/tratamento farmacológico , Colo/efeitos dos fármacos , Modelos Animais de Doenças , Metoclopramida/uso terapêutico , Pró-Fármacos/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Compostos Azo/administração & dosagem , Compostos Azo/uso terapêutico , Benzenossulfonatos , Colite/induzido quimicamente , Colite/patologia , Colo/patologia , Masculino , Mesalamina/administração & dosagem , Mesalamina/uso terapêutico , Metoclopramida/administração & dosagem , Metoclopramida/síntese química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley
20.
Nanoscale ; 11(3): 1423-1436, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30608103

RESUMO

Drug delivery to a tumor site with an insufficient microvascular network remains a challenge due to the size preference for transport in terms of circulation and distribution. In this work, an integrated nano-therapeutic parcel disintegrable by a photoacoustic shockwave was developed. Nano-therapeutic particles with red absorbance are packaged into a larger parcel to generate a longer circulation half-life and improved accumulation in tumor tissue. Pulse-laser irradiation is absorbed by the nanoparticles and it generates a photoacoustic shockwave. This triggers a liquid-gas phase transition of the nano-parcel, leading to the high-efficiency release of smaller nanoparticles, thus achieving excellent therapeutic diffusion with improved uniformity. This results in a highly effective therapeutic effect, as demonstrated with both in vitro and in vivo tumor models. Compared to previously reported work, this approach has the distinctive advantage of precisely controllable therapeutic release that is independent of the physiological environment in the tumor and it is less limited than a UV-based release mechanism. In addition, the concept of photoacoustic shockwave-based nanoparticle release can be extended over a wide wavelength range, including microwaves, to match specific needs and achieve optimal therapeutic depth. The results demonstrate that the proposed strategy holds great potential for improved tumor therapy efficacy.


Assuntos
Nanopartículas/química , Técnicas Fotoacústicas , Pró-Fármacos/química , Animais , Apoptose/efeitos dos fármacos , Carbocianinas/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Dendrímeros/química , Fluorcarbonetos/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micro-Ondas , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Transplante Heterólogo
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