RESUMO
Anticancer drug resistance almost invariably emerges and poses major obstacles towards curative therapy of various human malignancies. In the current review we will distinguish between mechanisms of chemoresistance that are predominantly mediated by ATP-driven multidrug resistance (MDR) efflux transporters, typically of the ATP-binding cassette (ABC) superfamily, and those that are independent of such drug efflux pumps. In recent years, multiple nanoparticle (NP)-based therapeutic systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps and other resistance mechanisms. NPs are being exploited for selective drug delivery to tumor cells, to cancer stem/tumor initiating cells and/or to the supportive cancer cell microenvironment, i.e. stroma or tumor vasculature. Some of these NPs are currently undergoing preclinical in vivo studies as well as advanced stages of clinical evaluation with promising results. Nanovehicles harboring a payload of therapeutic drug combinations for the selective targeting and elimination of tumor cells as well as the simultaneous overcoming of mechanisms of drug resistance are a subject of intense research efforts, some of which are expected to enter clinical trials in the near future. In the present review we highlight novel approaches to selectively target cancer cells and overcome drug resistance phenomena, through the use of various nanometric drug delivery systems. In the near future, it is anticipated that innovative theragnostic nanovehicles will be developed which will harbor four major components: (1) a selective targeting moiety, (2) a diagnostic imaging aid for the localization of the malignant tumor and its micro- or macrometastases, (3) a cytotoxic, small molecule drug(s) or novel therapeutic biological(s), and (4) a chemosensitizing agent aimed at neutralizing a resistance mechanism, or exploiting a molecular "Achilles hill" of drug resistant cells. We propose to name these envisioned four element-containing nanovehicle platform, "quadrugnostic" nanomedicine. This targeted strategy holds promise in paving the way for the introduction of highly effective nanoscopic vehicles for cancer therapeutics while overcoming drug resistance.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina/métodos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Meios de Contraste , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inativação Gênica , Humanos , Imagem Molecular/métodos , Terapia de Alvo Molecular , Nanopartículas/química , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
PURPOSE: To develop a novel oral drug delivery system comprising a hydrophobic chemotherapeutic drug entrapped within beta casein (ß-CN), a major milk protein, which self-associates into micelles in aqueous solutions. The efficient gastric digestibility of ß-CN suggests possible targeting to gastric cancers. METHODS: Antitumor drug entrapment was performed by stirring its dimethyl-sulfoxide solution into a phosphate-buffered saline containing ß-CN. The association of drugs to ß-CN was characterized by spectrophotometry and Trp143 fluorescence quenching; particle-size by dynamic light scattering, and colloidal stability by zeta potential. RESULTS: The optimal drug-to-ß-CN molar loading-ratios for paclitaxel and vinblastine at 1 mg/ml ß-CN were found to be 7.3 ± 1.2 and 5.3 ± 0.6 and the association constants were (6.3 ± 1.0) x 10(3) M(-1) and (2.0 ± 0.3) x 10(4) M(-1), respectively. Zeta potential analysis suggested that nanoencapsulation by ß-CN stabilized all studied drugs in aqueous solution. The initial drug-ß-CN association was apparently governed by hydrophobic interactions and at higher drug concentrations, also by electrostatic interactions. Up to the optimal drug:ß-CN loading-ratio, ~80% of the particles were below 100 nm in diameter. At higher drug concentrations, particle diameter increased, and bi- or tri-modal particle distributions were observed. CONCLUSIONS: Beta-CN forms colloidally-stable nanovehicles of hydrophobic anticancer drugs, and may be used for oral-delivery of chemotherapeutics.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Caseínas/química , Portadores de Fármacos/química , Nanopartículas/química , Administração Oral , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/química , Coloides , Docetaxel , Composição de Medicamentos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Irinotecano , Estrutura Molecular , Paclitaxel/administração & dosagem , Paclitaxel/química , Tamanho da Partícula , Relação Estrutura-Atividade , Taxoides/administração & dosagem , Taxoides/química , Vimblastina/administração & dosagem , Vimblastina/químicaRESUMO
Bovine beta-casein (beta-CN) is an abundant milk protein that is highly amphiphilic and self-assembles into stable micellar structures in aqueous solutions. Here we introduce a drug-delivery system comprising a model hydrophobic anticancer drug, mitoxantrone (MX), entrapped within beta-CN-based nanoparticles. This novel drug-delivery system allows hydrophobic drugs to be thermodynamically stable in aqueous solutions for oral-delivery applications aimed at treatment of various disorders. The gastric digestibility of beta-CN suggests possible targeting to stomach tumors. Dimethyl sulfoxide (DMSO)-dissolved MX was entrapped in beta-CN nanoparticles by stirring this solution into phosphate-buffered beta-CN solution. High-affinity MX-beta-CN association was found (K(a) = [2.15 +/- 0.30] x 10(6) M(-1)). The optimal nanovehicle formation conditions were 1 mg/mL beta-CN, Assuntos
Caseínas/metabolismo
, Portadores de Fármacos/química
, Mitoxantrona/administração & dosagem
, Mitoxantrona/farmacologia
, Nanopartículas/química
, Administração Oral
, Animais
, Bovinos
, Fluorescência
, Micelas
, Tamanho da Partícula
, Temperatura
, Fatores de Tempo
, Triptofano/metabolismo
RESUMO
Beta-casein (beta-CN), a major milk protein, is amphiphilic and self-associates into micelles in aqueous solutions. We have recently introduced a novel oral drug delivery system based on beta-CN nanoparticles. The current research builds on and complements this work by studying the interactions of mitoxantrone (MX) and beta-CN as they co-assemble into nanoparticles, using absorption and emission spectra, static and dynamic light scattering, and fluorescent emission of both MX and tryptophan 143 (Trp143) of beta-CN. The optimal loading molar ratio was 3.3 MX/beta-CN at 1 mg/mL beta-CN, and the association constant was (2.45 +/- 1.76) x 10(5) M(-1) based on beta-CN Trp143 fluorescence; independent MX fluorescence results provided supporting values. In these conditions a bimodal particle distribution was obtained (174.4 nm, 45.9%; 485.1 nm, 54.1%). The gastric digestibility of beta-CN suggests possible targeting to stomach tumors. Hence, beta-CN nanoparticles have potential to serve as effective vehicles of hydrophobic drugs for oral delivery preparations. From the clinical editor: Beta-casein (b-CN) is an amphiphilic milk protein that self-associates into micelles in aqueous solutions and can be utilized as a novel oral drug delivery system. This study investigates the basic properties of a mitoxantrone delivery system based on the above principles.
Assuntos
Antineoplásicos/química , Caseínas/química , Micelas , Mitoxantrona/química , Nanopartículas/química , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Caseínas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Interações Medicamentosas , Concentração de Íons de Hidrogênio , Mitoxantrona/administração & dosagem , Mitoxantrona/metabolismo , Tamanho da Partícula , Triptofano/química , Triptofano/metabolismoRESUMO
Peritoneal dialysis (PD) is commonly performed by using preprepared dialysis solutions containing glucose, which are thermally treated to achieve commercial sterilization. A series of glucose degradation products (GDPs) are being formed, which react with the tissue during the dialysis procedure, thus baring a negative effect on the patient and the dialysis process. The present study tested the efficacy of ohmic heating as an alternative thermal treatment for continuous sterilization of PD solutions. The process was compared to conventional retort treatment, and GDPs accumulation was measured. Thermal treatments using the ohmic heating system were performed at three temperatures (105, 125, and 150 degrees C) with residence time at each temperature ranging from 0.84 to 12.0 s. The resulting concentrations of glyoxal (GO), methylglyoxal (MGO), and 3-deoxyglucosone (3-DG) in the PD solutions were measured. None of these GDPs were found in PD fluids treated by ohmic heating at 105 degrees C. The concentration of 3-DG, after a standard sterilization treatment (121 degrees C, 20 or 40 min) was one order of magnitude higher (approximately 140 and 242 microM) than after ohmic heating treatment at 125 degrees C. The results of the present study suggest that this technique can be used to produce solutions with much lower content of GDPs. It also demonstrates the advantage of using the ohmic heating technology as a tool for high temperature short time treatment of PD fluids.
Assuntos
Soluções para Diálise/química , Glucose/química , Temperatura Alta , Diálise Peritoneal/efeitos adversos , Desoxiglucose/análogos & derivados , Desoxiglucose/análise , Glioxal/análise , Aldeído Pirúvico/análiseRESUMO
We studied a potential drug delivery system comprising the hydrophobic anticancer drug paclitaxel entrapped within ß-casein (ß-CN) nanoparticles and its cytotoxicity to human gastric carcinoma cells. Paclitaxel was entrapped by stirring its dimethyl sulfoxide (DMSO) solution into PBS containing ß-CN. Cryo-TEM analysis revealed drug nanocrystals, the growth of which was blocked by ß-CN. Entrapment efficiency was nearly 100%, and the nanovehicles formed were colloidally stable. Following encapsulation and simulated digestion with pepsin (2 hours at pH=2, 37 °C), paclitaxel retained its cytotoxic activity to human N-87 gastric cancer cells; the IC(50) value (32.5 ± 6.2 nM) was similar to that of non-encapsulated paclitaxel (25.4 ± 2.6 nM). Without prior simulated gastric digestion, ß-CN-paclitaxel nanoparticles were non-cytotoxic, suggesting the lack of untoward toxicity to bucal and esophageal epithelia. We conclude that ß-CN shows promise to be useful for target-activated oral delivery of hydrophobic chemotherapeutics in the treatment of gastric carcinoma, one of the leading causes of cancer mortality worldwide.