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Boronate ester bullvalenes are now accessible in two to four operationally simple steps. This unlocks late-stage diversification through Suzuki cross-coupling reactions to give mono-, di-, and trisubstituted bullvalenes. Moreover, a linchpin strategy enables preprogrammed installation of two different substituents. Analysis of solution phase isomer distributions and single-crystal X-ray structures reveals that isomer preference in the crystal lattice is due to general shape selectivity.
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Difficult biopharmaceutical characteristics of oligonucleotides, such as poor enzymatic stability, rapid clearance by reticuloendothelial organs, immunostimulation, and coagulopathies, limit their application as therapeutics. Many of these side effects are initiated via sequence-specific or nonsequence-specific interactions with proteins. Herein, we report a novel form of brush-polymer/DNA conjugate that provides the DNA with nanoscale steric selectivity: Hybridization kinetics with complementary DNA remains nearly unaffected, but interactions with proteins are significantly retarded. The relative lengths of the brush side chain and the DNA strand are found to play a critical role in the degree of selectivity. Being able to evade protein adhesion also improves in vivo biodistribution, thus making these molecular nanostructures promising materials for oligonucleotide-based therapies.
Assuntos
Nanoestruturas/química , Oligonucleotídeos/química , Polímeros/química , Animais , Coagulação Sanguínea , Camundongos , Estrutura MolecularRESUMO
Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery.
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Doenças Autoimunes/terapia , Portadores de Fármacos , Exossomos , Imunoterapia/métodos , Neoplasias/terapia , Células Apresentadoras de Antígenos/imunologia , Humanos , Inflamação/terapiaRESUMO
A novel amphiphilic cholesterol-based block copolymer comprised of a polymethacrylate bearing cholesterol block and a polyethylene glycol block with reducible disulfide bonds (PC5MA-SS-PEO) was synthesized and evaluated as a redox-sensitive nanoparticulate delivery system. The self-assembled PC5MA-SS-PEO nanoparticles (SS-NPs) encapsulated the anticancer drug doxorubicin (DOX) with high drug loading (18.2% w/w) and high encapsulation efficiency (94.9%). DOX-encapsulated PC5MA-SS-PEO self-assembled nanoparticles (DOX-encapsulated SS-NPs) showed excellent stability and exhibited a rapid DOX release in response to dithiothreitol reductive condition. Importantly, following internalization by lung cancer cells, the reducible DOX-encapsulated SS-NPs achieved higher cytotoxicity than the non-reducible thioester NPs whereas blank nanoparticles were non-cytotoxic. Furthermore, in vivo imaging studies in tumor-bearing severe combined immunodeficiency (SCID) mice showed that the nanoparticles preferentially accumulated in tumor tissue with remarkably reduced accumulation in the healthy non-target organs. The results indicated that the SS-NPs may be a promising platform for cancer-cell specific delivery of hydrophobic anticancer drugs. FROM THE CLINICAL EDITOR: The use of nanocarriers for drug delivery against tumors has been under intense research. One problem of using carrier system is the drug release kinetics at tumor site. In this article, the authors continued their previous study in the development of an amphiphilic cholesterol-based block copolymer with redox-sensitive modification, so that the payload drug could be released in response to the microenvironment. The interesting results should provide a new direction for designing future novel nanocarrier systems.
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Antibióticos Antineoplásicos/administração & dosagem , Colesterol/análogos & derivados , Preparações de Ação Retardada/química , Dissulfetos/química , Doxorrubicina/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Masculino , Camundongos SCID , Nanopartículas , Neoplasias/tratamento farmacológico , Oxirredução , Polietilenoglicóis/química , Ácidos Polimetacrílicos/químicaRESUMO
Amphiphilic brush-like block copolymers composed of polynorbonene-cholesterol/poly(ethylene glycol) (P(NBCh9-b-NBPEG)) self-assembled to form a long circulating nanostructure capable of encapsulating the anticancer drug doxorubicin (DOX) with high drug loading (22.1% w/w). The release of DOX from the DOX-loaded P(NBCh9-b-NBPEG) nanoparticles (DOX-NPs) was steady at less than 2% per day in PBS. DOX-NPs were effectively internalized by human cervical cancer cells (HeLa) and showed dose-dependent cytotoxicity, whereas blank nanoparticles were noncytotoxic. The DOX-NPs demonstrated a superior in vivo circulation time relative to that of free DOX. Tissue distribution and in vivo imaging studies showed that DOX-NPs preferentially accumulated in tumor tissue with markedly reduced accumulation in the heart and other vital organs. The DOX-NPs greatly improved survival and significantly inhibited tumor growth in tumor-bearing SCID mice compared to that for the untreated and free DOX-treated groups. The results indicated that self-assembled P(NBCh9-b-NBPEG) may be a useful carrier for improving tumor delivery of hydrophobic anticancer drugs.
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Antineoplásicos/química , Colesterol/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polímeros/química , Animais , Antineoplásicos/administração & dosagem , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.
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Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/fisiologia , Proteínas Wnt/fisiologia , beta Catenina/fisiologia , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.
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Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluorocarbonos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Oxigênio/farmacologia , Células A549 , Animais , Hipóxia Celular , Fluorocarbonos/química , Humanos , Hidrocarbonetos Bromados , Camundongos , Camundongos SCID , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oxigênio/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of this study was to evaluate macrophages repolarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype upon transfection with microRNA-223 (miR-223) duplexes and miR-223 expressing plasmid DNA encapsulated in CD44-targeting hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles (NPs). The HA-PEI/miR-223 NPs with spherical shape and an average diameter of 200 nm were efficiently internalized by J774A.1 alveolar and primary peritoneal macrophages and non-cytotoxic at HA-PEI concentration less than 200 µg/mL. Transfection of HA-PEI/miR-223 NPs in J774A.1 macrophages showed significantly higher miR-223 expression than that with HA-PEI/plasmid DNA expressing miR-223 (pDNA-miR-223). HA-PEI/miR-223 NPs mediated transfection increased miR-223 expression to 90 fold in primary peritoneal macrophages compared to untreated cells. The overexpression of miR-223 in both J774A.1 and peritoneal macrophages induced a phenotypic change from M1 to M2 state as indicated by a decrease in iNOS-2 (M1 marker) and an increase in Arg-1 (M2 marker) levels compared to those in lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)-stimulated macrophages (M1). The change in macrophage phenotype by HA-PEI/miR-223 NPs could suppress the inflammation in peritoneal macrophages induced by LPS as evidenced by a significant decrease in pro-inflammatory cytokine levels TNF-α, IL-1ß and IL-6, compared to LPS-stimulated peritoneal macrophages without treatment. The results demonstrated that miR-223-encapsulated HA-PEI NPs modulated macrophage polarity toward an anti-inflammatory M2 phenotype, which has potential for the treatment of inflammatory diseases.
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Anti-Inflamatórios/farmacologia , Receptores de Hialuronatos/imunologia , Ácido Hialurônico/metabolismo , Macrófagos Peritoneais/citologia , MicroRNAs/fisiologia , Nanopartículas , Animais , Linhagem Celular , Polaridade Celular , CamundongosRESUMO
INTRODUCTION: Inflammatory diseases, including autoimmune diseases and autoinflammatory diseases, are characterized by the imbalance of pro-inflammatory cytokines and anti-inflammatory cytokines. Targeted systems allow for specific delivery and sustained release of biological agents to inflamed tissues and macrophages, hence reducing their side effects. AREAS COVERED: This review discusses various targeting strategies for biological therapies of inflammatory diseases, with a focus on modulating macrophage functional polarization from an M1 to M2 phenotype. Furthermore, recent advances in the development of targeted delivery systems for gene therapy against inflammatory diseases including liposomal therapeutics, polymeric nanoparticles and microspheres, and multi-compartmental delivery systems are summarized. EXPERT OPINION: Molecular advances have uncovered various targets for biological therapies against inflammatory diseases. Despite substantial promise, the potential translation from the bench to the clinic is limited due to poor systemic stability of the delivery systems, low tissue distribution, and safety concerns. In order to develop clinically translatable targeted delivery systems, thorough evaluation of the efficacy and toxicity in relevant animal models and in different inflammatory diseases is needed. In addition, issues related to long-term storage stability, scale-up and manufacturing of the systems need to be addressed.
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Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/fisiopatologia , Terapia Biológica/métodos , Portadores de Fármacos/química , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Anticorpos Monoclonais/administração & dosagem , Citocinas , Regulação para Baixo , Terapia Genética/métodos , Humanos , Lipossomos/química , Microesferas , Nanopartículas/química , Polímeros/química , Linfócitos T Auxiliares-Indutores/metabolismo , Ativação Transcricional/fisiologiaRESUMO
With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current therapeutic strategies. Nanoparticle-based delivery of drugs has provided means of overcoming some of these limitations by ensuring the drug payload is directed to the disease site and insuring reduced off-target activity. This review highlights the challenges posed by the solid tumor microenvironment and the systemic limitations for effective chemotherapy. It then assesses the basis of nanoparticle-based targeting to the tumor tissues, which helps to overcome some of the microenvironmental and systemic limitations to therapy. We have extensively focused on some of the tumor multidrug resistance mechanisms (e.g., hypoxia and aerobic glycolysis) that contribute to the development of multidrug resistance and how targeted nano-approaches can be adopted to overcome drug resistance. Finally, we assess the combinatorial approach and how this platform has been used to develop multifunctional delivery systems for cancer therapy. The review article also focuses on inflammatory diseases, the biological therapies available for its treatment, and the concept of macrophage repolarization for the treatment of inflammatory diseases.
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Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Humanos , Inflamação/patologia , Macrófagos/metabolismo , Nanopartículas , Neoplasias/patologia , Pesquisa Translacional Biomédica , Microambiente TumoralRESUMO
In this study, we have shown for the first time the effectiveness of a non-viral gene transfection strategy to re-polarize macrophages from M1 to M2 functional sub-type for the treatment of rheumatoid arthritis (RA). An anti-inflammatory (IL-10) cytokine encoding plasmid DNA was successfully encapsulated into non-condensing alginate based nanoparticles and the surface of the nano-carriers was modified with tuftsin peptide to achieve active macrophage targeting. Enhanced localization of tuftsin-modified alginate nanoparticles was observed in the inflamed paws of arthritic rats upon intraperitoneal administration. Importantly, targeted nanoparticle treatment was successful in reprogramming macrophage phenotype balance as â¼66% of total synovial macrophages from arthritic rats treated with the IL-10 plasmid DNA loaded tuftsin/alginate nanoparticles were in the M2 state compared to â¼9% of macrophages in the M2 state from untreated arthritic rats. Treatment significantly reduced systemic and joint tissue pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) expression and prevented the progression of inflammation and joint damage as revealed by magnetic resonance imaging and histology. Treatment enabled animals to retain their mobility throughout the course of study, whereas untreated animals suffered from impaired mobility. Overall, this study demonstrates that targeted alginate nanoparticles loaded with IL-10 plasmid DNA can efficiently re-polarize macrophages from an M1 to an M2 state, offering a novel treatment paradigm for treatment of chronic inflammatory diseases.
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Artrite/terapia , Interleucina-10/genética , Macrófagos/imunologia , Nanocápsulas/química , Plasmídeos/administração & dosagem , Plasmídeos/química , Alginatos/química , Animais , Artrite/genética , Artrite/imunologia , Citocinas/imunologia , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Interleucina-10/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Nanocápsulas/ultraestrutura , Ratos , Ratos Endogâmicos Lew , Transfecção/métodos , Resultado do TratamentoRESUMO
The purpose of this study was to modulate macrophage polarity from the pro-inflammatory M1 to anti-inflammatory M2 phenotype using plasmid DNA (pDNA) expressing interleukin-4 (IL4) or interleukin-10 (IL10)-encapsulated in hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles (NPs). The HA-PEI/pDNA NPs with spherical shape, average size of 186 nm were efficiently internalized by J774A.1 macrophages. Transfection of HA-PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 NPs increased IL4 and IL10 gene expression in J774 macrophages which could re-program the macrophages from M1 to M2 phenotype as evidenced by a significant increase in the Arg/iNOS level, and upregulation of CD206 and CD163 compared to untreated macrophages. Following intraperitoneal (IP) injection to C57BL/6 mice, HA-PEI NPs effectively targeted peritoneal macrophages over-expressing CD44 receptor. In an in vivo model of stimulated peritoneal macrophages, IP administration of HA-PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 to C57BL/6 mice significantly increased the Arg/iNOS ratio and CD163 expression in the cells. Furthermore, HA-PEI/pDNA-IL10 NPs significantly increased peritoneal and serum IL10 levels which effectively suppressed LPS-induced inflammation by reducing level of TNF-α and IL-1ß in peritoneal macrophages and in the peritoneal fluid. The results demonstrated that pDNA-IL10-encapsulate HA-PEI NPs skewed macrophage functional polarity from M1 toward an anti-inflammatory M2 phenotype which may be a promising platform for the treatment of inflammatory diseases.
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Receptores de Hialuronatos/metabolismo , Ácido Hialurônico , Macrófagos/imunologia , Macrófagos/metabolismo , Nanopartículas , Fenótipo , Plasmídeos/genética , Animais , Citocinas/metabolismo , Expressão Gênica , Ácido Hialurônico/química , Mediadores da Inflamação/metabolismo , Interleucina-10/genética , Interleucina-4/genética , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , TransfecçãoRESUMO
Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween® 80, Cremophor® RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 ± 4.5 nm and zeta potential of -26.3 ± 1.2 mV. The presence of Tween® 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application.
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Antioxidantes/química , Sistemas de Liberação de Medicamentos , Emulsificantes/química , Enterócitos/metabolismo , Absorção Intestinal , Nanoestruturas/química , Quercetina/química , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Células CACO-2 , Óleo de Rícino/química , Composição de Medicamentos , Estabilidade de Medicamentos , Excipientes/química , Humanos , Masculino , Nanoestruturas/administração & dosagem , Polietilenoglicóis/química , Polissorbatos/química , Quercetina/administração & dosagem , Quercetina/metabolismo , Quercetina/farmacocinética , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
There have been significant advances in our understanding of cancer as a disease at the molecular level. Combined with improved diagnostic systems, the concept of personalized medicine was introduced where therapy for every patient can be customized according to their disease profile. The nanotechnology approach for formulation design and the advent of drug delivery systems for small molecules and biologics has contributed to the development of personalized medicine. Despite the progress, effective management and treatment of cancer remains a clinical challenge. The majority of drug delivery vectors that have undergone clinical trials have been discontinued prematurely because of poor therapeutic outcomes, off-target effects and non-specific toxicity due to the components of the formulation itself. Therefore, there is an urgent unmet requirement for a systematic approach to design drug delivery vectors that not only deliver the cargo to the desired site of action, but are also highly biocompatible and non-toxic. The past decade has seen the evolution of a combinatorial approach to drug delivery, a concept that has been classically successful in drug discovery research. In the present review, we summarize the wet-lab and in silico strategies to designing libraries of biocompatible delivery materials using combinatorial chemistry and support this strategy with pre-clinical success stories in cancer therapy.
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Amphiphilic heparin-retinoic acid (HR) and heparin-folate-retinoic acid bioconjugates (HFR) were synthesized by chemical conjugation of a hydrophobic anticancer agent all-trans-retinoic acid (RA) and a targeting ligand, folic acid (FA), to the high molecular weight heparin backbone. The HR and HFR bioconjugates had a high RA content (22%, w/w) and could self-assemble into nanoparticles with efficient encapsulation of a hydrophobic photosensitizer, pheophorbide a (PhA). The HFR bioconjugate demonstrated higher PhA loading content and loading efficiency compared to HR bioconjugate. The PhA-loaded HR and HFR nanoparticles had an average diameter of about 70 nm, a negatively charged surface, a sustained release pattern and self-quenching effect in a buffered solution. Furthermore, the cellular uptake of PhA-loaded HFR nanoparticles in folate receptor-positive HeLa cells was higher than that of PhA-loaded HR nanoparticles. Upon irradiation, HFR nanoparticles selectively enhanced the phototoxicity of PhA in HeLa cells while the dark-toxicity of the nanoparticles was minimal without light treatment. HFR nanoparticles also demonstrated targeted anti-cancer effect, improving the cytotoxicity of RA in HeLa cells compared to HR nanoparticles at RA concentration ≥50 µg/mL. The targeting effect of HFR and PhA-loaded HFR nanoparticles was not observed in folate receptor-negative HT-29 cells. The results indicated that HFR nanoparticles may be useful for targeted delivery of hydrophobic PDT agents and as a potential nanocarrier for dual chemo-and photodynamic therapies.
Assuntos
Antineoplásicos/química , Clorofila/análogos & derivados , Portadores de Fármacos/química , Ácido Fólico/química , Heparina/química , Interações Hidrofóbicas e Hidrofílicas , Tretinoína/química , Antineoplásicos/farmacologia , Transporte Biológico , Clorofila/química , Clorofila/farmacologia , Portadores de Fármacos/metabolismo , Células HT29 , Células HeLa , Humanos , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/química , Tretinoína/farmacologiaRESUMO
We designed a cancer-cell specific photosensitizer nano-carrier by synthesizing pheophorbide a (PheoA) conjugated glycol chitosan (GC) with reducible disulfide bonds (PheoA-ss-GC). The amphiphilic PheoA-ss-GC conjugates self-assembled in aqueous condition to form core-shell structured nanoparticles (PheoA-ss-CNPs) with good colloidal stability and switchable photoactivity. The photoactivity of PheoA-ss-CNPs in an aqueous environment was greatly suppressed by the self-quenching effect, which enabled the PheoA-ss-CNPs to remain photo-inactive and in a quenched state. However, after the cancer cell-specific uptake, the nanoparticular structure instantaneously dissociated by reductive cleavage of the disulfide linkers, followed by an efficient dequenching process. Compared to non-reducible PheoA-conjugated GC-NPs with stable amide linkages (PheoA-CNPs), PheoA-ss-CNPs rapidly restored their photoactivity in response to intracellular reductive conditions, thus presenting higher cytotoxicity with light treatment. In addition, the PheoA-ss-CNPs presented prolonged blood circulation in vivo compared to free PheoA, demonstrating enhanced tumor specific targeting behavior through the enhanced permeation and retention (EPR) effect. The enhanced tumor accumulation of PheoA-ss-CNPs enabled tumor therapeutic efficacy that was more efficient than free PheoA in tumor-bearing mice. Based on the enhanced intracellular release for cytosolic high dose and switchable photoactivity mechanism for reduced side effects, these results suggest that PheoA-ss-CNPs have good potential for photodynamic therapy (PDT) in cancer treatment.
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Quitosana/uso terapêutico , Clorofila/análogos & derivados , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Radiossensibilizantes/uso terapêutico , Animais , Quitosana/química , Quitosana/farmacocinética , Clorofila/química , Clorofila/farmacocinética , Clorofila/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/patologia , Oxirredução , Fotoquimioterapia , Radiossensibilizantes/química , Radiossensibilizantes/farmacocinéticaRESUMO
UNLABELLED: Mesoporous silica nanoparticles (MSNs) were explored as a carrier material for the stable isotope (165)Ho and, after neutron capture, its subsequent therapeutic radionuclide, (166)Ho (half-life, 26.8 h), for use in radionuclide therapy of ovarian cancer metastasis. METHODS: (165)Ho-MSNs were prepared using (165)Ho-acetylacetonate and MCM-41 silica particles, and stability was determined after irradiation in a nuclear reactor (reactor power, 1 MW; thermal neutron flux of approximately 5.5 × 10(12) neutrons/cm(2)s). SPECT/CT and tissue biodistribution studies were performed after intraperitoneal administration of (166)Ho-MSNs to SKOV-3 ovarian tumor-bearing mice. Radiotherapeutic efficacy was studied by using PET/CT with (18)F-FDG to determine tumor volume and by monitoring survival. RESULTS: The holmium-MSNs were able to withstand long irradiation times in a nuclear reactor and did not release (166)Ho after significant dilution. SPECT/CT images and tissue distribution results revealed that (166)Ho-MSNs accumulated predominantly in tumors (32.8% ± 8.1% injected dose/g after 24 h; 81% ± 7.5% injected dose/g after 1 wk) after intraperitoneal administration. PET/CT images showed reduced (18)F-FDG uptake in tumors, which correlated with a marked increase in survival after treatment with approximately 4 MBq of (166)Ho-MSNs. CONCLUSION: The retention of holmium in nanoparticles during irradiation and in vivo after intraperitoneal administration as well as their efficacy in extending survival in tumor-bearing mice underscores their potential as a radiotherapeutic agent for ovarian cancer metastasis.
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Hólmio/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Nêutrons , Neoplasias Ovarianas/radioterapia , Dióxido de Silício/química , Animais , Linhagem Celular Tumoral , Feminino , Raios gama , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hidroxibutiratos/química , Camundongos , Compostos Organometálicos/química , Neoplasias Ovarianas/patologia , Pentanonas/química , Porosidade , Radioisótopos/uso terapêuticoRESUMO
This paper demonstrates the highly efficient synthesis of amphiphilic heparin-folic acid-retinoic acid (HFR) bioconjugates with a high drug coupling ratio by a microfluidic approach. The microfluidic synthesis enabled the conjugation of 17 molecules of retinoic acid to each heparin chain with 21 possible groups for attachment after reacting for several minutes. In contrast, about 11 molecules of the drug were covalently conjugated to one heparin chain after 4 days in the bulk reaction. The microfluidic based-HFR bioconjugates readily self-assembled in aqueous media to form uniform nanoparticles, while the product from the bulk reaction formed non-uniform nanoparticles with broad size distribution. The HFR nanoparticles with high drug content effectively delivered the drug to folate receptor-positive cancer cells with superior cellular uptake and selective cytotoxicity in vitro compared to HFR nanoparticles synthesized in bulk reaction. With the ability to achieve high drug content in heparin carrier within a short reaction time, the microfluidic technique offers new alternatives for the efficient synthesis of polymer-based conjugates for drug delivery.
Assuntos
Heparina/biossíntese , Técnicas Analíticas Microfluídicas/métodos , Microfluídica/instrumentação , Reatores Biológicos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/biossíntese , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , Microscopia Confocal , Nanopartículas/química , Polímeros/química , Tretinoína/metabolismoRESUMO
Circadian rhythms regulate most body functions and are important factors to consider when administering drugs. The existence of circadian rhythms in nature and their influences on human biological systems have given rise to the concept of chronotherapy, which is the science of delivering drugs in a synchronized manner with the rhythm-dependent circadian variation inherent in the human body. The safety and efficacy of a drug can be improved by matching the peak plasma concentration during a 24 h period of the rhythms. An on-off pulsed (pulsatile or time-controlled) release drug-delivery system offers rapid and transient release; stepwise release; and the sustained release of a certain amount of drug within a short time period after a predetermined off-release period according to the circadian rhythm of disease states. These systems deliver the drug at the right time and at an appropriate dosage and are the best approach for chronotherapy. These systems show promise for the optimal therapy of chronic diseases such as asthma, hypertension, myocardial infarction and arthritis, which show a circadian dependency. Various technologies have been adopted to mimic circadian rhythms in physiological functions and diseases. This review focuses on the basic concept of circadian rhythm, chronotherapy and recent advances in the development of on-off pulsed oral drug-delivery systems for optimal therapy.
Assuntos
Cronofarmacoterapia , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Animais , Ritmo Circadiano/fisiologia , Preparações de Ação Retardada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Tecnologia Farmacêutica/métodos , Fatores de TempoRESUMO
Luminescent near-infrared (NIR) CdTe/CdSe QDs were synthesized and encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres to prepare stable and biocompatible QDs-loaded nanospheres for in vivo imaging. QDs were encapsulated with PLGA nanospheres by a solid dispersion method and optimized to have high fluorescence intensity for in vivo imaging detection. The resultant QDs-loaded PLGA nanospheres were characterized by various analytical techniques such as UV-Vis measurement, dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Finally, we evaluated toxicity and body distribution of QDs loaded in PLGA nanospheres in vitro and in vivo, respectively. From the results, the QDs loaded in PLGA nanospheres were spherical and showed a diameter range of 135.0-162.3 nm in size. The QD nanospheres increased their stability against photooxidation and photobleaching, which have the high potential for applications in biomedical imaging. We have also attained non-invasive in vivo imaging with light photons, representing an intriguing avenue for obtaining biological information by the use of NIR light.