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1.
ACS Nano ; 18(3): 2195-2209, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38194222

RESUMO

Nanocarrier-based cytoplasmic protein delivery offers opportunities to develop protein therapeutics; however, many delivery systems are positively charged, causing severe toxic effects. For enhanced therapeutics, it is also of great importance to design nanocarriers with intrinsic bioactivity that can be integrated with protein drugs due to the limited bioactivity of proteins alone for disease treatment. We report here a protein delivery system based on anionic phosphite-terminated phosphorus dendrimers with intrinsic anti-inflammatory activity. A phosphorus dendrimer termed AK-137 with optimized anti-inflammatory activity was selected to complex proteins through various physical interactions. Model proteins such as bovine serum albumin, ribonuclease A, ovalbumin, and fibronectin (FN) can be transfected into cells to exert their respective functions, including cancer cell apoptosis, dendritic cell maturation, or macrophage immunomodulation. Particularly, the constructed AK-137@FN nanocomplexes display powerful therapeutic effects in acute lung injury and acute gout arthritis models by integrating the anti-inflammatory activity of both the carrier and protein. The developed anionic phosphite-terminated phosphorus dendrimers may be employed as a universal carrier for protein delivery and particularly utilized to deliver proteins and fight different inflammatory diseases with enhanced therapeutic efficacy.


Assuntos
Dendrímeros , Fosfitos , Dendrímeros/farmacologia , Fósforo , Proteínas , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
2.
Biomacromolecules ; 24(7): 3215-3227, 2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37269298

RESUMO

The incessant, global increase in antimicrobial resistance (AMR) is a very big challenge for healthcare systems. AMR is predicted to grow at an alarming pace, with a dramatic increase in morbidity, mortality, and a 100 trillion US$ loss to the global economy by 2050. The mortality rate caused by methicillin-resistant S. aureus (MRSA) is much higher as compared to infections caused by drug-susceptible S. aureus. Additionally, there is a big paucity of therapeutics available for treatment of serious infections caused by MRSA. Thus, the discovery and development of novel therapies is an urgent, unmet medical need. In this context, we synthesized AE4G0, a low-generation cationic-phosphorus dendrimer expressing potent antimicrobial activity against S. aureus and Enterococcus sp., and demonstrating a broad selectivity index against eukaryotic cells. AE4G0 exhibits concentration-dependent, bactericidal activity and synergizes with gentamicin, especially against gentamicin-resistant MRSA NRS119. Fluorescence and scanning electron microscopy demonstrate that treatment with AE4G0 led to the utter destruction of S. aureus ATCC 29213 without inducing resistance, despite repeated exposure. When tested in vivo, AE4G0 demonstrates significant efficacy against S. aureus ATCC 29213, alone and in combination with gentamicin against gentamicin-resistant S. aureus NRS119 in the murine skin model of infection. Taken together, AE4G0 demonstrates the potential to be translated as a novel therapeutic option for the treatment of topical, drug-resistant S. aureus infections.


Assuntos
Anti-Infecciosos , Dendrímeros , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Camundongos , Antibacterianos , Staphylococcus aureus , Dendrímeros/farmacologia , Testes de Sensibilidade Microbiana , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Anti-Infecciosos/uso terapêutico , Fósforo/farmacologia , Infecções Estafilocócicas/tratamento farmacológico
3.
Adv Healthc Mater ; 12(6): e2202663, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36653312

RESUMO

Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxides, has emerged as an attractive strategy to reverse drug resistance. Of particular interest is the ferroptosis-apoptosis combination therapy for cancer treatment. Herein, a nanoplatform is reported for effective co-delivery of the anticancer drug sorafenib (S) and the ferroptosis inducer hemin (H), toward synergistic ferroptosis-apoptosis therapy of advanced hepatocellular carcinoma (HCC) as a proof-of-concept study. Liposome is an excellent delivery system; however, it is not sufficiently responsive to the acidic tumor microenvironment (TME) for tumor-targeted drug delivery. The pH-sensitive vesicles are therefore developed (SH-AD-L) by incorporating amphiphilic dendrimers (AD) into liposomes for controlled and pH-stimulated release of sorafenib and hemin in the acidic TME, thanks to the protonation of numerous amine functionalities in AD. Importantly, SH-AD-L not only blocked glutathione synthesis to disrupt the antioxidant system, but also increased intracellular Fe2+ and ·OH concentrations to amplify oxidative stress, both of which contribute to enhanced ferroptosis. Remarkably, high levels of ·OH also augmented sorafenib-mediated apoptosis in tumor cells. This study demonstrates the efficacy of ferroptosis-apoptosis combination therapy, as well as the promise of the AD-doped TME-responsive vesicles for drug delivery in combination therapy to treat advanced HCC.


Assuntos
Carcinoma Hepatocelular , Dendrímeros , Ferroptose , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Dendrímeros/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Hemina/farmacologia , Hemina/uso terapêutico , Apoptose , Lipossomos/farmacologia , Polímeros/farmacologia , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Microambiente Tumoral
4.
Nat Commun ; 13(1): 5925, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36207325

RESUMO

Periodontitis is a common type of inflammatory bone loss and a risk factor for systemic diseases. The pathogenesis of periodontitis involves inflammatory dysregulation, which represents a target for new therapeutic strategies to treat periodontitis. After establishing the correlation of cell-free DNA (cfDNA) level with periodontitis in patient samples, we test the hypothesis that the cfDNA-scavenging approach will benefit periodontitis treatment. We create a nanoparticulate cfDNA scavenger specific for periodontitis by coating selenium-doped hydroxyapatite nanoparticles (SeHANs) with cationic polyamidoamine dendrimers (PAMAM-G3), namely G3@SeHANs, and compare the activities of G3@SeHANs with those of soluble PAMAM-G3 polymer. Both G3@SeHANs and PAMAM-G3 inhibit periodontitis-related proinflammation in vitro by scavenging cfDNA and alleviate inflammatory bone loss in a mouse model of ligature-induced periodontitis. G3@SeHANs also regulate the mononuclear phagocyte system in a periodontitis environment, promoting the M2 over the M1 macrophage phenotype. G3@SeHANs show greater therapeutic effects than PAMAM-G3 in reducing proinflammation and alveolar bone loss in vivo. Our findings demonstrate the importance of cfDNA in periodontitis and the potential for using hydroxyapatite-based nanoparticulate cfDNA scavengers to ameliorate periodontitis.


Assuntos
Ácidos Nucleicos Livres , Dendrímeros , Periodontite , Selênio , Animais , Ácidos Nucleicos Livres/genética , Dendrímeros/farmacologia , Hidroxiapatitas , Camundongos , Periodontite/tratamento farmacológico
5.
Theranostics ; 12(7): 3407-3419, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547777

RESUMO

Rationale: Development of novel nanomedicines to inhibit pro-inflammatory cytokine expression and reactive oxygen species (ROS) generation for anti-inflammatory therapy of acute lung injury (ALI) remains challenging. Here, we present a new nanomedicine platform based on tyramine-bearing two dimethylphosphonate sodium salt (TBP)-modified amphiphilic phosphorus dendron (C11G3) nanomicelles encapsulated with antioxidant drug curcumin (Cur). Methods: C11G3-TBP dendrons were synthesized via divergent synthesis and self-assembled to generate nanomicelles in a water environment to load hydrophobic drug Cur. The created C11G3-TBP@Cur nanomicelles were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular ROS elimination, pro-inflammatory cytokine inhibition and alveolar macrophages M2 type repolarization in vitro, and evaluated to assay their anti-inflammatory and antioxidative therapy effects of ALI mice model through pro-inflammatory cytokine expression level in bronchoalveolar lavage fluid and lung tissue, histological analysis and micro-CT imaging detection of lung tissue injury in vivo. Results: The nanomicelles with rigid phosphorous dendron structure enable high-capacity and stable Cur loading. Very strikingly, the drug-free C11G3-TBP micelles exhibit excellent cytocompatibility and intrinsic anti-inflammatory activity through inhibition of nuclear transcription factor-kappa B, thus causing repolarization of alveolar macrophages from M1 type to anti-inflammatory M2 type. Taken together with the strong ROS scavenging property of the encapsulated Cur, the developed nanomicelles enable effective therapy of inflammatory alveolar macrophages in vitro and an ALI mouse model in vivo after atomization administration. Conclusion: The created phosphorus dendron nanomicelles can be developed as a general nanomedicine platform for combination anti-inflammatory and antioxidative therapy of inflammatory diseases.


Assuntos
Lesão Pulmonar Aguda , Curcumina , Dendrímeros , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Citocinas/metabolismo , Dendrímeros/farmacologia , Modelos Animais de Doenças , Pulmão/patologia , Camundongos , NF-kappa B/metabolismo , Fósforo , Espécies Reativas de Oxigênio/metabolismo
6.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204564

RESUMO

Based on phenotypic screening, the major advantages of phosphorus dendrimers and dendrons as drugs allowed the discovery of new therapeutic applications, for instance, as anti-cancer and anti-tuberculosis agents. These biological activities depend on the nature of the chemical groups (neutral or cationic) on their surface as well as their generation. As lessons to learn, in the oncology domain, the increase in the generation of metallo-dendrimers is in the same direction as the anti-proliferative activities, in contrast to the development of polycationic dendrimers, where the most potent anti-tuberculosis phosphorus dendrimer was observed to have the lowest generation (G0). The examples presented in this original analysis of phosphorus dendrimers and dendrons provide support for the lessons learned and for the development of new nanoparticles in nanomedicine.


Assuntos
Dendrímeros/farmacologia , Nanomedicina/tendências , Fósforo/farmacologia , Animais , Antineoplásicos/uso terapêutico , Antituberculosos/uso terapêutico , Dendrímeros/química , Humanos , Estrutura Molecular , Nanomedicina/métodos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fósforo/química , Tuberculose/tratamento farmacológico
7.
Biomacromolecules ; 22(6): 2659-2675, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-33970615

RESUMO

The long-term treatment of tuberculosis (TB) sometimes leads to nonadherence to treatment, resulting in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Inadequate bioavailability of the drug is the main factor for therapeutic failure, which leads to the development of drug-resistant cases. Therefore, there is an urgent need to design and develop novel antimycobacterial agents minimizing the period of treatment and reducing the propagation of resistance at the same time. Here, we report the development of original and noncytotoxic polycationic phosphorus dendrimers essentially of generations 0 and 1, but also of generations 2-4, with pyrrolidinium, piperidinium, and related cyclic amino groups on the surface, as new antitubercular agents active per se, meaning with intrinsic activity. The strategy is based on the phenotypic screening of a newly designed phosphorus dendrimer library (generations 0-4) against three bacterial strains: attenuated Mycobacterium tuberculosis H37Ra, virulent M. tuberculosis H37Rv, and Mangora bovis BCG. The most potent polycationic phosphorus dendrimers 1G0,HCl and 2G0,HCl are active against all three strains with minimum inhibitory concentrations (MICs) between 3.12 and 25.0 µg/mL. Both are irregularly shaped nanoparticles with highly mobile branches presenting a radius of gyration of 7 Å, a diameter of maximal 25 Å, and a solvent-accessible surface area of dominantly positive potential energy with very localized negative patches arising from the central N3P3 core, which steadily interacts with water molecules. The most interesting is 2G0,HCl, showing relevant efficacy against single-drug-resistant (SDR) M. tuberculosis H37Rv, resistant to rifampicin, isoniaid, ethambutol, or streptomycin. Importantly, 2G0,HCl displayed significant in vivo efficacy based on bacterial counts in lungs of infected Balb/C mice at a dose of 50 mg/kg oral administration once a day for 2 weeks and superior efficacy in comparison to ethambutol and rifampicin. This series of polycationic phosphorus dendrimers represents first-in-class drugs to treat TB infection, could fulfill the clinical candidate pipe of this high burden of infectious disease, and play a part in addressing the continuous demand for new drugs.


Assuntos
Dendrímeros , Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos/farmacologia , Dendrímeros/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
8.
Carbohydr Polym ; 258: 117706, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33593576

RESUMO

Combination treatment through the co-delivery of drugs and genes by nanoformulations may achieve a synergistic effect. In our previous study, poly(amidoamine) dendronized chitosan derivative (PAMAM-Cs) showed good gene transfection efficiency and low cytotoxicity. Here, we incorporated hydrophobic deoxycholic acid (DCA) onto the chitosan backbone of PAMAM-Cs to obtain an amphiphilic derivative-PAMAM-Cs-DCA, which could self-assemble into cationic nanoparticles (NPs). The resulting NPs with diameters of 140-220 nm can encapsulate the hydrophobic anticancer drug doxorubicin (DOX) in the core while bind pDNA via the positively charged PAMAM shell. PAMAM-Cs-DCA NPs could completely complex with pDNA at a ratio of nitrogen to phosphorous (N/P) low as 1 and the complexes achieved a transfection efficiency up to 74 % at N/P 20. Moreover, low-dose co-delivered DOX could enhance the transgene expression, showing a synergistic effect. These results suggest that PAMAM-Cs-DCA NPs hold great promise to co-deliver chemotherapeutics and nucleic acid drugs.


Assuntos
Quitosana/química , Ácido Desoxicólico/química , Doxorrubicina/administração & dosagem , Vetores Genéticos , Poliaminas/química , Antineoplásicos/farmacologia , Cátions , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Dendrímeros/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética/métodos , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Nanopartículas/química , Nitrogênio/química , Ácidos Nucleicos/química , Tamanho da Partícula , Fósforo/química
9.
Bioconjug Chem ; 32(2): 339-349, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33522223

RESUMO

We designed and synthesized several families of novel amphiphilic fluorescent phosphorus dendron-based micelles showing relevant antiproliferative activities for use in the field of theranostic nanomedicine. Based on straightforward synthesis pathways, 12 amphiphilic phosphorus dendrons bearing 10 protonated cyclic amino groups (generation one), or 20 protonated amino groups (generation two), and 1 hydrophobic chain carrying 1 fluorophore moiety were created. The amphiphilic dendron micelles had the capacity to aggregate in solution using hydrophilic/hydrophobic interactions, which promoted the formation of polymeric micelles. These dendron-based micelles showed moderate to high antiproliferative activities against a panel of tumor cell lines. This paper presents for the first time the synthesis and our first investigations of new phosphorus dendron-based micelles for cancer therapy applications.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Dendrímeros/síntese química , Dendrímeros/farmacologia , Corantes Fluorescentes/química , Micelas , Fósforo/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Transmissão
10.
ACS Appl Mater Interfaces ; 13(5): 6069-6080, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33501834

RESUMO

The development of functional intelligent theranostic nanoplatform for imaging-directed synchronous inhibition of primary tumor and tumor metastasis is still a challenging task. We present here the creation of functional dendrimer-entrapped CuS nanoparticles (CuS DENPs) complexed with plasmid DNA-encoding hypermethylation in cancer 1 (pDNA-HIC1) for photoacoustic (PA) imaging-directed simultaneous inhibition of tumors and tumor metastasis. Poly(amidoamine) dendrimers of generation 5 were covalently attached with 1,3-propane sultone and arginine-glycine-aspartic acid (RGD) peptide through a spacer of poly(ethylene glycol) and adopted for the templated synthesis of CuS NPs. The prepared functional RGD-CuS DENPs possess a mean CuS core diameter of 4.2 nm, good colloidal stability, and an excellent absorption feature in the second near-infrared window, thus having a photothermal conversion efficiency of 49.8% and an outstanding PA imaging capability. The functional DENPs can effectively deliver pDNA-HIC1 to prevent cancer cell invasion and metastasis in a serum-enhancing manner by virtue of zwitterionic modification-rendered antifouling property. The developed RGD-CuS DENPs/pDNA polyplexes display αvß3 integrin-targeted enhanced anticancer activity through the combined CuS NP-mediated photothermal therapy (PTT) and pDNA delivery-rendered cancer cell metastasis inhibition. This can also be proven by the therapeutic efficacy of a triple-negative breast cancer model in vivo, where inhibition of both the primary subcutaneous tumor and lung metastasis can be realized. The created dendrimer-CuS hybrid nanoplatform represents one of the updated designs of nanomedicine for PA imaging-directed combination PTT/gene therapy of tumors and tumor metastasis.


Assuntos
Antineoplásicos/farmacologia , Incrustação Biológica/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Cobre/farmacologia , Dendrímeros/farmacologia , Nanopartículas/química , Técnicas Fotoacústicas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Cobre/química , Dendrímeros/química , Feminino , Humanos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Tamanho da Partícula , Fototerapia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Propriedades de Superfície , Células Tumorais Cultivadas
11.
ACS Appl Bio Mater ; 4(3): 2591-2600, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35014376

RESUMO

Nitric oxide (NO) gas nanocarrier materials were prepared via a hierarchical assembly of poly(amido amine) dendrimers with fluorocarbon binding sites (DEN-F) and fluorinated poly(ethylene glycol) (F-PEG) on nitrogen-doped carbon nanohorns (NCNHs). The loading abilities of NO gas in these nanocarrier materials increased with the nitrogen doping of CNH and hierarchies formed by DEN-F and F-PEG. Especially, the ability of CNH-based nanocomposite materials was better than that of graphene-based materials. The loading of NO gas arose an infrared absorption band at 1387 cm-1 and increased the intensity ratio of D and G bands in Raman spectra, although these phenomena diminished after the degas treatment. The antimicrobial effects on bacteria (Escherichia coli and Staphylococcus aureus) increased depending on the loading amount of NO gas. It was confirmed from these results that NO gas weakly interacts with nitrogen-doped CNH and is trapped in the void volumes of DEN-F and F-PEG hierarchies. Thus, the concentric hierarchy is preferable for slow release of NO gas due to the void volumes in DEN-F, F-PEG, and CNH hierarchical organization. This sustained release of NO gas is advantageous with regards to the potential biomedical gas therapy against bacteria and other parasites.


Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Dendrímeros/farmacologia , Nanocompostos/química , Óxido Nítrico/farmacologia , Polietilenoglicóis/farmacologia , Antibacterianos/química , Materiais Biocompatíveis/química , Carbono/química , Carbono/farmacologia , Dendrímeros/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Escherichia coli/efeitos dos fármacos , Gases , Halogenação , Teste de Materiais , Testes de Sensibilidade Microbiana , Óxido Nítrico/química , Tamanho da Partícula , Polietilenoglicóis/química , Staphylococcus aureus/efeitos dos fármacos
12.
Mol Pharm ; 18(1): 65-73, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33236637

RESUMO

Dendrimers are macromolecules with well-defined, homogeneous, and monodispersed structures that form a branch-like structure. In general, they have a symmetric core, inner shells, and an outer shell. Over the past decade, metallodendritic architectures have developed into a new area in nanomedicine. Due to their versatility and facile customization, phosphorus dendrimers represent interesting platforms for biomedical applications. Metallo-conjugated phosphorus dendrimers have been developed within the dendrimer space, an important part of the chemical space. The first investigation was made using phosphorus dendrimers bearing copper(II) groups on their surface as the original anticancer drug candidates. The aim of this minireview is to present our powerful strategy to find and develop original multivalent copper(II)-conjugated phosphorus dendrimers. The most potent of them is G3 dendrimers with N-(pyridine-2-ylmethylene)ethanamine as the chelating motif complexed with Cu(II) (1G3-Cu), showing very good in vitro and in vivo antiproliferative efficacy. On the basis of these results, 1G3-Cu is a potential clinical candidate having progressed from hit to preclinical candidate status.


Assuntos
Antineoplásicos/farmacologia , Cobre/farmacologia , Dendrímeros/farmacologia , Fósforo/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Nanomedicina/métodos
13.
Int J Mol Sci ; 21(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003288

RESUMO

Current chemotherapeutic drugs, although effective, lack cell-specific targeting, instigate adverse side effects in healthy tissue, exhibit unfavourable bio-circulation and can generate drug-resistant cancers. The synergistic use of nanotechnology and gene therapy, using nanoparticles (NPs) for therapeutic gene delivery to cancer cells is hereby proposed. This includes the benefit of cell-specific targeting and exploitation of receptors overexpressed in specific cancer types. The aim of this study was to formulate dendrimer-functionalized selenium nanoparticles (PAMAM-SeNPs) containing the targeting moiety, folic acid (FA), for delivery of pCMV-Luc-DNA (pDNA) in vitro. These NPs and their gene-loaded nanocomplexes were physicochemically and morphologically characterized. Nucleic acid-binding, compaction and pDNA protection were assessed, followed by cell-based in vitro cytotoxicity, transgene expression and apoptotic assays. Nanocomplexes possessed favourable sizes (<150 nm) and ζ-potentials (>25 mV), crucial for cellular interaction, and protected the pDNA from degradation in an in vivo simulation. PAMAM-SeNP nanocomplexes exhibited higher cell viability (>85%) compared to selenium-free nanocomplexes (approximately 75%), confirming the important role of selenium in these nanocomplexes. FA-conjugated PAMAM-SeNPs displayed higher overall transgene expression (HeLa cells) compared to their non-targeting counterparts, suggesting enhanced receptor-mediated cellular uptake. Overall, our results bode well for the use of these nano-delivery vehicles in future in vivo studies.


Assuntos
Dendrímeros/química , Técnicas de Transferência de Genes , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Dendrímeros/farmacologia , Ácido Fólico/química , Ácido Fólico/genética , Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Humanos , Neoplasias/genética , Neoplasias/patologia , Selênio/química , Selênio/farmacologia
14.
ACS Appl Mater Interfaces ; 12(34): 37873-37884, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32687309

RESUMO

Injectable biphasic calcium phosphates have been proposed as a solution in the treatment of a range of clinical applications including as fillers in the augmentation of osteoporotic bone. To date, various biodegradable natural or synthetic organics have been used as a polymer component of bone materials to increase their cohesiveness. Herein, a novel bone material was developed combining osteoconductive biphasic calcium phosphate (BCP) nanoparticles with phosphoserine-tethered generation 3 poly(epsilon-lysine) dendron (G3-K PS), a class of hyperbranched peptides previously shown to induce biomineralization and stem cell osteogenic differentiation. Strontium was also incorporated into the BCP nanocrystals (SrBCP) to prevent bone resorption. Within 24 h, an antiwashout behavior was observed in G3-K PS-integrated pure BCP group (BCPG3). Moreover, both in vitro tests by relevant cell phenotypes and an in vivo tissue regeneration study by an osteoporotic animal bone implantation showed that the integration of G3-K PS would downregulate Cxcl9 gene and protein expressions, thus enhancing bone regeneration measured as bone mineral density, new bone volume ratio, and trabecular microarchitectural parameters. However, no synergistic effect was found when Sr was incorporated into the BCPG3 bone pastes. Notably, results indicated a concomitant reduction of bone regeneration potential assessed as reduced Runx2 and PINP expression when bone resorptive RANKL and CTX-I levels were reduced by Sr supplementation. Altogether, the results suggest the potential of injectable BCPG3 bone materials in the treatment of osteoporotic bone defects.


Assuntos
Cimentos Ósseos/química , Dendrímeros/química , Hidroxiapatitas/química , Fosfosserina/química , Animais , Cimentos Ósseos/farmacologia , Regeneração Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dendrímeros/administração & dosagem , Dendrímeros/farmacologia , Feminino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Nanopartículas/química , Osteogênese/efeitos dos fármacos , Polilisina/química , Próteses e Implantes , Ratos , Ratos Sprague-Dawley , Estrôncio/química , Alicerces Teciduais/química
15.
Carbohydr Polym ; 234: 115928, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070544

RESUMO

We developed a co-delivery system of nitric oxide (NO) and antibiotic for the antibiotic-resistant bacterial infection therapy. The NO could disperse the bacterial biofilms and convert the bacteria into an antibiotic-susceptible planktonic form. Using the chitosan-graft-poly(amidoamine) dendrimer (CS-PAMAM) as the co-delivery system, methicillin (MET) and NO were conjugated successively to form CS-PAMAM-MET/NONOate. The positive CS-PAMAM could efficiently capture the negatively charged bacteria and PAMAM provide abundant reaction points for high payloads of NO and MET. The CS-PAMAM-MET/NONOate displayed effective and combined antibacterial activity to the E. coli and S. aureus. Particularly, for the MET-resistant S. aureus (MRSA), the CS-PAMAM-MET/NONOate displayed the synergistic antibacterial activity. In vivo wound healing assays also confirmed that CS-PAMAM-MET/NONOate could heal the infection formed by MRSA and then accelerate the wound healing effectively. Moreover, CS-PAMAM-MET/NONOate showed no toxicity towards 3T3 cells in vitro and rats in vivo, providing a readily but high-efficient strategy to drug-resistant bacterial infection therapy.


Assuntos
Antibacterianos/farmacologia , Quitosana/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Meticilina/farmacologia , Óxido Nítrico/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Dendrímeros/química , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Masculino , Meticilina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Tamanho da Partícula , Poliaminas/química , Poliaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/patologia , Propriedades de Superfície
16.
Colloids Surf B Biointerfaces ; 188: 110762, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31911391

RESUMO

Co-delivery of therapeutic agents and small interfering RNA (siRNA) can be achieved by a suitable nanovehicle. In this work, the solubility and bioavailability of curcumin (Cur) were enhanced by entrapment in a polyamidoamine (PAMAM) dendrimer, and a polyplex was formed by grafting Bcl-2 siRNA onto the surface amine groups to produce PAMAM-Cur/Bcl-2 siRNA nanoparticles (NPs). The synthesized polyplex NPs had a particle size of ∼180 nm, and high Cur loading content of ∼82 wt%. Moreover, the PAMAM-Cur/Bcl-2 siRNA NPs showed more effective cellular uptake, and higher inhibition of tumor cell proliferation compared to PAMAM-Cur nanoformulation and free Cur, due to the combined effect of co-delivery of Cur and Bcl-2 siRNA. The newly described PAMAM-Cur/Bcl-2 siRNA polyplex NPs could be a promising co-delivery nanovehicle.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Curcumina/química , Dendrímeros/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Tamanho da Partícula , RNA Interferente Pequeno/química , Propriedades de Superfície
17.
Dalton Trans ; 48(22): 7483-7493, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31062819

RESUMO

Phosphorus dendrimers (dendrimers having one phosphorus atom at each branching point) possess versatile properties, depending on the type of their terminal functions. This perspective article focusses on the synthesis and study of properties of phosphorus dendrimers functionalised on their surface by nitrogen ligands and their complexes. It is organized depending on the type of N-ligands (P,N ligands, N,N ligands, and N,N,N-ligands). Most properties concern catalysis, with palladium, copper, and scandium complexes. Recent advances concern anti-cancer properties, with dendrimers functionalised by copper and gold complexes of N,N-ligands.


Assuntos
Dendrímeros/química , Nitrogênio/química , Fósforo/química , Catálise , Dendrímeros/farmacologia , Ligantes
18.
ACS Appl Mater Interfaces ; 11(1): 160-168, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525391

RESUMO

Malignant bone tumor accompanied by tumor-associated osteolysis remains a challenging task in clinical practice. Nanomedicines engineered with bone-targeting ligands, such as alendronate and pamidronate, are developed for targeted delivery of therapeutic agents to bone tumors. However, these targeting strategies usually show relatively poor selectivity toward the healthy skeletons and the osteolytic lesions because of the high binding affinity of bisphosphonates with all the bone tissues. Here, we reported a carboxyl-terminated dendrimer as the candidate to preferentially deliver therapeutic nanoparticles to the osteolytic lesions in a malignant bone tumor model. The high density of carboxyl groups on dendrimer surface endow the polymer with natural bone-binding capability. The dendrimer encapsulated with platinum nanoparticle predominantly accumulates at the osteolytic lesions around bone tumors rather than at healthy bone tissues in vivo. The therapeutic experiments reveal that the dendrimer-mediated photothermal therapy efficiently suppresses bone tumors and osteolysis, and the anionic polymer exhibits minimal cytotoxicity and hematologic toxicity. The results suggest that the carboxyl-terminated dendrimer is a promising candidate for selective delivery of therapeutics to the osteolytic lesions and photothermal treatment of malignant bone tumors.


Assuntos
Neoplasias Ósseas , Dendrímeros , Difosfonatos , Hipertermia Induzida , Osteólise , Fotoquimioterapia , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Dendrímeros/química , Dendrímeros/farmacologia , Difosfonatos/química , Difosfonatos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Osteólise/tratamento farmacológico , Osteólise/metabolismo , Osteólise/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Biomacromolecules ; 19(6): 2194-2201, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29684275

RESUMO

The assembly of low molecular weight polymers into highly efficient and nontoxic nanostructures has broad applicability in gene delivery. In this study, we reported the assembly of coumarin-anchored low generation dendrimers in aqueous solution via hydrophobic interactions. The synthesized material showed significantly improved DNA binding and gene delivery, and minimal toxicity on the transfected cells. Moreover, the coumarin moieties in the assembled nanostructures endow the materials with light-responsive drug delivery behaviors. The coumarin substitutes in the assembled nanostructures were cross-linked with each other upon irradiation at 365 nm, and the cross-linked assemblies were degraded upon further irradiation at 254 nm. As a result, the drug-loaded nanoparticle showed a light-responsive drug release behavior and light-enhanced anticancer activity. The assembled nanoparticle also exhibited a complementary anticancer activity through the codelivery of 5-fluorouracil and a therapeutic gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This study provided a facile strategy to develop light-responsive polymers for the codelivery of therapeutic genes and anticancer drugs.


Assuntos
Antineoplásicos , Cumarínicos , Dendrímeros , Sistemas de Liberação de Medicamentos , Fluoruracila , Técnicas de Transferência de Genes , Nanoestruturas , Neoplasias/terapia , Fototerapia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cumarínicos/química , Cumarínicos/farmacocinética , Cumarínicos/farmacologia , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Fluoruracila/química , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Células HEK293 , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
20.
Proc Natl Acad Sci U S A ; 114(37): E7660-E7669, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28847956

RESUMO

Inflammation is part of the physiological response of the organism to infectious diseases caused by organisms such as bacteria, viruses, fungi, or parasites. Innate immunity, mediated by mononuclear phagocytes, including monocytes and macrophages, is a first line of defense against infectious diseases and plays a key role triggering the delayed adaptive response that ensures an efficient defense against pathogens. Monocytes and macrophages stimulation by pathogen antigens results in activation of different signaling pathways leading to the release of proinflammatory cytokines. However, inflammation can also participate in the pathogenesis of several diseases, the autoimmune diseases that represent a relevant burden for human health. Dendrimers are branched, multivalent nanoparticles with a well-defined structure that have a high potential for biomedical applications. To explore new approaches to fight against the negative aspects of inflammation, we have used neutral high-generation phosphorus dendrimers bearing 48 (G3) or 96 (G4) bisphosphonate groups on their surface. These dendrimers show no toxicity and have good solubility and chemical stability in aqueous solutions. Here, we present data indicating that neutral phosphorus dendrimers show impressive antiinflammatory activities both in vitro and in vivo. In vitro, these dendrimers reduced the secretion of proinflammatory cytokines from mice and human monocyte-derived macrophages. In addition, these molecules present efficient antiinflammatory activity in vivo in a mouse model of subchronic inflammation. Taken together, these data suggest that neutral G3-G4 phosphorus dendrimers have strong potential applications in the therapy of inflammation and, likely, of autoimmune diseases.


Assuntos
Dendrímeros/metabolismo , Inflamação/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Técnicas de Cultura de Células , Citocinas/metabolismo , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Nanopartículas/uso terapêutico , Fósforo/metabolismo
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