RESUMEN
The development of nonviral dendritic polymers with a simple molecular backbone and great gene delivery efficiency to effectively tackle cancer remains a great challenge. Phosphorus dendrimers or dendrons are promising vectors due to their structural uniformity, rigid molecular backbones, and tunable surface functionalities. Here, we report the development of a new low-generation unsymmetrical cationic phosphorus dendrimer bearing 5 pyrrolidinium groups and one amino group as a nonviral gene delivery vector. The created AB5-type dendrimers with simple molecular backbone can compress microRNA-30d (miR-30d) to form polyplexes with desired hydrodynamic sizes and surface potentials and can effectively transfect miR-30d to cancer cells to suppress the glycolysis-associated SLC2A1 and HK1 expression, thus significantly inhibiting the migration and invasion of a murine breast cancer cell line in vitro and the corresponding subcutaneous tumor mouse model in vivo. Such unsymmetrical low-generation phosphorus dendrimers may be extended to deliver other genetic materials to tackle other diseases.
Asunto(s)
Dendrímeros , MicroARNs , Neoplasias , Animales , Ratones , Dendrímeros/química , Vectores Genéticos , MicroARNs/genética , Técnicas de Transferencia de Gen , Cationes , FósforoRESUMEN
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.
Asunto(s)
Antiinfecciosos , Dendrímeros , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , Ratones , Antibacterianos , Staphylococcus aureus , Dendrímeros/farmacología , Pruebas de Sensibilidad Microbiana , Gentamicinas/farmacología , Gentamicinas/uso terapéutico , Antiinfecciosos/uso terapéutico , Fósforo/farmacología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.
Asunto(s)
Artritis Experimental , Dendrímeros , Animales , Ratones , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Factor de Necrosis Tumoral alfa/genética , Antiinflamatorios/farmacologíaRESUMEN
Conventional small molecular chemical drugs always have challenging limitations in cancer therapy due to their high systemic toxicity and low therapeutic efficacy. Nanotechnology has been applied in drug delivery, bringing new promising potential to realize effective cancer treatment. In this context, we develop here a new nanomicellar drug delivery platform generated by amphiphilic phosphorus dendrons (1-C17G3.HCl), which could form micelles for effective encapsulation of a hydrophobic anticancer drug doxorubicin (DOX) with a high drug loading content (42.4%) and encapsulation efficiency (96.7%). Owing to the unique dendritic rigid structure and surface hydrophilic groups, large steady void space of micelles can be created for drug encapsulation. The created DOX-loaded micelles with a mean diameter of 26.3 nm have good colloidal stability. Strikingly, we show that the drug-free micelles possess good intrinsic anticancer activity and act collectively with DOX to take down breast cancer cells in vitro and the xenografted tumor model in vivo through upregulation of Bax, PTEN, and p53 proteins for enhanced cell apoptosis. Meanwhile, the resulting 1-C17G3.HCl@DOX micelles significantly abolish the toxicity relevant to the free drug. The findings of this study demonstrate a unique nanomicelle-based drug delivery system created with the self-assembling amphiphilic phosphorus dendrons that may be adapted for chemotherapy of different cancer types.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Dendrímeros , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Dendrímeros/química , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Micelas , FósforoRESUMEN
Phosphorus dendrimers are used for many applications in different domains including nanomedicine as cargo of drugs or as species active per se but also in a variety of other fields ranging from nanoscience to catalysis. Their properties depend on the nature of their internal structure and mainly of the diversity and versatility of the functional groups located on their outer shell. Therefore, there is a need to diversify their structure in order to use them for new applications and to propose alternative synthetic pathways to be built easily, at each step and in high yield a family of original stable phosphorus dendrimers of different generations. Such a goal is illustrated in this report with the original synthesis of 14 new phosphorus dendrimers of generation 0 to 2 and the possibility to modify at will their internal structure and the nature of their functional end groups.
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Dendrímeros , Fósforo , Catálisis , Dendrímeros/química , Nanomedicina , Fósforo/químicaRESUMEN
Nanoparticles are playing an increasing role in biomedical applications. Excitotoxicity plays a significant role in the pathophysiology of neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. Glutamate ionotropic receptors, mainly those activated by N-methyl-D-aspartate (NMDA), play a key role in excitotoxic death by increasing intraneuronal calcium levels; triggering mitochondrial potential collapse; increasing free radicals; activating caspases 3, 9, and 12; and inducing endoplasmic reticulum stress. Neutral phosphorous dendrimers, acting intracellularly, have neuroprotective actions by interfering with NMDA-mediated excitotoxic mechanisms in rat cortical neurons. In addition, phosphorous dendrimers can access neurons inside human brain organoids, complex tridimensional structures that replicate a significant number of properties of the human brain, to interfere with NMDA-induced mechanisms of neuronal death. Phosphorous dendrimers are one of the few nanoparticles able to gain access to the inside of neurons, both in primary cultures and in brain organoids, and to exert pharmacological actions by themselves.
Asunto(s)
Dendrímeros , Fármacos Neuroprotectores , Animales , Encéfalo/metabolismo , Células Cultivadas , Dendrímeros/farmacología , Ácido Glutámico/farmacología , Ratones , N-Metilaspartato , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Organoides/metabolismo , Ratas , Receptores de Glutamato , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Dendrímeros/síntesis química , Dendrímeros/farmacología , Colorantes Fluorescentes/química , Micelas , Fósforo/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía Electrónica de TransmisiónRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Cobre/farmacología , Dendrímeros/farmacología , Fósforo/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Nanomedicina/métodosRESUMEN
Polymeric micelles are nanoassemblies that are formed by spontaneous arrangement of amphiphilic block copolymers in aqueous solutions at critical micelle concentration (CMC). They represent an effective system for drug delivery of, for instance, poorly water-soluble anticancer drugs. Then, the development of polyion complexes (PICs) were emphasized. The morphology of these complexes depends on the topology of the polyelectrolytes used and the way they are assembled. For instance, ionic-hydrophilic block copolymers have been used for the preparation of PIC micelles. The main limitation in the use of PIC micelles is their potential instability during the self-assembly/disassembly processes, influenced by several parameters, such as polyelectrolyte concentration, deionization associated with pH, ionic strength due to salt medium effects, mixing ratio, and PIC particle cross-linking. To overcome these issues, the preparation of stable PIC micelles by increasing the rigidity of their dendritic architecture by the introduction of dendrimers and controlling their number within micelle scaffold was highlighted. In this original concise Review, we will describe the preparation, molecular characteristics, and pharmacological profile of these stable nanoassemblies.
Asunto(s)
Dendrímeros , Micelas , Iones , Polielectrolitos , PolímerosRESUMEN
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.
Asunto(s)
Dendrímeros , Mycobacterium tuberculosis , Tuberculosis , Animales , Antituberculosos/farmacología , Dendrímeros/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Tuberculosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Dendrímeros/farmacología , Nanomedicina/tendencias , Fósforo/farmacología , Animales , Antineoplásicos/uso terapéutico , Antituberculosos/uso terapéutico , Dendrímeros/química , Humanos , Estructura Molecular , Nanomedicina/métodos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fósforo/química , Tuberculosis/tratamiento farmacológicoRESUMEN
The goal of nanomedicine is to address specific clinical problems optimally, to fight human diseases, and to find clinical relevance to change clinical practice. Nanomedicine is poised to revolutionize medicine via the development of more precise diagnostic and therapeutic tools. The field of nanomedicine encompasses numerous features and therapeutic disciplines. A plethora of nanomolecular structures have been engineered and developed for therapeutic applications based on their multitasking abilities and the wide functionalization of their core scaffolds and surface groups. Within nanoparticles used for nanomedicine, dendrimers as well polymers have demonstrated strong potential as nanocarriers, therapeutic agents, and imaging contrast agents. In this review, we present and discuss the different criteria and parameters to be addressed to prepare and develop druggable nanoparticles in general and dendrimers in particular. We also describe the major requirements, included in the preclinical and clinical roadmap, for NPs/dendrimers for the preclinical stage to commercialization. Ultimately, we raise the clinical translation of new nanomedicine issues.
Asunto(s)
Medios de Contraste/administración & dosificación , Dendrímeros/química , Portadores de Fármacos/química , Nanopartículas/química , Preparaciones Farmacéuticas/administración & dosificación , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Nanomedicina/métodos , Nanotecnología/métodosRESUMEN
First-in-class CuII and AuIII metaled phosphorus dendrons were synthesized and showed significant antiproliferative activity against several aggressive breast cancer cell lines. The data suggest that the cytotoxicity increases with reducing length of the alkyl chains, whereas the replacement of CuII with AuIII considerably increases the antiproliferative activity of metaled phosphorus dendrons. Very interestingly, we found that the cell death pathway is related to the nature of the metal complexed by the plain dendrons. CuII metaled dendrons showed a potent caspase-independent cell death pathway, whereas AuIII metaled dendrons displayed a caspase-dependent apoptotic pathway. The complexation of plain dendrons with AuIII increased the cellular lethality versus dendrons with CuII and promoted the translocation of Bax into the mitochondria and the release of Cytochrome C (Cyto C).
Asunto(s)
Citocromos c/metabolismo , Dendrímeros/metabolismo , Metales/química , Mitocondrias/química , Fósforo/química , Apoptosis , Muerte Celular , Citocromos c/química , Dendrímeros/química , Humanos , Células MCF-7 , Metales/metabolismo , Mitocondrias/metabolismo , Estructura Molecular , Fósforo/metabolismoRESUMEN
Gene delivery, one important cancer-therapy mode, still remains to be challenging because of the shortage of highly efficient and safe nonviral vectors. Here, we revisit the development of cationic phosphorus dendrimers by synthesizing them with different generations (G1-3) and surface ligands (1-(2-aminoethyl) pyrrolidine, 1-(3-aminopropyl) piperidine, or 1-(2-aminoethyl) piperidine) for optimized gene delivery toward cancer-gene-therapy applications. First, the synthesized dendrimer derivatives were employed to condense plasmid DNA (pDNA) encoding enhanced green fluorescent protein (EGFP) to optimize their gene-delivery efficiency by varying the dendrimer generations and surface polycationic ligands. We show that all dendrimer/pDNA polyplexes display good cytocompatibility, and the 1-(2-aminoethyl) pyrrolidine-modified protonated G1 dendrimers (1-G1) display the best gene-delivery efficiency to HeLa cells under the same conditions through flow cytometry and fluorescence microscopic imaging analyses. Hence, 1-G1 dendrimers were then used as a vector to transfect pDNA encoding both EGFP and p53 protein for cancer-gene-therapy applications. Our results reveal that under the optimized conditions, the transfection of pDNA induces the significant p53 protein expression as verified through the resulted cell cycle arrest (regulation of p21 and Cdk4/Cyclin-D1 expression) and Western blotting. The cancer-gene-therapy potential of the polyplexes was finally validated through therapy of a xenografted tumor model after intratumoral injection without systemic toxicity. The developed cationic 1-G1 dendrimers may be adopted as a powerful vector system for gene therapy of cancer, as well as for highly effective gene therapy of other diseases.
Asunto(s)
Dendrímeros , Neoplasias , Supervivencia Celular , Técnicas de Transferencia de Gen , Terapia Genética , Células HeLa , Humanos , Neoplasias/genética , Neoplasias/terapia , Fósforo , Plásmidos/genética , TransfecciónRESUMEN
The development of a powerful nanoplatform to realize the simultaneous therapy and diagnosis of cancer using a similar element for theranostics remains a critical challenge. Herein, we report such a theranostic nanoplatform based on pyridine (Pyr)-functionalized generation 5 (G5) poly(amidoamine) dendrimers complexed with copper(II) (Cu(II)) for radiotherapy-enhanced T1-weighted magnetic resonance (MR) imaging and the synergistic radio-chemotherapy of both tumors and tumor metastasis. In this study, amine-terminated G5 dendrimers were covalently linked with 2-pyridinecarboxylic acid, acetylated to neutralize their remaining terminal amines, and complexed with Cu(II) through both the internal tertiary amines and the surface Pyr groups to form the G5.NHAc-Pyr/Cu(II) complexes. We show that the complexes are able to inhibit the proliferation of different cancer cell lines with half-maximal inhibitory concentrations ranging from 4 to 10 µM and induce significant cancer cell apoptosis. Due to the presence of Cu(II), the G5.NHAc-Pyr/Cu(II) complexes display an r1 relaxivity of 0.7024 mM-1 s-1, enabling effective in vivo MR imaging of tumor xenografts and lung metastatic nodules. Further, under radiotherapy (RT) conditions, the tumor MR imaging sensitivity can be significantly enhanced, and the G5.NHAc-Pyr/Cu(II) complexes enable the enhanced chemotherapy of both a xenografted tumor model and a blood-vessel metastasis model. With the demonstrated theranostic potential of the dendrimer-Cu(II) nanocomplexes without additional agents or elements for RT-enhanced MR imaging and chemotherapy of tumor and tumor metastasis, this novel Cu(II)-based nanohybrids may hold great promise for the theranostics of different cancer types and metastases.
RESUMEN
Photodynamic therapy (PDT) is a skin cancer treatment alternative to chemotherapy and radiotherapy. This method exploits three elements: a phototoxic compound (photosensitizer), light source and oxygen. Upon irradiation by light of a specific wavelength, the photosensitizer generates reactive oxygen species triggering the cascade of reactions leading to cell death. The positive therapeutic effect of PDT may be limited due to low solubility, low tumor specificity and inefficient cellular uptake of photosensitizers. A promising approach to overcome these obstacles involves the use of nanocarrier systems. The aim of this initial study was to determine the potential of the application of phosphorus dendrimers as carriers of a photosensitizer-rose bengal (RB). The primary goal involved the synthesis and in vitro studies of covalent drug-dendrimer conjugates. Our approach allowed us to obtain RB-dendrimer conjugates with the use of tyramine as an aromatic linker between the carrier and the drug. The compounds were characterized by FT-IR, 1H NMR, 13C NMR, 31P NMR, size and zeta potential measurements and spectrofluorimetric analysis. The dialysis to check the drug release from the conjugate, flow cytometry to specify intracellular uptake, and singlet oxygen generation assay were also applied. Finally, we used MTT assay to determine the biological activity of the tested compounds. The results of our experiments indicate that the conjugation of RB to phosphorus dendrimers via the tyramine linker decreases photodynamic activity of RB.
Asunto(s)
Carcinoma Basocelular/tratamiento farmacológico , Dendrímeros/química , Fósforo/química , Fármacos Fotosensibilizantes/farmacología , Rosa Bengala/química , Neoplasias Cutáneas/tratamiento farmacológico , Tiramina/química , Animales , Carcinoma Basocelular/patología , Muerte Celular , Portadores de Fármacos/química , Colorantes Fluorescentes/química , Ratones , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Oxígeno Singlete , Neoplasias Cutáneas/patología , Células Tumorales CultivadasRESUMEN
The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Benzotiazoles/síntesis química , Fármacos Neuroprotectores/síntesis química , Pramipexol/química , Riluzol/química , Animales , Benzotiazoles/química , Benzotiazoles/farmacología , Ensayos Clínicos como Asunto , Aprobación de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Fármacos Neuroprotectores/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Tolueno/análogos & derivados , Tolueno/química , Resultado del TratamientoRESUMEN
Antisense oligonucleotide (AON)-based therapies concern the treatment for genetic disorders or infections such as a range of neurodegenerative and neuromuscular diseases and have shown benefits in animal models and patients. Nevertheless, successes in the clinic are still strongly limited by unfavorable biodistribution and poor cellular uptake of AONs. Dendrimer macromolecules are synthetically accessible and consist of a core with repeated iterations (named branches) surrounding this core, and on the periphery functional groups which can be modified for ligand attachment. The generations of these branched nanoparticles are based on the number of branches emanating from the core with layered architectures. Dendrimers show promise in several biomedical applications based on their tunable surface modifications allowing the adjustment of their in vivo behavior related to biocompatibility and pharmacokinetic parameters. Dendrimers can be used as nanocarriers of various types of drugs including AONs or nanodrugs. As nanocarriers, polycationic dendrimers can complex multiple negatively charged DNA oligonucleotides on their surface and form stable complexes to promote internalization into the cells based on a good cell membrane affinity. These nanocarriers complexing antisense oligonucleotides must be stable enough to reach the cellular target, but with adequate in vivo global clearance, and have good pharmacokinetic (PK) and pharmacodynamic (PD) profiles. This Review was designed to analyze the development of AONs carried by polycationic and polyanionic (few example) dendrimers. This Review strongly supports the idea that dendrimers, with adequate modulation of their terminal groups, could be used to carry AONs in cells.
Asunto(s)
Dendrímeros/química , Portadores de Fármacos/química , Nanopartículas/química , Oligonucleótidos Antisentido/administración & dosificación , Animales , Sistemas de Liberación de Medicamentos , Humanos , Modelos Moleculares , Oligonucleótidos Antisentido/farmacocinética , Poliaminas/química , Polielectrolitos , Polímeros/químicaRESUMEN
The aim of this original review is to highlight and analyze the most recent progress and challenges in the synthesis and surface modifications of superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) for multimodal imaging and therapy applications, which represent important fields in medicine in general and cancer in particular. Thus, the oncology domain is rapidly moving to a more personalized medicine including precision imaging and theranostic approaches. Novel biocompatible Fe3O4 nanoparticulate systems have been designed for enhanced and targeted cellular uptake by surface layer coating modifications, to have improved r2 relaxivity for sensitive magnetic resonance (MR) imaging applications, to have the ability to be used for dual mode imaging, and to be used for imaging-guided cancer therapy. In this review, we analyzed in depth the new strategies for generating biocompatible multifunctional Fe3O4 nanoplatforms for both the diagnosis and therapy of cancer.
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Compuestos Férricos/uso terapéutico , Nanopartículas de Magnetita/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Nanomedicina Teranóstica/métodos , Compuestos Férricos/química , Humanos , Nanopartículas de Magnetita/química , Imagen Multimodal , Nanopartículas/químicaRESUMEN
For the first time, an overview of dendrimers in combination with natural products and analogues as anti-cancer agents is presented. This reflects the development of drug delivery systems, such as dendrimers, to tackle cancers. The most significant advantages of using dendrimers in nanomedicine are their high biocompatibility, good water solubility, and their entry - with or without encapsulated, complexed or conjugated drugs - through an endocytosis process. This strategy has accelerated over the years in order to develop nanosystems as nanocarriers, to decrease the intrinsic toxicity of anti-cancer agents, to decrease the drug side effects, to increase the efficacy of the treatment, and consequently to improve patient compliance.