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1.
Chem Sci ; 14(7): 1808-1819, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36819853

RESUMO

Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.

2.
Biomaterials ; 289: 121781, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36113331

RESUMO

Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.


Assuntos
Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Família Aldeído Desidrogenase 1 , Caspase 3 , Linhagem Celular Tumoral , Humanos , Irinotecano , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
3.
J Am Chem Soc ; 143(35): 14115-14124, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34374290

RESUMO

Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Acetazolamida/análogos & derivados , Acetazolamida/uso terapêutico , Animais , Antineoplásicos/síntese química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/uso terapêutico , Diarileptanoides/síntese química , Diarileptanoides/uso terapêutico , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/uso terapêutico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/diagnóstico por imagem , Esferoides Celulares/efeitos dos fármacos , Tiofenos/síntese química , Tiofenos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Adv Funct Mater ; 31(5)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33776614

RESUMO

Nanoparticle-based nucleic acid conjugates (NP-NACs) hold great promise for theragnostic (diagnostic and therapeutic) applications. However, several limitations have hindered the realization of their full potential in the clinical treatment of cancer and other diseases. In diagnosis, NP-NACs, combined with conventional optical sensing systems, have been applied for cancer detection in vitro, but low signal-to-noise ratios limit their broad in vivo applications. Meanwhile, the efficiency of NP-NAC-mediated cancer therapies has been limited through the adaptation of alternative pro-survival pathways in cancer cells. The recent emergence of personalized and precision medicine has outlined the importance of both accurate diagnosis and efficient therapeutics in a single platform. As such, we report the controlled assembly of hybrid graphene oxide/gold nanoparticle-based cancer-specific NACs (Au@GO NP-NACs) for multimodal imaging and combined therapeutics. Our developed Au@GO NP-NACs shows excellent surface-enhanced Raman scattering (SERS)-mediated live-cell cancer detection and multimodal synergistic cancer therapy through the use of photothermal, genetic, and chemotherapeutic strategies. Synergistic and selective killing of cancer cells were then demonstrated by using in vitro microfluidic models and nine different cancer cell lines by further incorporating near-infrared photothermal hyperthermia, a Topoisomerase II anti-cancer drug, and cancer targeting peptides. Moreover, with distinctive advantages of the Au@GO NP-NACs for cancer theragnostics, we further demonstrated precision cancer treatment through the detection of cancer cells in vivo using SERS followed by efficient ablation of the tumor. Therefore, our Au@GO NP-NACs could pave a new road for the advanced theragnostics of cancer as well as many other diseases.

5.
Biomaterials ; 269: 120529, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33257114

RESUMO

Recent advances in pluripotent stem cell technology provide an alternative source of human hepatocytes to overcome the limitations of current toxicity tests. However, this approach requires optimization and standardization before it can be used as a fast and reliable toxicity screening system. Here, we designed and tested microwell culture platforms with various diameters. We found that large quantities of uniformly-sized hepatocyte-like cell (HLC) spheroids (3D-uniHLC-Ss) could be efficiently and reproducibly generated in a short period time from a small number of differentiating human pluripotent stem cells (hPSCs). The hPSC-3D-uniHLC-Ss that were produced in 500-µm diameter microwells consistently exhibited high expressions of hepatic marker genes and had no significant signs of cell death. Importantly, a hepatic master gene hepatocyte nuclear factor 4α (HNF4α) was maintained at high levels, and the epithelial-mesenchymal transition was significantly attenuated in hPSC-3D-uniHLC-Ss. Additionally, when compared with 3D-HLC-Ss that were produced in other 3D platforms, hPSC-3D-uniHLC-Ss showed significantly higher hepatic gene expressions and drug-metabolizing activity of the enzyme, CYP3A4. Imaging-based drug toxicity studies demonstrated that hPSC-3D-uniHLC-Ss exhibited enhanced sensitivity to various hepatotoxicants, compared to HLCs, which were differentiated under 2D conditions. Precise prediction of drug-induced hepatotoxicity is a crucial step in the early phases of drug discovery. Thus, the hPSC-3D-uniHLC-Ss produced using our microwell platform could be used as an imaging-based toxicity screening system to predict drug hepatotoxicity.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Células-Tronco Pluripotentes , Técnicas de Cultura de Células , Diferenciação Celular , Hepatócitos , Humanos , Fígado
6.
Mol Med Rep ; 22(6): 4947-4955, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173958

RESUMO

Charcot­Marie­Tooth disease (CMT) is the most common inherited neurological disorder of the peripheral nervous system. The major subtype, CMT type 1A (CMT1A), accounts for ~40% of CMT cases and is characterized by distal muscle atrophy and gait disturbances. Short hairpin (sh) RNA sequences are potentially advantageous therapeutic tools for distal muscle atrophy­induced gait disturbance. Therefore, the current study focused on the effects of an optimal shRNA injection using the myostatin (mstn) gene inhibition system. shLenti­Mstn A demonstrated significant suppression of endogenous mstn gene expression (>40%) via RT­qPCR following direct injection into the gastrocnemius and rectus femoris of the hind limb in C22 mice. The results also reported that shLenti­Mstn A treatment increased muscle mass and size of the hind limbs compared with mock­treated mice via measurement of the mass of injected muscles and magnetic resonance imaging study. Furthermore, electrophysiological measurement using a Nicolet Viking Quest device revealed significantly improved compound muscle action potential (CMAP) in shLenti­Mstn A­treated mice compared with the mock group (P<0.05) whereas nerve conduction velocity (NCV) showed no difference between groups. The shLenti­Mstn A treatment directly affected increased muscle regeneration, including mass and size, but not regeneration of peripheral nerve. Additionally, shLenti­Mstn A treatment significantly enhanced mobility, including locomotor coordination (P<0.01) and grip strength of the hindlimbs (P<0.01). Furthermore, MotoRater analysis using real­time recording with a high­speed camera revealed that shLenti­Mstn­treated mice exhibited an improved walking pattern in terms of step length, base support and duty factor compared with the mock group. It was hypothesized that treatment with shLenti­Mstn A may provide a novel therapeutic strategy for improving gait in patients with CMT1A.


Assuntos
Doença de Charcot-Marie-Tooth/terapia , Miostatina/genética , RNA Interferente Pequeno/uso terapêutico , Animais , Doença de Charcot-Marie-Tooth/genética , Modelos Animais de Doenças , Marcha/genética , Marcha/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Atrofia Muscular/terapia , Miostatina/uso terapêutico , Condução Nervosa , RNA Interferente Pequeno/genética
7.
Chem Soc Rev ; 49(22): 7856-7878, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-32633291

RESUMO

Cancer stem cells (CSCs), also called tumor-initiating cells (TICs), have been studied intensively due to their rapid proliferation, migration, and role in the recurrence of cancer. In general, CSC marker-positive cells [CD133, CD44, CD166, aldehyde dehydrogenase (ALDH), and epithelial cell adhesion molecule (EpCAM)] exhibit a 100-fold increased capacity to initiate cancer. Within a heterogeneous tumor mass, only approximately 0.05-3% of cells are suspected to be CSCs and able to proliferate under hypoxia. Interestingly, CSCs, cancer cells, and normal stem cells share many cytochemical properties, such as inhibition of the redox system for reactive oxygen species (ROS) production and high expression of drug resistance transporters. However, compared to normal stem cells, CSCs develop unique metabolic flexibility, which involves switching between oxidative phosphorylation (OXPHOS) and glycolysis as their main source of energy. Due to the similarities between CSCs and other cancer cells and normal stem cells, limited chemotherapeutic and bio-imaging reagents specific for CSCs have been developed. In this short review, we address the current knowledge regarding CSCs with a focus on designing chemotherapeutic and bio-imaging reagents that target CSCs.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Humanos , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
8.
Cancers (Basel) ; 12(2)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050643

RESUMO

Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.

9.
Biomaterials ; 222: 119431, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31450160

RESUMO

Hepatocytes derived from human pluripotent stem cells (hPSCs) are promising candidates for cell therapy and drug discovery. However, it remains challenging to efficiently purify hepatocytes from undesired cell types after differentiation and to accurately monitor grafted cells after transplantation. Indocyanine Green (ICG), an FDA-approved, near-infrared (NIR) dye, has been used for various clinical purposes and is exclusively taken up by hepatocytes. However, ICG has a long emission wavelength (λem > 800 nm) that is beyond the detection range of fluorescence-activated cell sorting (FACS) systems. Moreover, it is easily eliminated from hepatocytes, hindering its application for NIR imaging. Here, we designed and synthesized two different probes based on the properties of ICG; 1) hepatocyte purifying agent (HPA, λem = 562 nm) for in vitro sorting and 2) hepatocyte imaging agent (HIA, λem = 817 nm) for efficient in vivo NIR imaging. We obtained highly enriched populations of hPSC-derived hepatocytes (hPSC-Heps) from various hPSC lines using HPA probe-based FACS purification. In addition, HIA labelling and NIR imaging allowed the direct visualization and tracking of grafted hPSC-Heps in animals with liver injuries. These results demonstrated that these two probes could be used as powerful tools with hPSC-Heps in both cell replacement therapy and drug screening.


Assuntos
Hepatócitos/citologia , Células-Tronco Pluripotentes/citologia , Técnicas de Cultura de Células/métodos , Células Cultivadas , Citometria de Fluxo , Humanos , Verde de Indocianina/química
10.
ACS Appl Mater Interfaces ; 11(27): 23909-23918, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31252451

RESUMO

Multifunctional nanoparticles that carry chemotherapeutic agents can be innovative anticancer therapeutic options owing to their tumor-targeting ability and high drug-loading capacity. However, the nonspecific release of toxic DNA-intercalating anticancer drugs from the nanoparticles has significant side effects on healthy cells surrounding the tumors. Herein, we report a tumor homing reactive oxygen species nanoparticle (THoR-NP) platform that is highly effective and selective for ablating malignant tumors. Sodium nitroprusside (SNP) and diethyldithiocarbamate (DDC) were selected as an exogenous reactive oxygen species (ROS) generator and a superoxide dismutase 1 inhibitor, respectively. DDC-loaded THoR-NP, in combination with SNP treatment, eliminated multiple cancer cell lines effectively by the generation of peroxynitrite in the cells (>95% cell death), as compared to control drug treatments of the same concentration of DDC or SNP alone (0% cell death). Moreover, the magnetic core (ZnFe2O4) of the THoR-NP can specifically ablate tumor cells (breast cancer cells) via magnetic hyperthermia, in conjunction with DDC, even in the absence of any exogenous RS supplements. Finally, by incorporating iRGD peptide moieties in the THoR-NP, integrin-enriched cancer cells (malignant tumors, MDA-MB-231) were effectively and selectively killed, as opposed to nonmetastatic tumors (MCF-7), as confirmed in a mouse xenograft model. Hence, our strategy of using nanoparticles embedded with ROS-scavenger-inhibitor with an exogenous ROS supplement is highly selective and effective cancer therapy.


Assuntos
Ditiocarb , Nanopartículas , Neoplasias Experimentais , Nitroprussiato , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1 , Animais , Ditiocarb/química , Ditiocarb/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/economia , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Nitroprussiato/química , Nitroprussiato/farmacologia , Superóxido Dismutase-1/química , Superóxido Dismutase-1/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Angew Chem Int Ed Engl ; 58(17): 5648-5652, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30809896

RESUMO

The aggregation of amyloid beta (Aß) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aß-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two-photon microscopy (TPM) has emerged as one of the most powerful. To date, several near-infrared-emissive two-photon dyes with a high affinity for Aß fibrils have been developed, but there has often been a tradeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)-based de-excitation pathway, which results in a remarkable fluorescence increase of around 167-fold in the presence of Aß fibrils, while maintaining an excellent two-photon cross section, thereby enabling high-contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal-to-background ratio.


Assuntos
Corantes Fluorescentes/metabolismo , Imagem Óptica/métodos , Placa Amiloide/metabolismo , Humanos
12.
Biomaterials ; 185: 63-72, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30223141

RESUMO

Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Indometacina/administração & dosagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Células A549 , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Indometacina/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Pró-Fármacos/uso terapêutico , Nanomedicina Teranóstica , Hipóxia Tumoral/efeitos dos fármacos
13.
J Control Release ; 288: 14-22, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30170068

RESUMO

We report herein, an azo-derivative (AzP1) of FDA approved antineoplastic drug SN-38 (irinotecan analogue) as a theranostic agent with a potential for both tumor hypoxia-specific activation and therapy. The theranostic AzP1 was found to be stable within a biologically relevant pH scale and was chemically inert towards other competitive biological analytes. However, upon treatment with rat-liver microsomes, AzP1 showed a self-calibrated fluorescence enhancement at λem = 560 nm. The cytotoxicity profile of AzP1 was tested in various cancer lines. Under hypoxic conditions, prodrug AzP1 exhibited activation to release the parent drug (SN-38) and enhanced cytotoxicity in cancer cells with concomitant fluorescence enhancement at 560 nm, which served to monitor both the drug activation and tracing purposes. The therapeutic potential of AzP1 for both tumor-specific activation and suppression of tumor weights was validated in xenograft mouse model. Collectively, the synthetic ease and hypoxia-sensitive activation along with promising therapeutic properties highlight the potential of theranostic AzPI in future cancer treatment programs.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Azo/administração & dosagem , Irinotecano/análogos & derivados , Irinotecano/administração & dosagem , Neoplasias/tratamento farmacológico , Hipóxia Tumoral/efeitos dos fármacos , Animais , Caenorhabditis elegans , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/efeitos dos fármacos , Neoplasias/diagnóstico por imagem , Ratos , Nanomedicina Teranóstica
14.
ACS Appl Mater Interfaces ; 10(32): 26954-26963, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30028120

RESUMO

In this study, we report the use of a multifunctional magnetic core-shell nanoparticle (MCNP), composed of a highly magnetic zinc-doped iron oxide (ZnFe2O4) core nanoparticle and a biocompatible mesoporous silica (mSi) shell, for the simultaneous delivery of let-7a microRNA (miRNA) and anticancer drugs (e.g., doxorubicin) to overcome chemoresistance in breast cancer. Owing to the ability of let-7a to repress DNA repair mechanisms (e.g., BRCA1 and BRCA2) and downregulate drug efflux pumps (e.g., ABCG2), delivery of let-7a could sensitize chemoresistant breast cancer cells (MDA-MB-231) to subsequent doxorubicin chemotherapy both in vitro and in vivo. Moreover, the multifunctionality of our MCNPs allows for the monitoring of in vivo delivery via magnetic resonance imaging. In short, we have developed a multifunctional MCNP-based therapeutic approach to provide an attractive method with which to enhance our ability not only to deliver combined miRNA therapeutics with small-molecule drugs in both selective and effective manner but also to sensitize cancer cells for the enhanced treatment via the combination of miRNA replacement therapy using a single nanoplatform.


Assuntos
Nanopartículas de Magnetita , Doxorrubicina , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imageamento por Ressonância Magnética , Magnetismo , MicroRNAs , Neoplasias
15.
Biosens Bioelectron ; 102: 372-382, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29174970

RESUMO

Circulating cancer stem cells (CCSCs), a rare circulating tumor cell (CTC) type, recently arose as a useful resource for monitoring and characterizing both cancers and their metastatic derivatives. However, due to the scarcity of CCSCs among hematologic cells in the blood and the complexity of the phenotype confirmation process, CCSC research can be extremely challenging. Hence, we report a nanoparticle-mediated Raman imaging method for CCSC characterization which profiles CCSCs based on their surface marker expression phenotypes. We have developed an integrated combinatorial Raman-Active Nanoprobe (RAN) system combined with a microfluidic chip to successfully process complete blood samples. CCSCs and CTCs were detected (90% efficiency) and classified in accordance with their respective surface marker expression via completely distinct Raman signals of RANs. Selectively isolated CCSCs (93% accuracy) were employed for both in vitro and in vivo tumor phenotyping to identify the tumorigenicity of the CCSCs. We utilized our new method to predict metastasis by screening blood samples from xenograft models, showing that upon CCSC detection, all subjects exhibited liver metastasis. Having highly efficient detection and noninvasive isolation capabilities, we have demonstrated that our RAN-based Raman imaging method will be valuable for predicting cancer metastasis and relapse via CCSC detection. Moreover, the exclusion of peak overlapping in CCSC analysis with our Raman imaging method will allow to expand the RAN families for various cancer types, therefore, increasing therapeutic efficacy by providing detailed molecular features of tumor subtypes.


Assuntos
Técnicas Biossensoriais , Células Neoplásicas Circulantes/patologia , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Separação Celular/métodos , Humanos , Técnicas Analíticas Microfluídicas , Nanopartículas/química , Análise Espectral Raman
16.
Clin Exp Reprod Med ; 44(2): 63-72, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28795044

RESUMO

OBJECTIVE: Hyperstimulation methods are broadly used for in vitro fertilization (IVF) in patients with infertility; however, the side effects associated with these therapies, such as ovarian hyperstimulation syndrome (OHSS), have not been well studied. N-glycoproteomes are subproteomes used for the remote sensing of ovarian stimulation in follicular growth. Glycoproteomic variation in human follicular fluid (hFF) has not been evaluated. In this study, we aimed to identify and quantify the glycoproteomes and N-glycoproteins (N-GPs) in natural and stimulated hFF using label-free nano-liquid chromatography/electrospray ionization-quad time-of-flight mass spectrometry. METHODS: For profiling of the total proteome and glycoproteome, pooled protein samples from natural and stimulated hFF samples were selectively isolated using hydrazide chemistry to obtain the total proteomes and glycoproteomes. N-GPs were validated by the consensus sequence N-X-S/T (92.2% specificity for the N-glycomotif at p<0.05). All data were compared between natural versus hyperstimulated hFF samples. RESULTS: We detected 41 and 44 N-GPs in the natural and stimulated hFF samples, respectively. Importantly, we identified 11 N-GPs with greater than two-fold upregulation in stimulated hFF samples compared to natural hFF samples. We also validated the novel N-GPs thyroxine-binding globulin, vitamin D-binding protein, and complement proteins C3 and C9. CONCLUSION: We identified and classified N-GPs in hFF to improve our understanding of follicular physiology in patients requiring assisted reproduction. Our results provided important insights into the prevention of hyperstimulation side effects, such as OHSS.

17.
J Am Chem Soc ; 139(22): 7595-7602, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28459562

RESUMO

A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.


Assuntos
Anidrase Carbônica IX/química , Sistemas de Liberação de Medicamentos , Fotoquimioterapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Anidrase Carbônica IX/metabolismo , Feminino , Células HeLa , Humanos , Hipóxia , Microscopia Confocal
18.
Gastroenterology ; 152(5): 1174-1186, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27956229

RESUMO

BACKGROUND & AIMS: Mesenchymal stem cells (MSCs) mediate tissue repair and might be used to prevent or reduce liver fibrosis. However, little is known about the anti-fibrotic factors secreted from MSCs or their mechanisms. METHODS: Umbilical cord-derived MSCs (UCMSCs) were differentiated into hepatocyte-like cells (hpUCMSCs), medium was collected, and secretome proteins were identified and quantified using nanochip-liquid chromatography/quadrupole time-of-flight mass spectrometry. Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide or CCl4; some mice were then given injections of secretomes or proteins. Liver tissues were collected and analyzed by histology or polymerase chain reaction array to analyze changes in gene expression patterns. We analyzed the effects of MSC secretomes and potential anti-fibrotic proteins on transforming growth factor ß 1 (TGFß1)-mediated activation of human hepatic stellate cell (HSC) lines (hTert-HSC and LX2) and human primary HSCs. Liver tissues were collected from 16 patients with liver cirrhosis and 16 individuals without cirrhosis (controls) in Korea and analyzed by immunohistochemistry and immunoblots. RESULTS: In mice with fibrosis, accumulation of extracellular matrix proteins was significantly reduced 3 days after injecting secretomes from UCMSCs, and to a greater extent from hpUCMSCs; numbers of activated HSCs that expressed the myogenic marker α-smooth muscle actin (α-SMA, encoded by ACTA2 [actin, alpha 2, smooth muscle]) were also reduced. Secretomes from UCMSCs, and to a greater extent from hpUCMSCs, reduced liver expression of multiple fibrotic factors, collagens, metalloproteinases, TGFß, and Smad proteins in the TGFß signaling pathways. In HSC cell lines and primary HSCs, TGFß1-stimulated upregulation of α-SMA was significantly inhibited (and SMAD2 phosphorylation reduced) by secretomes from UCMSCs, and to a greater extent from hpUCMSCs. We identified 32 proteins in secretomes of UCMSCs that were more highly concentrated in secretomes from hpUCMSCs and inhibited TGFß-mediated activation of HSCs. One of these, milk fat globule-EGF factor 8 (MFGE8), was a strong inhibitor of activation of human primary HSCs. We found MFGE8 to down-regulate expression of TGFß type I receptor by binding to αvß3 integrin on HSCs and to be secreted by MSCs from umbilical cord, teeth, and bone marrow. In mice, injection of recombinant human MFGE8 had anti-fibrotic effects comparable to those of the hpUCMSC secretome, reducing extracellular matrix deposition and HSC activation. Co-injection of an antibody against MFGE8 reduced the anti-fibrotic effects of the hpUCMSC secretome in mice. Levels of MFGE8 were reduced in cirrhotic liver tissue from patients compared with controls. CONCLUSIONS: MFGE8 is an anti-fibrotic protein in MSC secretomes that strongly inhibits TGFß signaling and reduces extracellular matrix deposition and liver fibrosis in mice.


Assuntos
Antígenos de Superfície/metabolismo , Cirrose Hepática/metabolismo , Proteínas do Leite/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Células Estreladas do Fígado , Hepatócitos , Humanos , Integrina alfaVbeta3/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Metaboloma , Metaloproteases/metabolismo , Camundongos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad2/metabolismo , Tioacetamida/toxicidade , Fator de Crescimento Transformador beta1/metabolismo
19.
Biomaterials ; 115: 104-114, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27886551

RESUMO

An azobenzene scaffold serves as both a fluorescence quencher and nitrogen mustard deactivator in a mitochondrial targeting unit bearing theranostic drug delivery system (DDS). The DDS exhibited a tissue selectivity for tumors with aggressive phenotypes, and the efficient in vitro and in vivo azoreduction under hypoxia conditions resulted in bright fluorescence at the tumor site as well as the in situ activation of the prodrug. In vivo therapeutic experiments demonstrated a significant reduction in tumor growth versus number of controls and ex vivo tissue analysis confirmed tissue normalization with strongly reduced angiogenic markers and suppressed cell proliferation. Mechanistic insight of the DDS's mode of action was gained by gene and protein expression experiments, aided by a proteomic analysis, revealing the circumvention of cellular drug resistance pathways as well as the normalization of Slit-Robo signaling, and the involvement of granzyme-triggered mitochondria-mediated apoptosis. Overall, the combined high sensitivity and synthetic ease as well as excellent therapeutic response suggests a revival of the azobenzene class of hypoxia activated drugs, especially applied to theranostics, is warranted.


Assuntos
Compostos Azo/administração & dosagem , Microscopia de Fluorescência/métodos , Nanocápsulas/administração & dosagem , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Hipóxia Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos Alquilantes/administração & dosagem , Compostos Azo/química , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Neoplasias Experimentais/patologia , Resultado do Tratamento
20.
Sci Rep ; 6: 29018, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27374023

RESUMO

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic ("phototheranostic").


Assuntos
Camptotecina/análogos & derivados , DNA Topoisomerases Tipo I/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/farmacologia , Inibidores da Topoisomerase I/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Camptotecina/síntese química , Camptotecina/farmacologia , Caspases/genética , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Xenoenxertos , Humanos , Irinotecano , Lasers , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/síntese química , Pró-Fármacos/síntese química , Inibidores da Topoisomerase I/síntese química
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