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1.
Chem Soc Rev ; 52(3): 1156, 2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36655561

RESUMO

Correction for 'Toxicity of metal-organic framework nanoparticles: from essential analyses to potential applications' by Romy Ettlinger et al., Chem. Soc. Rev., 2022, 51, 464-484, https://doi.org/10.1039/D1CS00918D.

2.
J Appl Toxicol ; 43(6): 874-886, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36594553

RESUMO

The aim of this study is to validate an in vitro skin irritation test (SIT) using three-dimensional reconstructed human epidermal (RhE) skin equivalents prepared by layer-by-layer (LbL) method (LbL-3D Skin) in a series of interlaboratory studies. The goal of these validation studies is to evaluate the ability of this in vitro test to reliably discriminate skin irritant from nonirritant chemicals, as defined by OECD and UN GHS. This me-too validation study is to assess the within- and between-laboratory reproducibility, as well as the predictive capacity, of the LbL-3D Skin SIT in accordance with performance standards for OECD TG 439. The developed skin model, LbL-3D Skin had a highly differentiated epidermis and dermis, similar to the validated reference methods (VRM) and native human skin. The quality parameters (cell survival in controls, tissue integrity, and barrier function) were similar to VRM and in accordance with OECD TG 439. The LbL-3D Skin SIT validation study was performed by three participating laboratories and consisted of three independent tests using 20 reference chemicals. The results obtained with the LbL-3D Skin demonstrated high within-laboratory and between-laboratory reproducibility, as well as high accuracy for use as a stand-alone assay to distinguish skin irritants from nonirritants. The predictive potency of LbL-3D Skin SIT using total 54 test chemicals were comparable to those in other RhE models in OECD TG 439. The validation study demonstrated that LbL-3D Skin has proven to be a robust and reliable method for predicting skin irritation.


Assuntos
Irritantes , Testes de Irritação da Pele , Humanos , Animais , Reprodutibilidade dos Testes , Testes de Irritação da Pele/métodos , Irritantes/toxicidade , Pele , Epiderme , Técnicas In Vitro , Alternativas aos Testes com Animais
3.
Chem Soc Rev ; 51(2): 464-484, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-34985082

RESUMO

In the last two decades, the field of metal-organic frameworks (MOFs) has exploded, and MOF nanoparticles in particular are being investigated with increasing interest for various applications, including gas storage and separation, water harvesting, catalysis, energy conversion and storage, sensing, diagnosis, therapy, and theranostics. To further pave their way into real-world applications, and to push the synthesis of MOF nanoparticles that are 'safe-and-sustainable-by-design', this tutorial review aims to shed light on the importance of a systematic toxicity assessment. After clarifying and working out the most important terms and aspects from the field of nanotoxicity, the current state-of-the-art of in vitro and in vivo toxicity studies of MOF nanoparticles is evaluated. Moreover, the key aspects affecting the toxicity of MOF nanoparticles such as their chemical composition, their physico-chemical properties, including their colloidal and chemical stability, are discussed. We highlight the need of more targeted synthesis of MOF nanoparticles that are 'safe-and-sustainable-by-design', and their tailored hazard assessment in the context of their potential applications in order to tap the full potential of this versatile material class in the future.


Assuntos
Estruturas Metalorgânicas , Nanopartículas , Catálise , Estruturas Metalorgânicas/toxicidade , Nanopartículas/toxicidade
4.
Bioconjug Chem ; 32(4): 782-793, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33797231

RESUMO

A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.


Assuntos
Desoxicitidina/análogos & derivados , Lipídeos/química , Nanopartículas/química , Pró-Fármacos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Coloides/química , Desoxicitidina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Difração de Pó , Pró-Fármacos/síntese química , Gencitabina
5.
Nanomedicine ; 35: 102404, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33932593

RESUMO

Intracellular distribution of doxorubicin (DOX) and its squalenoylated (SQ-DOX) nanoparticles (NPs) form in murine lung carcinoma M109 and human breast carcinoma MDA-MB-231 cells was investigated by Raman microspectroscopy. Pharmacological data showed that DOX induced higher cytotoxic effect than SQ-DOX NPs. Raman data were obtained using single-point measurements and imaging on the whole cell areas. These data showed that after DOX treatment at 1 µM, the spectral features of DOX were not detected in the M109 cell cytoplasm and nucleus. However, the intracellular distribution of SQ-DOX NPs was higher than DOX in the same conditions. In addition, SQ-DOX NPs were localized into both cell cytoplasm and nucleus. After 5 µM treatment, Raman bands of DOX at 1211 and 1241 cm-1 were detected in the nucleus. Moreover, the intensity ratio of these bands decreased, indicating DOX intercalation into DNA. However, after treatment with SQ-DOX NPs, the intensity of these Raman bands increased. Interestingly, with SQ-DOX NPs, the intensity of 1210/1241 cm-1 ratio was higher suggesting a lower fraction of intercalated DOX in DNA and higher amount of non-hydrolyzed SQ-DOX. Raman imaging data confirm this subcellular localization of these drugs in both M109 and MDA-MB-231 cells. These finding brings new insights to the cellular characterization of anticancer drugs at the molecular level, particularly in the field of nanomedicine.


Assuntos
Neoplasias da Mama , Doxorrubicina , Neoplasias Pulmonares , Nanopartículas , Análise de Célula Única , Esqualeno , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Análise Espectral Raman , Esqualeno/química , Esqualeno/farmacocinética , Esqualeno/farmacologia
6.
Bull Acad Natl Med ; 205(7): 694-702, 2021 Aug.
Artigo em Francês | MEDLINE | ID: mdl-34092797

RESUMO

The COVID-19 pandemic occurred in the context of a dramatic decline in support for biological and health research in France. An analysis of resources allocated to this sector shows that the credits in 2020 correspond to only 17.2 % of the total credits allocated to research, the lowest ratio inat least 15 years. Another weakness in the system of support for hospital research is the way funds from the health insurance system are allocated. To bring it into line with international best practices, the task of allocating these funds should be entrusted to a "Hospital Research Orientation Council", which should also be involved in the implementation of national research programming. Another article deals with the organization of research. Recommendations are also made to improve the functioning of the research system at the local level, particularly in university hospitals, and at the national level.

7.
Nanomedicine ; 24: 102125, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31751769

RESUMO

Drug delivery systems are promising for targeting antibiotics directly to infected tissues. To reach intracellular Staphylococcus aureus and Mycobacterium abscessus, we encapsulated clarithromycin in PLGA nanocapsules, suitable for aerosol delivery by nebulization of an aqueous dispersion. Compared to the same dose of free clarithromycin, nanoencapsulation reduced 1000 times the number of intracellular S. aureus in vitro. In RAW cells, while untreated S. aureus was located in acidic compartments, the treated ones were mostly situated in non-acidic compartments. Clarithromycin-nanocapsules were also effective against M. abscessus (70-80% killing efficacy). The activity of clarithromycin-nanocapsules against S. aureus was also confirmed in vivo, using a murine wound model as well as in zebrafish. The permeability of clarithromycin-nanocapsules across Calu-3 monolayers increased in comparison to the free drug, suggesting an improved delivery to sub-epithelial tissues. Thus, clarithromycin-nanocapsules are a promising strategy to target intracellular S. aureus and M. abscessus.


Assuntos
Claritromicina , Portadores de Fármacos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/crescimento & desenvolvimento , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/crescimento & desenvolvimento , Animais , Cápsulas , Claritromicina/química , Claritromicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Camundongos , Infecções por Mycobacterium não Tuberculosas/metabolismo , Infecções por Mycobacterium não Tuberculosas/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Células RAW 264.7 , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/patologia , Peixe-Zebra
8.
Molecules ; 25(6)2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32213875

RESUMO

Nanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)-palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low temperature in water without any organic co-solvent. Combined with an improved one-step synthesis of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of 4'-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional group tolerance.


Assuntos
Aminoácidos/química , Calixarenos/química , Nanopartículas/química , Paládio/química , Água/química , Catálise
9.
Angew Chem Int Ed Engl ; 59(26): 10292-10296, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32243047

RESUMO

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Nanopartículas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Tobramicina/farmacologia , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/toxicidade , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Muco/microbiologia , Nanopartículas/toxicidade , Pseudomonas aeruginosa/fisiologia , Quinolonas/farmacologia , Esqualeno/análogos & derivados , Esqualeno/toxicidade , Ésteres do Ácido Sulfúrico/química , Ésteres do Ácido Sulfúrico/toxicidade , Peixe-Zebra
10.
J Pharmacol Exp Ther ; 370(3): 625-635, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30635473

RESUMO

Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131- metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albumin-bound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanotecnologia/tendências , Neuroblastoma/tratamento farmacológico , Animais , Humanos
11.
J Pharmacol Exp Ther ; 369(1): 144-151, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30670479

RESUMO

Adenosine receptors (ARs) represent key drug targets in many human pathologies, including cardiovascular, neurologic, and inflammatory diseases. To overcome the very rapid metabolization of adenosine, metabolically stable AR agonists and antagonists were developed. However, few of these molecules have reached the market due to efficacy and safety issues. Conjugation of adenosine to squalene to form squalene-adenosine (SQAd) nanoparticles (NPs) dramatically improved the pharmacological efficacy of adenosine, especially for neuroprotection in stroke and spinal cord injury. However, the mechanism by which SQAd NPs displayed therapeutic activity remained totally unknown. In the present study, two hypotheses were discussed: 1) SQAd bioconjugates, which constitute the NP building blocks, act directly as AR ligands; or 2) adenosine, once released from intracellularly processed SQAd NPs, interacts with these receptors. The first hypothesis was rejected, using radioligand displacement assays, as no binding to human ARs was detected, up to 100 µM SQAd, in the presence of plasma. Hence, the second hypothesis was examined. SQAd NPs uptake by HepG2 cells, which was followed using radioactive and fluorescence tagging, was found to be independent of equilibrative nucleoside transporters but rather mediated by low-density lipoprotein receptors. Interestingly, it was observed that after cell internalization, SQAd NPs operated as an intracellular reservoir of adenosine, followed by a sustained release of the nucleoside in the extracellular medium. This resulted in a final paracrine-like activation of the AR pathway, evidenced by fluctuations of the second messenger cAMP. This deeper understanding of the SQAd NPs mechanism of action provides a strong rational for extending the pharmaceutical use of this nanoformulation.


Assuntos
Adenosina/química , Adenosina/metabolismo , Nanopartículas/química , Pró-Fármacos/metabolismo , Receptores Purinérgicos P1/metabolismo , Esqualeno/química , Esqualeno/metabolismo , Animais , Transporte Biológico , Células CHO , Cricetulus , Espaço Extracelular/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Ligantes
12.
Biomacromolecules ; 20(7): 2464-2476, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31150219

RESUMO

" Drug-initiated" nitroxide-mediated synthesis of two well-defined, heterotelechelic polymer prodrugs ( Mn = 1960-5260 g·mol-1, D = 1.31-1.37) was performed by using the newly developed nitroxide exchange reaction. These polymers comprised, at the chain end, gemcitabine (Gem) as anticancer drug and either cyanine 7.5 (Cy7.5) as a near-infrared (NIR) dye suitable for in vivo imaging or biotin (Biot) for cancer cell targeting. These materials were co-nanoprecipitated into fluorescently labeled polymer prodrug nanoparticles of average diameter in the 100-180 nm range with narrow particle size distribution and variable surface amounts of biotin. Nanoparticles containing 15 wt % biotinylated polymer showed superior uptake and the highest cytotoxicity in vitro on A549 human lung cancer cells. In vivo, on A549 tumor bearing mice, biotinylated nanoparticles showed significantly higher efficacy than free Gem and maintained the same anticancer activity than nontargeted nanoparticles without inducing prohibitive body weight loss. Biotinylated polymer prodrug nanoparticles did not result in an improved anticancer activity or significant increase in tumor accumulation, which may be the result of a nonoptimal biotin surface display and/or insufficient affinity toward the target. They however displayed delayed liver accumulation compared to nonbiotinylated counterparts, suggesting the premise of a stealth property likely due to the hydrophilic tetraethylene glycol-Biot positioned at the nanoparticle surface. This work showed for the first time the applicability of this simple construction method to in vivo imaging and cancer cell targeting and might stimulate the design of new functional materials for biomedical applications.


Assuntos
Antineoplásicos , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares , Nanopartículas , Imagem Óptica , Pró-Fármacos , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Desoxicitidina/química , Desoxicitidina/farmacologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Gencitabina
13.
Small ; 14(40): e1801900, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30091524

RESUMO

Controlling the outer surface of nanometric metal-organic frameworks (nanoMOFs) and further understanding the in vivo effect of the coated material are crucial for the convenient biomedical applications of MOFs. However, in most studies, the surface modification protocol is often associated with significant toxicity and/or lack of selectivity. As an alternative, how the highly selective and general grafting GraftFast method leads, through a green and simple process, to the successful attachment of multifunctional biopolymers (polyethylene glycol (PEG) and hyaluronic acid) on the external surface of nanoMOFs is reported. In particular, effectively PEGylated iron trimesate MIL-100(Fe) nanoparticles (NPs) exhibit suitable grafting stability and superior chemical and colloidal stability in different biofluids, while conserving full porosity and allowing the adsorption of bioactive molecules (cosmetic and antitumor agents). Furthermore, the nature of the MOF-PEG interaction is deeply investigated using high-resolution soft X-ray spectroscopy. Finally, a cell penetration study using the radio-labeled antitumor agent gemcitabine monophosphate (3 H-GMP)-loaded MIL-100(Fe)@PEG NPs shows reduced macrophage phagocytosis, confirming a significant in vitro PEG furtiveness.

14.
Bioconjug Chem ; 29(6): 1961-1972, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29727181

RESUMO

The aim of the present study is to take advantage of the unique property of polyisoprenoid chains to adopt a compact molecular conformation and to use these natural and biocompatible lipids as nanocarriers of drugs to deliver siRNA. A new chemical strategy is applied here to conjugate squalene (SQ) and solanesol (SOLA) to siRNA consisting of an activated variant of the azide-alkyne Huisgen cycloaddition also known as copper-free (Cu-free) click chemistry. We conjugated siRNA against TMPRSS2-ERG, a fusion oncogene found in more than 50% of prostate cancers to SQ or SOLA. First, several parameters such as molar ratio, solvents, temperature, incubation time, and the annealing schedule between both siRNA strands were investigated to bioconjugate the SQ or SOLA via Cu-free click chemistry. The best parameters of the new bioconjugation approach allowed us to (i) increase the synthesis yield up to 95%, (ii) avoid the formation of byproducts during the synthesis, and (iii) improve the reproducibility of the bioconjugation. Then, the biological activity of the resulting nanoparticles was assessed. In vitro, all four formulations were able to decrease the corresponding oncogene and oncoprotein expression. In vivo, only two of the four nanoformulations showed anti-neoplastic activity that seems to be tightly related to their dissimilar biodistribution behavior. In conclusion, we performed a new approach easily transposable for pharmaceutical development to synthesize siRNA-SQ and siRNA-SOLA and to obtain efficient siRNA-nanoparticles. The robustness of the process could be extended to several other polyterpenes and likely applied to other siRNA targeting genes whose overexpression results in the development of cancers or other genetic diseases.


Assuntos
Química Click , Neoplasias/terapia , Oligonucleotídeos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi , Alcinos/química , Animais , Azidas/química , Linhagem Celular Tumoral , Química Click/métodos , Reação de Cicloadição/métodos , Humanos , Camundongos SCID , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/genética , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/uso terapêutico , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos , Esqualeno/química , Terpenos/química
15.
Mol Pharm ; 15(2): 585-591, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29298487

RESUMO

We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of docking simulations. It is shown that HSA could also act as a passive carrier of this bioconjugate. It should be noted that the binding of squalene moiety to HSA was unspecific and did not occur in the binding pockets devoted to fatty acids.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Lipoproteínas LDL/química , Albumina Sérica Humana/química , Esqualeno/química , Adenina/administração & dosagem , Adenina/química , Sítios de Ligação , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nanopartículas/química , Ligação Proteica , Albumina Sérica Humana/metabolismo , Gencitabina
16.
Mol Ther ; 25(7): 1596-1605, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28606375

RESUMO

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo.


Assuntos
Adenocarcinoma/terapia , Neoplasias da Mama/terapia , Regulação Neoplásica da Expressão Gênica , Lipoproteínas LDL/metabolismo , Nanopartículas/administração & dosagem , Receptores de LDL/genética , Esqualeno/química , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Portadores de Fármacos , Feminino , Humanos , Lipoproteínas LDL/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos SCID , Nanopartículas/química , Receptores de LDL/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
17.
Nanomedicine ; 14(2): 609-618, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248676

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-ß peptide (Aß) and especially the Aß peptide 1-42 (Aß1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aß1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aß1-42. Treatment of AD-like transgenic mice with anti-Aß1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aß soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aß levels in plasma. This study represents the first example of Aß1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.


Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/química , Modelos Animais de Doenças , Transtornos da Memória/terapia , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Animais , Anticorpos Monoclonais/imunologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/metabolismo , Polímeros/química , Polímeros/metabolismo , Recuperação de Função Fisiológica
18.
Proc Natl Acad Sci U S A ; 111(2): E217-26, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24385587

RESUMO

We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol's biosynthesis, led to the formation of squalenoyl doxorubicin (SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original "loop-train" structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy, compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a fivefold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions, such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug's therapeutic index.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Conformação Molecular , Nanomedicina/métodos , Esqualeno/química , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Microscopia Crioeletrônica , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Feminino , Fluorescência , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Ratos , Esqualeno/metabolismo , Troponina T/sangue
19.
J Microencapsul ; 34(7): 659-666, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28862080

RESUMO

The blood-brain barrier (BBB) is the major problem for the treatment of central nervous system diseases. A previous study from our group showed that the brain-targeted chitosan nanoparticles-loaded with large peptide moieties can rapidly cross the barrier and provide neuroprotection. The present study aims to determine the efficacy of the brain-targeted chitosan nanoparticles' uptake by the human BBB cerebral microvessel endothelial cells (hCMECs) and to investigate the underlying mechanisms for enhanced cellular entry. Fluorescently labelled nanoparticles either conjugated with antibodies recognising human transferrin receptor (anti-TfR mAb) or not were prepared, characterised and their interaction with cerebral endothelial cells was evaluated. The antibody decoration of chitosan nanoparticles significantly increased their entry into hCMEC/D3 cell line. Inhibition of cellular uptake by chlorpromazine indicated that the anti-TfR mAb-conjugated nanoparticles were preferentially cell internalised through receptor-mediated endocytosis pathway. Alternatively, as primarily observed with control chitosan nanoparticles, aggregation of nanoparticles may also have induced macropinocytosis.


Assuntos
Barreira Hematoencefálica , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Quitosana/administração & dosagem , Microvasos/efeitos dos fármacos , Nanopartículas , Anticorpos Monoclonais/imunologia , Corantes Fluorescentes , Humanos , Microvasos/metabolismo , Receptores da Transferrina/imunologia , Receptores da Transferrina/metabolismo
20.
Angew Chem Int Ed Engl ; 56(49): 15565-15569, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-28960750

RESUMO

Despite high morbidity and mortality associated with lung diseases, addressing drugs towards lung tissue remains a pending task. Particle lung filtration has been proposed for passive lung targeting and drug delivery. However, toxicity issues derived from the long-term presence of the particles must be overcome. By exploiting some of the ignored properties of nanosized metal-organic frameworks it is possible to achieve impressive antitumoral effects on experimental lung tumors, even without the need to engineer the surface of the material. In fact, it was discovered that, based on unique pH-responsiveness and reversible aggregation behaviors, nanoMOF was capable of targeting lung tissue. At the neutral pH of the blood, the nanoMOFs form aggregates with the adequate size to be retained in lung capillaries. Within 24 h they then disaggregate and release their drug payload. This phenomenon was compatible with lung tissue physiology.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Estruturas Metalorgânicas/farmacologia , Nanoestruturas/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Estruturas Metalorgânicas/química , Tamanho da Partícula , Propriedades de Superfície
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