RESUMO
Multidrug resistance (MDR) presents a major obstacle to curing cancer. Chemotherapy failure can occur through both cell membrane drug resistance (CMDR) and nuclear drug resistance (NDR), and anticancer effectiveness of chemotherapeutic agents is especially reduced by their nuclear export. Here we report an exciting magnetically-targeted nanomedicine formed by conjugation of epirubicin (EPI) to non-toxic and high-magnetization nanocarrier (HMNC). Strikingly, HMNC-EPI overcomes both CMDR and NDR in human bladder cancer cell models, without using P-glycoprotein (P-gp) and nuclear pore inhibitors. Besides, the half-life of drug is prolonged ~1.8-fold (from 45 h to 81 h) at 37 °C, with a ~10-fold increase in concentration at the tumor site through magnetic targeting (MT). Moreover, malignant NDR bladder cancer can be effectively inhibited after 14 days in mice by just two injections and MT. We are the first to demonstrate the nanomedical strategy that can overcome the CMDR and NDR bladder cancers simultaneously, and proceed to the excellent MT therapy, significantly reducing the dosage and cardiotoxicity and holding great promise for incurable human MDR bladder cancer.
Assuntos
Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Epirubicina/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Nanoestruturas/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Meios de Contraste/farmacologia , Reagentes de Ligações Cruzadas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Epirubicina/metabolismo , Epirubicina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Magnetismo , Camundongos , Nanoestruturas/ultraestrutura , Imagens de Fantasmas , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
The successful delivery of anti-cancer drugs relies on the simultaneous capability to actively target a specific location, a sufficient lifetime in the active form in the circulation, and traceability and quantification of drug distribution via in vivo medical imaging. Herein, a highly magnetic nanocarrier (HMNC) composed of an Fe(3)O(4) core and an aqueous-stable, self-doped poly[N-(1-one-butyric acid)]aniline (SPAnH) shell was chemically synthesized. This nanocarrier exhibited a high capacity for 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) drug loading. BCNU and o-(2-aminoethyl)polyethylene glycol (EPEG) were covalently immobilized on the surface of the HMNC to form a self-protecting magnetic nanomedicine (i.e., SPMNM) that could simultaneously provide low reticuloendothelial system uptake, high active-targeting, and in vivo magnetic resonance imaging (MRI) traceability. Meanwhile, the SPMNM was found to reduce the phagocytosis by macrophages and reduce the hydrolysis rate of BCNU. The high magnetization (approximately 1.2-fold higher than Resovist) of the HMNC allowed efficient magnetic targeting to the tumor. The synergetic drug delivery approach provided approximately a 3.4-fold improvement of the drug's half-life (from 18 h to 62 h) and significantly prolonged the median survival rate in animals that received a low dose of BCNU, compared with those that received a high dose of free BCNU (63 days for those that received 4.5 mg BCNU/kg carried by the nanocarrier versus 50 days for those that received 13.5 mg of free-BCNU). This improvement could enhance the potential of magnetic targeting therapy in clinical applications of cancer treatments.
Assuntos
Carmustina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Nanopartículas de Magnetita/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carmustina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Reagentes de Ligações Cruzadas/farmacologia , DNA/metabolismo , Portadores de Fármacos/química , Estabilidade de Medicamentos , Meia-Vida , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Imagem Molecular , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Temperatura , Resultado do TratamentoRESUMO
This study describes the creation and characterization of drug carriers prepared using the polymer poly[aniline-co-N-(1-one-butyric acid) aniline] (SPAnH) coated on Fe(3)O(4) cores to form three types of magnetic nanoparticles (MNPs); these particles were used to enhance the therapeutic capacity and improve the thermal stability of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a compound used to treat brain tumors. The average hydrodynamic diameter of the MNPs was 89.2 ± 8.5 nm and all the MNPs displayed superparamagnetic properties. A maximum effective dose of 379.34 µg BCNU could be immobilized on 1 mg of MNP-3 (bound-BCNU-3). Bound-BCNU-3 was more stable than free-BCNU when stored at 4 °C, 25 °C or 37 °C. Bound-BCNU-3 could be concentrated at targeted sites in vitro and in vivo using an externally applied magnet. When applied to brain tumors, magnetic targeting increased the concentration and retention of bound-BCNU-3. This drug delivery system promises to provide more effective tumor treatment using lower therapeutic doses and potentially reducing the side effects of chemotherapy.
