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Adv Healthc Mater ; 8(13): e1900160, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30969015


Cancer stem cells (CSCs) are responsible for malignant tumor initiation, recurrences, and metastasis. Therefore, targeting CSCs is a promising strategy for the development of cancer therapies. A big challenge for CSC-based cancer therapy is the overexpression of therapeutic stress protein, heat shock protein 90 (Hsp90), which protects CSCs from further therapeutic-induced damage, leading to the failure of treatment. Thus, efficient strategies to target CSCs are urgently needed for cancer therapy. To this end, a multifunctional nanoparticle (MNP) for CSC-based combined thermotherapy and chemotherapy is reported. This strategy dramatically suppresses tumor growth in breast CSC xenograft-bearing mice. Furthermore, a new mechanism is present that the MNP exerts its striking effects on CSCs by inhibiting the secretion of extracellular Hsp90 (eHsp90), resulting in the interruption of several key signaling pathways. These findings open new perspectives on the use of an MNP for effective CSC-based cancer treatment by inhibiting the function of eHsp90.

Biomaterials ; 200: 1-14, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30743049


Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.

Biomaterials ; 178: 83-94, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29913389


Improving the supply of O2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O2-evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen (1O2) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O2 from UiO-66. Subsequently, the generated O2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors.

Materiais Biomiméticos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Oxigênio/química , Fotoquimioterapia , Hipóxia Tumoral , Animais , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Verde de Indocianina/farmacologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Células RAW 264.7 , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Superóxidos/química , Distribuição Tecidual , Hipóxia Tumoral/efeitos dos fármacos
Anal Chim Acta ; 1024: 177-186, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-29776544


Hypoxia plays a crucial role in cancer progression, and it has great significance for monitoring hypoxic level in biosystems. Cancer stem cells (CSCs) represent a small population of tumour cells that regard as the key to seed tumours. The survival of CSCs depend on the tumour microenvironment, which is distinct region has the hypoxic property. Therefore, the detection of the hypoxic CSC niche plays a pivotal role in the destructing the 'soil' of CSCs, and eliminating CSCs population. Numerous one-photon excited fluorescent probes have been developed to indicate the hypoxic status in tumours through the detection of nitroreductase (NTR) level. However, the biomedical application of one-photon fluorescent probes is limited due to the poor tissue penetration. In the present work, we reported a two-photon fluorescent probe to detect the NTR in CSCs and monitor the hypoxic microenvironment in vivo. The two-photon fluorescent molecular probe with a hypoxic specific response group can be reduced by NTR under hypoxic conditions. We used the two-photon probe to detect the hypoxia status of 3D cultured-CSCs in vitro and in vivo CSCs' microenvironment in tumour. The two-photon absorption cross section extends fluorescent excitation spectra to the near infrared region, which dramatically promotes the tissue penetration for hypoxic microenvironment detection of CSC in vivo.

Corantes Fluorescentes/química , Hipóxia/diagnóstico por imagem , Células-Tronco Neoplásicas/enzimologia , Nitrorredutases/análise , Microambiente Tumoral , Animais , Sobrevivência Celular , Corantes Fluorescentes/síntese química , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Sondas Moleculares/síntese química , Sondas Moleculares/química , Fótons , Ensaios Antitumorais Modelo de Xenoenxerto
Int J Nanomedicine ; 13: 1707-1721, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599615


Introduction: poly(l-lactic acid) (PLLA) has been approved for clinical use by the US Food and Drug Administration (FDA); however, their stronger hydrophobicity and relatively fast degradation rate restricted their widespread application. In consideration of the composition of bone, the inorganic-organic composite has a great application prospect in bone tissue engineering. Many inorganic-organic composite scaffolds were prepared by directly mixing the active ingredient, but this method is uncontrolled and will lead to lack of homogeneity in the polymer matrix. Strontium (Sr) is an admirable addition to improve the bioactivity and bone induction of hydroxyapatite (HA). To our knowledge, the application of biomimetic mineralized strontium-doped hydroxyapatite on porous poly(l-lactic acid) (Sr-HA/PLLA) scaffolds for bone defect repair has never been reported till date. Biomimetic mineralized Sr-HA/PLLA porous scaffold was developed in this study. The results indicated that the Sr-HA/PLLA porous scaffold could improve the surface hydrophobicity, reduce the acidic environment of the degradation, and enhance the osteoinductivity; moreover, the ability of protein adsorption and the modulus of compression were increased. The results also clearly showed the effectiveness of the Sr-HA/PLLA porous scaffold in promoting cell adhesion, proliferation, and alkaline phosphatase (ALP) activity. The micro computed tomography (micro-CT) results showed that more new bones were formed by Sr-HA/PLLA porous scaffold treatment. The histological results confirmed the osteoinductivity of the Sr-HA/PLLA porous scaffold. The results suggested that the Sr-HA/PLLA porous scaffold has a good application prospect in bone tissue engineering in the future. Purpose: The purpose of this study was to promote the bone repair. Materials and methods: Surgical operation of rabbits was carried out in this study. Results: The results showed that formation of a large number of new bones by the Sr-HA/PLLA porous scaffold treatment is possible. Conclusion: Biomimetic mineralized Sr-HA/PLLA porous scaffold could effectively promote the restoration of bone defects in vivo.

Biomimética/métodos , Hidroxiapatitas/química , Poliésteres/química , Estrôncio/química , Tecidos Suporte/química , Animais , Regeneração Óssea , Osso e Ossos , Calcificação Fisiológica/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Teste de Materiais , Poliésteres/farmacologia , Porosidade , Coelhos , Engenharia Tecidual/métodos , Microtomografia por Raio-X
Zhongguo Dang Dai Er Ke Za Zhi ; 16(7): 745-8, 2014 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-25008885


OBJECTIVE: To observe the clinical efficacy and safety of sildenafil in the treatment of high altitude heart disease associated with severe pulmonary arterial hypertension (PAH) in children. METHODS: Fifty children (aged 2 months to 2 years) with high altitude heart disease associated with severe PAH, who were continuously transferred to the Intensive Care Unit between January 2011 and October 2013, were randomly assigned to observation and control groups. The control group was given conventional treatment, while the observation group received oral sildenafil [1 mg/(kg . d)] three times daily for 7-10 days in addition to the conventional treatment. Before and after treatment, hemodynamics, blood gas, routine blood parameters, and blood biochemical parameters were recorded. RESULTS: After treatment, the observation group had a significantly higher decrease in mean pulmonary artery pressure and significantly higher increases in arterial partial pressure of oxygen, cardiac output, cardiac index, and oxygenation index compared with the control group (P<0.05). In the observation group, there were no significant changes in mean arterial pressure, routine blood parameters and blood biochemical parameters (P>0.05), and no obvious adverse reactions were found. CONCLUSIONS: For children with high altitude heart disease associated with severe PAH, sildenafil can effectively reduce pulmonary artery pressure and improve cardiac function and does not cause adverse reactions. This therapy has good safety according to the preliminary evaluation.

Altitude , Cardiopatias/tratamento farmacológico , Hipertensão Pulmonar/complicações , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Vasodilatadores/uso terapêutico , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Masculino , Piperazinas/efeitos adversos , Purinas/efeitos adversos , Purinas/uso terapêutico , Citrato de Sildenafila , Sulfonas/efeitos adversos , Vasodilatadores/efeitos adversos