RESUMO
The presence of blood-brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80-modified paclitaxel-loaded PLGA nanoparticles (PS-80-PTX-NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P-glycoprotein expression and ApoE-dependent PS-80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour-bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/terapia , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/terapia , Nanopartículas/química , Paclitaxel/farmacologia , Polissorbatos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Tratamento por Ondas de Choque Extracorpóreas/métodos , Feminino , Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Paclitaxel/farmacocinética , Análise de Sobrevida , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologiaRESUMO
The efficiency of drug delivery and bioavailability to tumor cells are crucial for effective cancer chemotherapy. Herein, a doxorubicin (DOX) encapsulated lysolipid-based thermosensitive liposome decorated with cRGD peptide (RTSL) is conjugated on the surface of an IR780-loaded microbubble (IMB) to synthesize RTSL-IMBs. Sequentially taking advantage of acoustic-assisted early extravasation and thermo-triggered interstitium ultrafast drug release, RTSL-IMBs combine with ultrasound (US) and laser irradiation can advance drug delivery and bioavailability. In vitro experiments demonstrate that RTSL-IMBs associated with a two-step protocol (subsequently US irradiation for 1 min and laser irradiation for 5 min) can dramatically enhance the cellular uptake and bioavailability of DOX. In vivo fluorescence imaging studies reveal that the combination of RTSL-IMBs and US shows a 2.8-fold intratumoral drug accumulation increase at 0.5 h post-injection, while it will take 48 h to reach the same level of intratumoral drug accumulation for the RTSL-IMB group alone. Interestingly, the following localized application of a laser can further increase drug accumulation and slow tumor clearance. Histological analysis demonstrates that the combinational RTSL-IMBs, US and laser significantly improve the drug penetration distance and delivery efficiency in the tumor core. In this study, the acoustic/thermo-responsive hybrid system shows potential for advancing DOX chemotherapy in breast cancer cell MCF-7 xenograft nude mice.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Acústica , Animais , Antibióticos Antineoplásicos/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Feminino , Humanos , Lipossomos , Células MCF-7 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Microbolhas , Peptídeos Cíclicos/química , Temperatura , Carga Tumoral/efeitos dos fármacos , Ondas Ultrassônicas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Radiotherapy (RT) is one of the most widely used cancer treatments in the clinical setting, while hypoxia-associated resistance often occurs. Herein, a PEGylated TaOx-based oxygen-carrying nanoplatform was constructed for triple sensitizing tumor radiotherapy. The high-Z element based hollow mesoporous TaOx nanospheres were prepared following the in situ growth of ultrasmall CuS nanocrystals and then packaged with O2-saturated perfluoropentane (PFP). NIR laser-triggered mild hyperthermia would lead to the increase of intratumoral blood flow, together with the release of O2, the radiotherapeutic efficiency would be enhanced. Alternatively, radiant energy would be deposited inside the tumor by the Ta element, therefore triple sensitization of radiotherapy could be achieved. The in vivo studies showed that the as-prepared nanospheres could achieve almost total inhibition of tumor growth without obvious side effects, which provides new possibilities for multisensitizing tumor radiotherapy.