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1.
Artigo em Inglês | MEDLINE | ID: mdl-37815783

RESUMO

PURPOSE: After September 11, 2001, nuclear threat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality. METHODS AND MATERIALS: For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GI-ARS lethal dose for this mouse strain. RESULTS: Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy + BMT + scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these findings, mice receiving 15 Gy + BMT + scFv exhibit prolonged survival. At day 90, before sacrifice, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined. CONCLUSIONS: Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies.

2.
Nanotheranostics ; 7(4): 353-367, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151801

RESUMO

Indocyanine green (ICG) is one of the FDA-approved near infra-red fluorescent (NIRF) probes for cancer imaging and image-guided surgery in the clinical setting. However, the limitations of ICG include poor photostability, high concentration toxicity, short circulation time, and poor cancer cell specificity. To overcome these hurdles, we engineered a nanoconstruct composed of poly (vinyl pyrrolidone) (PVP)-indocyanine green that is cloaked self-assembled with tannic acid (termed as indocyanine green-based glow nanoparticles probe, ICG-Glow NPs) for the cancer cell/tissue-specific targeting. The self-assembled ICG-Glow NPs were confirmed by spherical nanoparticles formation (DLS and TEM) and spectral analyses. The NIRF imaging characteristic of ICG-Glow NPs was established by superior fluorescence counts on filter paper and chicken tissue. The ICG-Glow NPs exhibited excellent hemo and cellular compatibility with human red blood cells, kidney normal, pancreatic normal, and other cancer cell lines. An enhanced cancer-specific NIRF binding and imaging capability of ICG-Glow NPs was confirmed using different human cancer cell lines and human tumor tissues. Additionally, tumor-specific binding/accumulation of ICG-Glow NPs was confirmed in MDA-MB-231 xenograft mouse model. Collectively, these findings suggest that ICG-Glow NPs have great potential as a novel and safe NIRF imaging probe for cancer cell/tumor imaging. This can lead to a quicker cancer diagnosis facilitating precise disease detection and management.


Assuntos
Neoplasias , Nanopartículas , Verde de Indocianina , Neoplasias/diagnóstico por imagem , Humanos , Linhagem Celular , Feminino , Animais , Camundongos
3.
Cancer Res ; 82(15): 2678-2691, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35919990

RESUMO

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. SIGNIFICANCE: Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.


Assuntos
Radioisótopos de Césio , Irradiação Corporal Total , Animais , Raios gama , Camundongos , Raios X
4.
ACS Appl Bio Mater ; 5(3): 1104-1119, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35179871

RESUMO

Chemotherapy often experiences several challenges including severe systemic toxicity and adverse effects. The combination chemotherapy arose as an effective clinical practice aimed at reducing doses of drugs to achieve synergistic actions with low toxicity. Our recent efforts demonstrated a synergistic therapeutic benefit of gambogic acid (GA) and gemcitabine (Gem) against lung cancer. However, simultaneous delivery of these two drugs at the tumor site is highly challenging. Therefore, the development of an injectable formulation that can effectively deliver both hydrophobic (GA) and hydrophilic (Gem) drugs in one formulation is a clinically unmet need. Herein, this study reports an in situ human serum albumin (HSA)- and tannic acid (TA)-mediated complexed GA and Gem nanoparticles (G-G@HTA NPs). G-G@HTA NP formation was confirmed by the particle size, Fourier transform infrared spectroscopy, and 1H NMR spectroscopy. The superior therapeutic activity of G-G@HTA NPs was demonstrated by multiple in vitro functional assays. Additionally, G-G@HTA NPs revealed an obvious and precise targeting of tumors in vivo. The promoted and more synergistic anti-tumor efficacy of G-G@HTA NPs was attained than that of combined treatments and single drug treatments. These events have resulted in no apparent systemic and organ toxicities. Together, this study suggests that in situ HSA-TA-based combinatorial treatment strategy is a suitable approach for application in lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Portadores de Fármacos/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Tamanho da Partícula , Albumina Sérica Humana/uso terapêutico
5.
Eur J Pharmacol ; 888: 173486, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32805254

RESUMO

Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer accounting up to 80-85% of all lung cancer (LC) cases. Gemcitabine (Gem), a pyrimidine nucleoside antimetabolite, is widely used chemotherapy offering several months survival benefit in patients with NSCLC. The emergence of Gem resistance is a main clinical concern in cancer treatment and thus a continuous demand for development of new therapeutic strategies to improve its antitumor activity. Hence, we report an adjuvant therapeutic regimen based on natural compound, gambogic acid (GA) which has been shown to enhanced Gem induced inhibition of cancer cell growth, arrest cell cycle, and induce apoptosis by enhanced accumulation of Gem. The in vitro cell viability, clonogenicity, invasion, and migration assays demonstrated a significant higher therapeutic effect of Gem when it was combined with GA in A549 and H1299 cells. A better access of internalization of drug molecules achieved in rhodamine 123 assay when GA was used as adjuvant treatment. Further, GA and Gem combination significantly reduced tubular formation of HUVEC cells indicates lowering angiogenesis potential. Microarray and Western blot studies confirm that GA + Gem co-treatment strategy promotes cancer cell death by downregulating anti-apoptotic proteins, chemoresistance-associated proteins, and upregulation of apoptosis proteins. More importantly, a significant higher therapeutic benefit was noticed for GA and Gem combination in A549 xenograft mice model. Together, these results offer a rationale to evaluate the clinical translational possibility of GA as adjuvant therapy to overcome Gem resistance. This combination regimen can be a new therapeutic concept to eradicate this devastating disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/patologia , Xantonas/administração & dosagem , Células A549 , Adulto , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sobrevivência Celular/fisiologia , Desoxicitidina/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Projetos Piloto , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Gencitabina
6.
Viruses ; 12(5)2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32443728

RESUMO

Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication in the brain and in subsequent HAND pathogenesis. However, due to the limited ability of ART drugs to cross the blood-brain barrier (BBB) after systemic administration, in addition to efflux transporter expression on microglia, the efficacy of ART drugs for viral suppression in microglia is suboptimal. Previously, we developed novel poly (lactic-co-glycolic acid) (PLGA)-based elvitegravir nanoparticles (PLGA-EVG NPs), which showed improved BBB penetration in vitro and improved viral suppression in HIV-1-infected primary macrophages, after crossing an in vitro BBB model. Our objective in the current study was to evaluate the efficacy of our PLGA-EVG NPs in an important central nervous system (CNS) HIV-1 reservoir, i.e., microglia. In this study, we evaluated the cyto-compatibility of the PLGA-EVG NPs in microglia, using an XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and cellular morphology observation. We also studied the endocytosis pathway and the subcellular localization of PLGA NPs in microglia, using various endocytosis inhibitors and subcellular localization markers. We determined the ability of PLGA-EVG NPs to suppress HIV-1 replication in microglia, after crossing an in vitro BBB model. We also studied the drug levels in mouse plasma and brain tissue, using immunodeficient NOD scid gamma (NSG) mice, and performed a pilot study, to evaluate the efficacy of PLGA-EVG NPs on viral suppression in the CNS, using an HIV-1 encephalitic (HIVE) mouse model. From our results, the PLGA-EVG NPs showed ~100% biocompatibility with microglia, as compared to control cells. The internalization of PLGA NPs in microglia occurred through caveolae-/clathrin-mediated endocytosis. PLGA NPs can also escape from endo-lysosomal compartments and deliver the therapeutics to cells efficiently. More importantly, the PLGA-EVG NPs were able to show ~25% more viral suppression in HIV-1-infected human-monocyte-derived microglia-like cells after crossing the in vitro BBB compared to the EVG native drug, without altering BBB integrity. PLGA-EVG NPs also showed a ~two-fold higher level in mouse brain and a trend of decreasing CNS HIV-1 viral load in HIV-1-infected mice. Overall, these results help us to create a safe and efficient drug delivery method to target HIV-1 reservoirs in the CNS, for potential clinical use.


Assuntos
Fármacos Anti-HIV/farmacologia , Antirretrovirais/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Inibidores de Integrase/farmacologia , Microglia/virologia , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Nanopartículas/química , Projetos Piloto , Plasma/virologia , Quinolonas/farmacologia , Carga Viral
7.
ACS Omega ; 5(15): 8982-8991, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32337462

RESUMO

Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients.

8.
Sci Rep ; 10(1): 3835, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123217

RESUMO

The use of antiretroviral therapy (ART) has remarkably decreased the morbidity associated with HIV-1 infection, however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. The blood-brain barrier (BBB) is the major impediment for penetration of antiretroviral drugs, causing therapeutics to reach only suboptimal level to the brain. Conventional antiretroviral drug regimens are not sufficient to improve the treatment outcomes of HAND. In our recent report, we have developed a poloxamer-PLGA nanoformulation loaded with elvitegravir (EVG), a commonly used antiretroviral drug. The nanoformulated EVG is capable of elevating intracellular drug uptake and simultaneously enhance viral suppression in HIV-1-infected macrophages. In this work, we identified the clinical parameters including stability, biocompatibility, protein corona, cellular internalization pathway of EVG nanoformulation for its potential clinical translation. We further assessed the ability of this EVG nanoformulation to cross the in vitro BBB model and suppress the HIV-1 in macrophage cells. Compared with EVG native drug, our EVG nanoformulation demonstrated an improved BBB model penetration cross the in vitro BBB model and an enhanced HIV-1 suppression in HIV-1-infected human monocyte-derived macrophages after crossing the BBB model without altering the BBB model integrity. Overall, this is an innovative and optimized treatment strategy that has a potential for therapeutic interventions in reducing HAND.


Assuntos
Barreira Hematoencefálica/metabolismo , Composição de Medicamentos , HIV-1/efeitos dos fármacos , Macrófagos/virologia , Nanopartículas/química , Quinolonas/química , Quinolonas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Humanos , Teste de Materiais , Tamanho da Partícula , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quinolonas/metabolismo
9.
Sci Rep ; 10(1): 980, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969643

RESUMO

Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipogenic signaling and suppression of lipid metabolic pathways. The expression of proteins responsible for lipogenesis was down regulated. The membrane permeability and functionality of PCa were severely affected and caused nuclear disorganization during drug exposure. Finally, these consolidated events shifted the cell's survival balance towards apoptosis. These results suggest that TA distinctly interferes with the lipid signaling and metabolism of PCa cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taninos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Cancer Lett ; 470: 64-74, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809801

RESUMO

In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the phosphorylation of Jak2(Tyr1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the G2/M phase and modulated cell cycle regulatory proteins (cyclin B1, p21, p34cdc2 and pcdk1). Moreover, VERU-111 treatment induced apoptosis and modulated the expression of Bid, Bcl-xl, Survivin, Bax, Bcl2 and cleavage in PARP. In functional assays, VERU-111 markedly reduced the migratory and invasive potential of cervical cancer cells via modulations of MMPs. VERU-111 treatment also showed significant (P < 0.05) inhibition of orthotopic xenograft tumor growth in athymic nude mice. Taken together, our results demonstrate the potent anti-cancer efficacy of VERU-111 in experimental cervical cancer models.Thus, VERU-111 can be explored as a promising therapeutic agent for the treatment of cervical cancer.


Assuntos
Benzimidazóis/farmacologia , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Benzimidazóis/uso terapêutico , Feminino , Células HeLa , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Janus Quinase 2/metabolismo , Camundongos , Proteínas E7 de Papillomavirus/antagonistas & inibidores , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Biomed Opt Express ; 10(12): 6422-6431, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31853408

RESUMO

A mesoscopic physics-based optical imaging technique, partial wave spectroscopy (PWS), has been used for the detection of cancer by probing nanoscale structural alterations in cells/tissue. The development of drug-resistant cancer cells/tissues during chemotherapy is a major challenge in cancer treatment. In this paper, using a mouse model and PWS, the structural properties of tumor tissue grown in 3D structures by xenografting drug-resistant and drug-sensitive human prostate cancer cells having 2D structures, are studied. The results show that the 3D xenografted tissues maintain a similar hierarchy of the degree of structural disorder properties as that of the 2D original drug-sensitive and drug-resistant cells.

12.
ACS Appl Mater Interfaces ; 11(42): 38537-38554, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31553876

RESUMO

Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid-docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced in vitro therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFßR1/FOXO1/p21 signaling. Decrease in ß-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, in vivo and ex vivo imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing PC-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown in vivo by inhibiting TGFßR1 proteins and regressing tumor growth through apoptotic induction in the PC-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Docetaxel/química , Nanoestruturas/química , Polifenóis/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Proteína Forkhead Box O1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taninos/química , Transplante Heterólogo
13.
Expert Opin Drug Deliv ; 16(8): 869-882, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31328582

RESUMO

Introduction: Antiretroviral therapy (ART) has led to a significant reduction in HIV-1 morbidity and mortality. Many antiretroviral drugs (ARVs) are metabolized by cytochrome P450 (CYP) pathway, and the majority of these drugs are also either CYP inhibitors or inducers and few possess both activities. These CYP substrates, when used for HIV treatment in the conventional dosage form, have limitations such as low systemic bioavailability, potential drug-drug interactions, and short half-lives. Thus, an alternative mode of delivery is needed in contrast to conventional ARVs. Areas covered: In this review, we summarized the limitations of conventional ARVs in HIV treatment, especially for ARVs which are CYP substrates. We also discussed the preclinical and clinical studies using the nanotechnology strategy to overcome the limitations of these CYP substrates. The preclinical studies and clinical studies published from 2000 to February 2019 were discussed. Expert opinion: Since preclinical and clinical studies for prevention and treatment of HIV using nanotechnology approaches have shown considerable promise in recent years, nanotechnology could become an alternative strategy for daily oral therapy as a future treatment.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Infecções por HIV/tratamento farmacológico , Animais , Formas de Dosagem , Infecções por HIV/metabolismo , HIV-1 , Humanos , Nanotecnologia
14.
J Exp Clin Cancer Res ; 38(1): 29, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674344

RESUMO

BACKGROUND: The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, ßIII and ßIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. METHODS: We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of ß-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. RESULTS: We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, ßIII and ßIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model. CONCLUSIONS: This study has identified an inhibitor of ßIII/ßIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.


Assuntos
Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Moduladores de Tubulina/administração & dosagem , Tubulina (Proteína)/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Metástase Neoplásica , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Tubulina (Proteína)/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Colloid Interface Sci ; 535: 133-148, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30292104

RESUMO

Paclitaxel (PTX) is a gold standard chemotherapeutic agent for breast, ovarian, pancreatic and non-small cell lung carcinoma. However, in clinical use PTX can have adverse side effects or inadequate pharmacodynamic parameters, limiting its use. Nanotechnology is often employed to reduce the therapeutic dosage required for effective therapy, while also minimizing the systemic side effects of chemotherapy drugs. However, there is no nanoformulation of paclitaxel with chemosensitization motifs built in. With this objective, we screened eleven pharmaceutical excipients to develop an alternative paclitaxel nanoformulation using a self-assembly method. Based on the screening results, we observed tannic acid possesses unique properties to produce a paclitaxel nanoparticle formulation, i.e., tannic acid-paclitaxel nanoparticles. This stable TAP nanoformulation, referred to as TAP nanoparticles (TAP NPs), showed a spherical shape of ~ 102 nm and negative zeta potential of ~ -8.85. The presence of PTX in TAP NPs was confirmed by Fourier Transform Infrared (FTIR) spectra, thermogravimetric analyzer (TGA), and X-ray diffraction (XRD). Encapsulation efficiency of PTX in TAP NPs was determined to be ≥96%. Intracellular drug uptake of plain drug PTX on breast cancer cells (MDA-MB-231) shows more or less constant drug levels in 2 to 6 h, suggesting drug efflux by the P-gp transporters, over TAP NPs, in which PTX uptake was more than 95.52 ±â€¯11.01% in 6 h, as analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Various biological assays such as proliferation, clonogenic formation, invasion, and migration confirm superior anticancer effects of TAP NPs over plain PTX at all tested concentrations. P-gp expression, beta-tubulin stabilization, Western blot, and microarray analysis further confirm the improved therapeutic potential of TAP NPs. These results suggest that the TAP nanoformulation provides an important reference for developing a therapeutic nanoformulation affording pronounced, enhanced effects in breast cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/química , Paclitaxel/farmacologia , Taninos/química , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Paclitaxel/química , Tamanho da Partícula , Propriedades de Superfície , Espectrometria de Massas em Tandem , Células Tumorais Cultivadas
16.
Pharmaceutics ; 10(3)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071698

RESUMO

Lung cancer (LC) is one of the leading causes of death in both men and women in the United States. Tannic acid (TA), a water-soluble polyphenol, exhibits a wide range of biological activities. TA has received much attention as a promising compound in the biomaterial and drug delivery fields. Lung fluid (LF) is a major barrier for distribution of drugs to the lungs. Therefore, the purpose of this study was to examine TA interaction with LF for effective delivery of anti-cancer drug molecules via pulmonary delivery. The extent of adsorption of LF proteins by TA was revealed by fluorescence quenching in fluorescence spectroscopy. The presence of LF in TA-LF complexes was noticed by the presence of protein peaks at 1653 cm-1. Both protein dot and SDS-PAGE analysis confirmed LF protein complexation at all TA concentrations employed. A stable particle TA-LF complex formation was observed through transmission electron microscopy (TEM) analysis. The complexation pattern measured by dynamic light scattering (DLS) indicated that it varies depending on the pH of the solutions. The degree of LF presence in TA-LF complexes signifies its interactive behavior in LC cell lines. Such superior interaction offered an enhanced anti-cancer activity of drugs encapsulated in TA-LF complex nanoformulations. Our results indicate that TA binds to LF and forms self-assemblies, which profoundly enhance interaction with LC cells. This study demonstrated that TA is a novel carrier for pharmaceutical drugs such as gemcitabine, carboplatin, and irinotecan.

17.
Acta Pharm Sin B ; 8(4): 602-614, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30109184

RESUMO

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel self-assembly (PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone (PVP)-based PTX-SAs (PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTX-SAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an average size range of 53.81 nm as detected by transmission electron microscopy (TEM). FTIR spectral analysis demonstrates incorporation of polymer and paclitaxel functional groups in PVP/PTX-SAs. Both proliferation (MTS) and clonogenic (colony formation) assays were used to validate superior anticancer activity of PVP/PTX-SAs in breast cancer cells over paclitaxel. Such superior anticancer activity was also demonstrated by downregulation of the expression of pro-survival protein (Bcl-xL), upregulation of apoptosis-associated proteins (Bid, Bax, cleaved caspase 7, and cleaved PARP) and ß-tubulin stabilization. These results support the hypothesis that PVP/PTX-SAs improved paclitaxel delivery to cancer cells.

18.
Cancers (Basel) ; 10(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149628

RESUMO

The therapeutic application of microRNA(s) in the field of cancer has generated significant attention in research. Previous studies have shown that miR-205 negatively regulates prostate cancer cell proliferation, metastasis, and drug resistance. However, the delivery of miR-205 is an unmet clinical need. Thus, the development of a viable nanoparticle platform to deliver miR-205 is highly sought. A novel magnetic nanoparticle (MNP)-based nanoplatform composed of an iron oxide core with poly(ethyleneimine)-poly(ethylene glycol) layer(s) was developed. An optimized nanoplatform composition was confirmed by examining the binding profiles of MNPs with miR-205 using agarose gel and fluorescence methods. The novel formulation was applied to prostate cancer cells for evaluating cellular uptake, miR-205 delivery, and anticancer, antimetastasis, and chemosensitization potentials against docetaxel treatment. The improved uptake and efficacy of formulations were studied with confocal imaging, flow cytometry, proliferation, clonogenicity, Western blot, q-RT-PCR, and chemosensitization assays. Our findings demonstrated that the miR-205 nanoplatform induces significant apoptosis and enhancing chemotherapeutic effects in prostate cancer cells. Overall, these study results provide a strong proof-of-concept for a novel nonviral-based nanoparticle protocol for effective microRNA delivery to prostate cancer cells.

19.
J Biophotonics ; 11(12): e201800056, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29869394

RESUMO

As cancer progresses, macromolecules, such as DNA, RNA or lipids, inside cells undergo spatial structural rearrangements and alterations. Mesoscopic light transport-based optical partial wave spectroscopy (PWS) was recently introduced to quantify changes in the nanoscale structural disorder in biological cells. The PWS measurement is performed using a parameter termed as "disorder strength" (L d ), which represents the degree of nanoscale structural disorder inside the cells. It was shown that cancerous cells have higher disorder strength than normal cells. In this work, we first used the PWS to analyze the hierarchy of different types of prostate cancer cells, namely, C4-2, DU-145 and PC-3, by quantifying their average disorder strengths. Results expectedly showed that L d values increases in accordance with the increasing aggressiveness/tumorigenicity levels of these cells. Using the L d parameter, we then analyzed the chemoresistance properties of these prostate cancer cells to docetaxel drug compared to their chemosensitivity. Results show that chemoresistant cancer cells have increased L d values, that is, higher disorder strength, relative to chemosensitive cancer cells. Thus, use of the L d metric can be effective in determining the efficacy of particular chemotherapy.


Assuntos
Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Análise Espectral , Linhagem Celular Tumoral , Humanos , Masculino , Resultado do Tratamento
20.
Cancers (Basel) ; 10(3)2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518944

RESUMO

Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine the ER stress mediated UPR pathway in prostate cancer cells. Tannic acid treatment inhibited the growth, clonogenic, invasive, and migratory potential of prostate cancer cells. Tannic acid demonstrated activation of ER stress response (Protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1 (IRE1)) and altered its regulatory proteins (ATF4, Bip, and PDI) expression. Tannic acid treatment affirmed upregulation of apoptosis-associated markers (Bak, Bim, cleaved caspase 3, and cleaved PARP), while downregulation of pro-survival proteins (Bcl-2 and Bcl-xL). Tannic acid exhibited elevated G1 population, due to increase in p18INK4C and p21WAF1/CIP1 expression, while cyclin D1 expression was inhibited. Reduction of MMP2 and MMP9, and reinstated E-cadherin signifies the anti-metastatic potential of this compound. Altogether, these results demonstrate that tannic acid can promote apoptosis via the ER stress mediated UPR pathway, indicating a potential candidate for cancer treatment.

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