RESUMO
BACKGROUND: Nano-drug delivery systems have become a promising approach to overcoming problems such as low solubility and cellular uptake of drugs. Along with various delivery devices, dendrimers are widely used through their unique features. PEG-citrate dendrimers are biocompatible and nontoxic, with the ability to improve drug solubility. Curcumin, a naturally occurring polyphenol, has multiple beneficial properties, such as antiviral activities. However, its optimum potential has been significantly hampered due to its poor water solubility, which leads to reduced bioavailability. So, the present study attempted to address this issue and investigate its antiviral effects against HIV-1. METHOD: The G2 PEG-citrate dendrimer was synthesized. Then, curcumin was conjugated to it directly. FTIR, HNMR, DLS, and LCMS characterized the structure of products. The conjugate displayed an intense yellow color. In addition, increased aqueous solubility and cell permeability of curcumin were achieved based on flow cytometry results. So, it could be a suitable vehicle for improving the therapeutic applications of curcumin. Moreover, cell toxicity was assessed using XTT method. Ultimately, the SCR HIV system provided an opportunity to evaluate the level of HIV-1 inhibition by the curcumin-dendrimer conjugate using a p24 HIV ELISA kit. RESULTS: The results demonstrated a 50% up to 90% inhibition of HIV proliferation at 12 µm and 60 µm, respectively. Inhibition of HIV-1 at concentrations much lower than CC50 (300 µM) indicates a high potential of curcumin-dendrimer conjugate against this virus. CONCLUSION: Thereby, curcumin-dendrimer conjugate proves to be a promising tool to use in HIV-1 therapy.
Assuntos
Curcumina , Dendrímeros , Infecções por HIV , HIV-1 , Polietilenoglicóis , Curcumina/farmacologia , Curcumina/química , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , HIV-1/efeitos dos fármacos , Polietilenoglicóis/química , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Ácido Cítrico/química , Nanopartículas/químicaRESUMO
OBJECTIVE: The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. METHODS: Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. RESULTS: PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood-brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. CONCLUSION: By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. SIGNIFICANCE: This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.
Assuntos
Curcumina , Golpe de Calor , Nanopartículas , Curcumina/farmacologia , Curcumina/química , Animais , Golpe de Calor/tratamento farmacológico , Camundongos , Nanopartículas/química , Masculino , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Dendrímeros/química , Dendrímeros/farmacologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular , PoliaminasRESUMO
Poly(amidoamine) dendrimer (PAMAM)/carbon quantum dot (CQD) nanohybrids are promising candidates for many biomedical applications, including drug delivery. Effectively designing a hybrid nanocarrier requires a deep understanding of the interactions of the hybrid nanoparticle with the drug to ensure drug stability and therapeutic efficiency. In this study, we utilized fully atomistic molecular dynamics (MD) simulations to investigate the adsorption behavior of a doxorubicin (DOX) anticancer drug onto a zwitterion/PAMAM/CQD hybrid nanocarrier. The hybrid nanoparticles were composed of CQD, at two oxidation levels, grafted with PAMAM dendrimers of generation 3 (G3) or 4 (G4) decorated with zwitterion monomers. Our work reveals that the generation of the grafted dendrimer was the primary determinant of efficient adsorption of DOX, unlike the oxidation level of CQD or dendrimer surface chemistry. After grafting, the G4 dendrimers assume a more stretched conformation compared to the G3 dendrimers. This allowed DOX molecules to penetrate inside the dendritic cavities of G4 dendrimers, resulting in enhanced drug protection. The hydrophobic interaction, between the aromatic structure of DOX molecules and the nonpolar parts of dendrimers, has been proven to play a crucial role in mediating the adsorption of drug molecules. These findings provide valuable insights to assist in the design of a zwitterion/PAMAM/CQD hybrid nanoplatform for drug delivery applications.
Assuntos
Dendrímeros , Doxorrubicina , Portadores de Fármacos , Simulação de Dinâmica Molecular , Pontos Quânticos , Doxorrubicina/química , Dendrímeros/química , Portadores de Fármacos/química , Pontos Quânticos/química , Nanopartículas/química , Carbono/química , AdsorçãoRESUMO
The rapid emergence and spread of multidrug-resistant bacterial pathogens require the development of antibacterial agents that are robustly effective while inducing no toxicity or resistance development. In this context, we designed and synthesized amphiphilic dendrimers as antibacterial candidates. We report the promising potent antibacterial activity shown by the amphiphilic dendrimer AD1b, composed of a long hydrophobic alkyl chain and a tertiary amine-terminated poly(amidoamine) dendron, against a panel of Gram-negative bacteria, including multidrug-resistant Escherichia coli and Acinetobacter baumannii. AD1b exhibited effective activity against drug-resistant bacterial infections in vivo. Mechanistic studies revealed that AD1b targeted the membrane phospholipids phosphatidylglycerol (PG) and cardiolipin (CL), leading to the disruption of the bacterial membrane and proton motive force, metabolic disturbance, leakage of cellular components, and, ultimately, cell death. Together, AD1b that specifically interacts with PG/CL in bacterial membranes supports the use of small amphiphilic dendrimers as a promising strategy to target drug-resistant bacterial pathogens and addresses the global antibiotic crisis.
Assuntos
Antibacterianos , Dendrímeros , Fosfatidilgliceróis , Dendrímeros/química , Dendrímeros/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Fosfatidilgliceróis/química , Testes de Sensibilidade Microbiana , Escherichia coli/efeitos dos fármacos , Animais , Acinetobacter baumannii/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismoRESUMO
In this study, we hypothesized that biotinylated and/or glycidol-flanked fourth-generation polyamidoamine (PAMAM G4) dendrimers could be a tool for efficient drug transport into glioma and liver cancer cells. For this purpose, native PAMAM (G4) dendrimers, biotinylated (G4B), glycidylated (G4gl), and biotinylated and glycidylated (G4Bgl), were synthesized, and their cytotoxicity, uptake, and accumulation in vitro and in vivo were studied in relation to the transport mediated by the sodium-dependent multivitamin transporter (SMVT). The studies showed that the human temozolomide-resistant glioma cell line (U-118 MG) and hepatocellular carcinoma cell line (HepG2) indicated a higher amount of SMVT than human HaCaT keratinocytes (HaCaTs) used as a model of normal cells. The G4gl and G4Bgl dendrimers were highly biocompatible in vitro (they did not affect proliferation and mitochondrial activity) against HaCaT and U-118 MG glioma cells and in vivo (against Caenorhabditis elegans and Wistar rats). The studied compounds penetrated efficiently into all studied cell lines, but inconsistently with the uptake pattern observed for biotin and disproportionately for the level of SMVT. G4Bgl was taken up and accumulated after 48 h to the highest degree in glioma U-118 MG cells, where it was distributed in the whole cell area, including the nuclei. It did not induce resistance symptoms in glioma cells, unlike HepG2 cells. Based on studies on Wistar rats, there are indications that it can also penetrate the blood-brain barrier and act in the central nervous system area. Therefore, it might be a promising candidate for a carrier of therapeutic agents in glioma therapy. In turn, visualization with a confocal microscope showed that biotinylated G4B penetrated efficiently into the body of C. elegans, and it may be a useful vehicle for drugs used in anthelmintic therapy.
Assuntos
Biotinilação , Dendrímeros , Portadores de Fármacos , Glioma , Neoplasias Hepáticas , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Ratos , Portadores de Fármacos/química , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Poliaminas/química , Linhagem Celular Tumoral , Células Hep G2 , Ratos Wistar , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
The design of efficient multifunctional nanomedicines to overcome adverse side effects within biological systems and to achieve desirable computed tomography (CT) imaging and therapeutics of tumors remains challenging. Herein, we report the design of multifunctional nanoclusters (NCs) based on generation 3 (G3) poly(amidoamine) (PAMAM) dendrimers. In brief, G3 dendrimers were crosslinked with 4,4'-dithiodibutryic acid (DA) to generate disulfide-bond-containing dendrimer nanoclusters (DNCs), functionalized with 1,3-propane sultone (1,3-PS) to be zwitterionic, in situ loaded with gold nanoparticles (Au NPs), and finally encapsulated with the drug doxorubicin (DOX). The designed DOX/Au@DNCs-PS possess a favorable colloidal stability with a hydrodynamic size of 249.4 nm, a redox-responsive drug release profile, and enhanced cellular uptake in vitro. We show that DOX/Au@DNCs-PS have a greater DOX penetration and growth inhibition of three-dimensional (3D) tumor spheroids than the single dendrimer counterpart in vitro. Furthermore, the developed Au@DNCs-PS enable a better Au-mediated X-ray attenuation property than the single dendrimer counterpart material. Likely due to the amplified enhanced permeability and retention (EPR) effect, the created Au@DNCs-PS and DOX/Au@DNCs-PS enable better CT imaging and chemotherapeutic effect of a mouse breast tumor model, respectively, than the single dendrimer counterparts. With its proven biocompatibility, the constructed formulation may hold promising potential for development for different cancer nanomedicine applications.
Assuntos
Dendrímeros , Doxorrubicina , Ouro , Nanopartículas Metálicas , Tomografia Computadorizada por Raios X , Dendrímeros/química , Ouro/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Animais , Nanopartículas Metálicas/química , Humanos , Camundongos , Feminino , Camundongos Endogâmicos BALB C , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Tamanho da PartículaRESUMO
Using halloysite clay and vitamin B1 hydrochloride, a novel acidic halloysite-dendrimer catalytic composite has been developed for conversion of fructose to 5-hydroxymthylfurfural. To grow the dendritic moiety on halloysite, it was first functionalized and then reacted with melamine, epichlorohydrin and vitamin B1 hydrochloride respectively. Then, the resulting composite was treated with ZnCl2 to furnish Lewis acid sites. Use of vitamin B1 as the cationic moiety of ionic liquid obviated use of toxic chemicals and resulted in more environmentally friendly composite. Similarly, dendritic moiety of generation 2 was also grafted on halloysite and the activity of both catalysts for conversion of fructose to 5-hydroxymthylfurfural was investigated to disclose the role of dendrimer generation. For the best catalytic composite, the reaction variables were optimized via RSM and it was revealed that use of 0.035 g catalyst per 0.1 g fructose at 95 °C furnished HMF in 96% yield in 105 min. Turnover numbers (TONs) and frequencies (TOFs) were estimated to be 10,130 and 5788 h-1, respectively. Kinetic studies also underlined that Ea was 22.85 kJ/mol. The thermodynamic parameters of Δ H ≠ , Δ S ≠ and Δ G ≠ , were calculated to be 23 kJ/mol, - 129.2 J/mol and 72.14 kJ/mol, respectively. Notably, the catalyst exhibited good recyclability and hot filtration approved heterogeneous nature of catalysis.
Assuntos
Argila , Dendrímeros , Furaldeído , Tiamina , Catálise , Argila/química , Furaldeído/análogos & derivados , Furaldeído/química , Dendrímeros/química , Dendrímeros/síntese química , Tiamina/química , Tiamina/análogos & derivados , Frutose/química , Cinética , Silicatos de Alumínio/química , Triazinas/química , Cloretos/química , Compostos de Zinco/químicaRESUMO
An ideal adhesive hydrogel must possess high adhesion to the native tissue, biocompatibility, eligible biodegradability, and good mechanical compliance with the substrate tissues. We constructed an interpenetrating double-network hydrogel containing polysaccharides (alginate and dextran) and nanosized spherical dendrimer by both physical and chemical crosslinking, thus endowing the hydrogel with a broad range of mechanical properties, adhesive properties, and biological functions. The double-network hydrogel has moderate pore sizes and swelling properties. The chelation of calcium ions significantly enhances the tensile and compressive properties. The incorporation of dendrimer improves both the mechanical and adhesive properties. This multicomponent interpenetrating network hydrogel has excellent biocompatibility, tunable mechanical and adhesive properties, and satisfied multi-functions to meet the complex requirements of wound healing and tissue engineering. The hydrogel exhibits promising corneal adhesion capabilities in vitro, potentially supplanting the need for sutures in corneal stromal surgery and mitigating the risks associated with donor corneal damage and graft rejection during corneal transplantation. This novel polysaccharide and dendrimer hydrogel also shows good results in sutureless keratoplasty, with high efficiency and reliability. Based on the clinical requirements for tissue bonding and wound closure, the hydrogel provides insight into solving the mechanical properties and adhesive strength of tissue adhesives.
Assuntos
Alginatos , Dendrímeros , Dextranos , Hidrogéis , Adesivos Teciduais , Alginatos/química , Hidrogéis/química , Dextranos/química , Dendrímeros/química , Adesivos Teciduais/química , Animais , Transplante de Córnea/métodos , Humanos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Resistência à Tração , Coelhos , Córnea/cirurgia , Cicatrização/efeitos dos fármacos , Reagentes de Ligações Cruzadas/químicaRESUMO
We report the successful synthesis of an injectable dendrimer hydrogel (DH) carrying melphalan, a clinical drug for retinoblastoma treatment, in both conjugated and free forms. Polyamidoamine (PAMAM) dendrimer generation 5 (G5) is surface-modified with an acid-sensitive acetal-dibenzocyclooctyne linker and then undergoes azide-alkyne cycloaddition with melphalan-PEG-N3 conjugate to form G5-acetal-melphalan. During the DH gelation between G5-acetal-melphalan and PEG-diacrylate, free melphalan is added, resulting in a hydrogel (G5-acetal-melphalan-DH/melphalan) that carries the drug in both conjugated and free forms. Melphalan is slowly released from G5-acetal-melphalan-DH/melphalan, with the conjugated melphalan released more quickly at pH 5.3 due to acid-triggered acetal bond cleavage. The formulation's in vitro safety and efficacy were established on human corneal epithelia (HCE-2) and retinoblastoma cells (Y79). In an in vivo Y79 tumor xenograft model of retinoblastoma, intratumorally injected G5-melphalan-DH formulation prolonged tumor suppression. This injectable, multimodal, pH-responsive formulation shows promise for intravitreal injection to treat retinoblastoma.
Assuntos
Dendrímeros , Hidrogéis , Melfalan , Retinoblastoma , Dendrímeros/química , Melfalan/administração & dosagem , Melfalan/química , Melfalan/farmacologia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/patologia , Animais , Humanos , Hidrogéis/química , Camundongos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Linhagem Celular Tumoral , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologiaRESUMO
Bacterial resistance to antibiotics is a significant challenge that is associated with increased morbidity and mortality. Gram-negative bacteria are particularly problematic due to an outer membrane (OM). Current alternatives to antibiotics include antimicrobial peptides or proteins and multifunctional systems such as dendrimers. Antimicrobial proteins such as lysins can degrade the bacterial cell wall, whereas dendrimers can permeabilize the OM, enhancing the activity of endolysins against gram-negative bacteria. In this study, we present a three-stage action of endolysin combined with two different carbosilane (CBS) silver metallodendrimers, in which the periphery is modified with N-heterocyclic carbene (NHC) ligands coordinating a silver atom. The different NHC ligands contained hydrophobic methyl or N-donor pyridyl moieties. The effects of these endolysin/dendrimer combinations are based on OM permeabilization, peptidoglycan degradation, and reactive oxygen species production. The results showed that CBS possess a permeabilization effect (first action), significantly reduced bacterial growth at higher concentrations alone and in the presence of endolysin, increased ROS production (second action), and led to bacterial cell damage (third action). The complex formed between the CHAP domain of endolysin and a CBS silver metallodendrimer, with a triple mechanism of action, may represent an excellent alternative to other antimicrobials with only one resistance mechanism.
Assuntos
Antibacterianos , Dendrímeros , Endopeptidases , Bactérias Gram-Negativas , Peptidoglicano , Espécies Reativas de Oxigênio , Silanos , Peptidoglicano/metabolismo , Peptidoglicano/química , Espécies Reativas de Oxigênio/metabolismo , Silanos/química , Silanos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Dendrímeros/química , Dendrímeros/farmacologia , Endopeptidases/metabolismo , Endopeptidases/química , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Prata/química , Prata/farmacologia , Domínios Proteicos , Permeabilidade da Membrana Celular/efeitos dos fármacosRESUMO
Bacteria in tumor microenvironments promote carcinogenesis and trigger complications, suggesting the significance of intervening in bacterial growth in cancer treatment. Here, dendrimer-derived mimics (DMs) of host defense peptides (HDPs) were designed for antibacterial and anticancer therapy, which feature a dendronized polylysine core and polycaprolactone arms. DMs displayed not only remarkable activities against Staphylococcus aureus and human lung cancer cells, but also exceptional selectivity. The membranolytic mechanism revealed by morphology analysis explained their low susceptibility to induce resistance. Further, the optimized DM inhibited tumor growth in the subcutaneous tumor model when administered via intraperitoneal injection and exhibited negligible toxicity to tissues. Overall, we combined the superiority of dendrimers and the mechanism from HDPs to design agents with dual antibacterial and anticancer activities that possess great potential for clinical oncology therapy.
Assuntos
Antibacterianos , Antineoplásicos , Dendrímeros , Polilisina , Staphylococcus aureus , Humanos , Dendrímeros/química , Dendrímeros/farmacologia , Dendrímeros/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Polilisina/química , Polilisina/farmacologia , Polilisina/uso terapêutico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Linhagem Celular Tumoral , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Poliésteres/química , Poliésteres/farmacologiaRESUMO
Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.
Assuntos
Antígenos de Superfície , Dendrímeros , Desoxiglucose , Glutamato Carboxipeptidase II , Neoplasias da Próstata , Piridinas , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Animais , Camundongos , Desoxiglucose/farmacologia , Desoxiglucose/química , Piridinas/química , Piridinas/administração & dosagem , Piridinas/farmacologia , Glutamato Carboxipeptidase II/metabolismo , Glutamato Carboxipeptidase II/antagonistas & inibidores , Dendrímeros/química , Antígenos de Superfície/metabolismo , Anilidas/farmacologia , Anilidas/administração & dosagem , Anilidas/farmacocinética , Anilidas/química , Nanomedicina/métodos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Sistemas de Liberação de Medicamentos/métodosRESUMO
Geometric isomers tend to have similar polarities and differ only in molecular shape. Vigorously developing new stationary phases to meet the requirements for the separation of isomers that have similar physicochemical properties is still an urgent topic in separation science. Poly (arylene ether)-based dendrimers are known for their multifunctional branched peripheral structures and high self-assembly properties. In this paper, two amphiphilic dendritic organic small molecule gelling agents based on poly (aryl ether), PAE-ANT and PAE-PA, were prepared and conjugated to the silica surface. SiO2@PAE-ANT and SiO2@PAE-PA were used as HPLC stationary phases for the separation of non-polar shape-restricted isomers. Both stationary phases have very high molecular shape selectivity for isomers such as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), tocopherols and carotenoids. Separation of cis-trans geometric isomers such as diethylstilbestrol and polar compounds such as monosubstituted benzenes and anilines can also be achieved. These two columns offer more flexible selectivity and higher separation performance than commercial C18 and phenyl columns. There is a difference in molecular shape selectivity between the two stationary phases for the same analyte test probes. SiO2@PAE-ANT showed slightly better linear selectivity for non-polar shape-restricted isomers compared to SiO2@PAE-PA with Janus-type PAE-PA bonding phase. This separation behavior may be attributed to the ordered spatial structure formed by the gel factor on the surface of the stationary phase and the combined effect of multiple weak interaction centers (hydrophobic, hydrophilic, hydrogen bonding and π-π interactions). It was also possible to separate nucleoside and nucleobase strongly polar compounds well in the HILIC mode, suggesting that hydrophilic groups in PAE-ANT and PAE-PA are involved in the interactions, reflecting their amphiphilic nature. The results show that the ordered gelation of dendritic organic small molecule gelators on the SiO2 surface, along with multiple carbonyl-π, π-π and other interactions, play a crucial role in the separating shape-restricted isomers. The integrated and ordered functional groups serve as the primary driving force behind the exceptionally high molecular shape selectivity of SiO2@PAE-ANT and SiO2@PAE-PA phases. Alterations in the structure of dendritic organic small molecule gelators can impact both molecular orientation and recognition ability, while changes in the type of functional groups influences the separation mechanism of shape-restricted isomers.
Assuntos
Dendrímeros , Dióxido de Silício , Dióxido de Silício/química , Cromatografia Líquida de Alta Pressão/métodos , Isomerismo , Dendrímeros/química , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Bifenilos Policlorados/química , Bifenilos Policlorados/análise , Bifenilos Policlorados/isolamento & purificação , Carotenoides/química , Carotenoides/análise , Carotenoides/isolamento & purificação , Tensoativos/químicaRESUMO
INTRODUCTION: Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance, and unavailability of validated biomarkers. AREA COVERED: This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects. EXPERT OPINION: Dendrimer-mediated targeting of angiogenic biomarkers has efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limit their application at market scale.
Assuntos
Inibidores da Angiogênese , Biomarcadores Tumorais , Dendrímeros , Sistemas de Liberação de Medicamentos , Neoplasias , Neovascularização Patológica , Dendrímeros/química , Humanos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/metabolismo , Portadores de Fármacos/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , NanopartículasRESUMO
For the first time, dendrimers based on thiacalix[4]arenes bearing imidazolium dendrons on one side and alkyl fragments on another side of the macrocyclic platform and symmetrical dendrimers with four dendrons on both sides were synthesized. Dendrons consist of gallic acid-based branches functionalized with imidazolium and triazolium groups. The physicochemical properties of the dendrimers such as micellar concentration (CMC), size, and solubilization capacity were measured. Novel dendrimers exhibit high binding efficiency with calf thymus DNA (ctDNA) as revealed by fluorescence quenching of the DNA-EtBr complex in the presence of macrocycles. Dendrimers have been used as supports for Pd nanoparticles, which show high catalytic activity for the reduction of nitroaromatic compounds.
Assuntos
DNA , Dendrímeros , Imidazóis , DNA/química , Dendrímeros/química , Imidazóis/química , Catálise , Fenóis/química , Micelas , Animais , Paládio/química , Bovinos , Nanopartículas Metálicas/química , SulfetosRESUMO
A nanohybrid-modified glassy carbon electrode based on conducting polypyrrole doped with carbon quantum dots (QDs) was developed and used for the electrochemical detection of anti-tissue transglutaminase (anti-tTG) antibodies. To improve the polypyrrole conductivity, carrier mobility, and carrier concentration, four types of carbon nanoparticles were tested. Furthermore, a polypyrrole-modified electrode doped with QDs was functionalized with a PAMAM dendrimer and transglutaminase 2 protein by cross-linking with N-hydroxysuccinimide (NHS)/N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC). The steps of electrode surface modification were surveyed via electrochemical measurements (differential pulse voltammetry (DPV), impedance spectroscopy, and X-ray photoelectron spectroscopy (XPS)). The surface characteristics were observed by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and contact angle measurements. The obtained modified electrode exhibited good stability and repeatability. DPV between - 0.1 and 0.6 V (vs. Ag/AgCl 3 M KCl reference electrode) was used to evaluate the electrochemical alterations that occur after the antibody interacts with the antigen (transglutaminase 2 protein), for which the limit of detection was 0.79 U/mL. Without the use of a secondary label, (anti-tTG) antibodies may be detected at low concentrations because of these modified electrode features.
Assuntos
Dendrímeros , Proteína 2 Glutamina gama-Glutamiltransferase , Pirróis , Pontos Quânticos , Transglutaminases , Humanos , Anticorpos/imunologia , Anticorpos/química , Técnicas Biossensoriais/métodos , Carbono/química , Dendrímeros/química , Técnicas Eletroquímicas/métodos , Eletrodos , Proteínas de Ligação ao GTP/imunologia , Polímeros/química , Pirróis/química , Pontos Quânticos/química , Transglutaminases/imunologia , Transglutaminases/químicaRESUMO
Nanotechnology has ushered in significant advancements in drug design, revolutionizing the prevention, diagnosis, and treatment of various diseases. The strategic utilization of nanotechnology to enhance drug loading, delivery, and release has garnered increasing attention, leveraging the enhanced physical and chemical properties offered by these systems. Polyamidoamine (PAMAM) dendrimers have been pivotal in drug delivery, yet there is room for further enhancement. In this study, we conjugated PAMAM dendrimers with chitosan (CS) to augment cellular internalization in tumor cells. Specifically, doxorubicin (DOX) was initially loaded into PAMAM dendrimers to form DOX-loaded PAMAM (DOX@PAMAM) complexes via intermolecular forces. Subsequently, CS was linked onto the DOX-loaded PAMAM dendrimers to yield CS-conjugated PAMAM loaded with DOX (DOX@CS@PAMAM) through glutaraldehyde crosslinking via the Schiff base reaction. The resultant DOX@CS@PAMAM complexes were comprehensively characterized using Fourier-transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Notably, while the drug release profile of DOX@CS@PAMAM in acidic environments was inferior to that of DOX@PAMAM, DOX@CS@PAMAM demonstrated effective acid-responsive drug release, with a cumulative release of 70% within 25 h attributed to the imine linkage. Most importantly, DOX@CS@PAMAM exhibited significant selective cellular internalization rates and antitumor efficacy compared to DOX@PAMAM, as validated through cell viability assays, fluorescence imaging, and flow cytometry analysis. In summary, DOX@CS@PAMAM demonstrated superior antitumor effects compared to unconjugated PAMAM dendrimers, thereby broadening the scope of dendrimer-based nanomedicines with enhanced therapeutic efficacy and promising applications in cancer therapy.
Assuntos
Quitosana , Dendrímeros , Doxorrubicina , Dendrímeros/química , Quitosana/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Poliaminas/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular TumoralRESUMO
Nanotechnology-based cancer treatment has received considerable attention, and these treatments generally use drug-loaded nanoparticles (NPs) to target and destroy cancer cells. Nanotechnology combined with photodynamic therapy (PDT) has demonstrated positive outcomes in cancer therapy. Combining nanotechnology and PDT is effective in targeting metastatic cancer cells. Nanotechnology can also increase the effectiveness of PDT by targeting cells at a molecular level. Dendrimer-based nanoconjugates (DBNs) are highly stable and biocompatible, making them suitable for drug delivery applications. Moreover, the hyperbranched structures in DBNs have the capacity to load hydrophobic compounds, such as photosensitizers (PSs) and chemotherapy drugs, and deliver them efficiently to tumour cells. This review primarily focuses on DBNs and their potential applications in cancer treatment. We discuss the chemical design, mechanism of action, and targeting efficiency of DBNs in tumour metastasis, intracellular trafficking in cancer treatment, and DBNs' biocompatibility, biodegradability and clearance properties. Overall, this study will provide the most recent insights into the application of DBNs and PDT in cancer therapy.
DBNs' intracellular journey in cancer-PDT refines targeted therapy, boosting efficacy.DBN in PDT for tumour metastasis: targeting and drug release mechanisms.DBNs' biocompatibility, biodegradability and clearance were explored thoroughly.
Assuntos
Dendrímeros , Nanoconjugados , Neoplasias , Fotoquimioterapia , Humanos , Dendrímeros/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Nanoconjugados/química , Nanoconjugados/uso terapêutico , Animais , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Transporte Biológico , Espaço Intracelular/metabolismo , Espaço Intracelular/efeitos dos fármacos , Portadores de Fármacos/químicaRESUMO
Cancer affects millions of people worldwide, causing death and serious health problems. Despite significant investment in the development of new anticancer compounds, there are still several limitations that can still be found. Many compounds exhibit high levels of toxicity and low bioavailability. Therefore, it is urgent to design safer, more effective, and particularly more selective compounds for oncological treatment. Dendrimers are polymeric structures that have been shown to be potential drug nanocarriers to overcome physicochemical, pharmacokinetic, and indirect pharmacodynamic issues. Due to their versatility, they can be used in the design of nanovaccines, lipophilic complexes, amphiphilic complexes, smart nanocomplexes, and others. This work targets the use of dendrimers in oncological treatment and their importance and effectiveness as drug delivery systems for the development of new therapies. For this review, only publications from the last two years are considered in this review.
Assuntos
Antineoplásicos , Dendrímeros , Sistemas de Liberação de Medicamentos , Neoplasias , Dendrímeros/química , Dendrímeros/administração & dosagem , Humanos , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Animais , Portadores de Fármacos/química , NanopartículasRESUMO
The negligible cytotoxicity of anion surface-linked dendrons makes glutamic acid-based dendrons a potential candidate for materials and biological applications. Despite the inherent drawbacks of the conventional solution phase synthesis of glutamic acid-based dendrons, there have been no advancements in these protocols. Herein, we demonstrate the first-ever convergent solid phase synthesis of dendrons, up to fourth generation, having glutamic acid branching points produced by preactivation of dicarboxylic acid groups with N-hydroxysuccinimide and simultaneous coupling with amine groups of two growing peptide chains, with excellent yields (30-70%). In addition to the general advantages, such as the easy workup, a final single purification step, and an overall short synthesis duration, the convergent solid phase synthesis allowed us to chemically synthesize glutamic acid branching-based dendrons that cannot be accessed by standard divergent solid phase synthesis. This method has also been validated for its application in synthesizing hard-to-achieve Janus peptide dendrimers in a single stretch on a solid support. Our work corroborates the efficacy of controlled -COOH activation to accomplish an atypical solid phase synthesis of diverse glutamic acid dendrons in a convergent fashion. This is the first example of a Janus peptide dendrimer being synthesized on a solid support, utilizing both convergent and divergent approaches simultaneously.