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Multidrug resistance (MDR) is the main challenge in cancer treatment. In this sense, we designed transferrin (Tf)-conjugated PLGA nanoparticles (NPs) containing an organoselenium compound as an alternative to enhance the efficacy of cancer therapy and sensitize MDR tumor cells. Cytotoxicity studies were performed on different sensitive tumor cell lines and on an MDR tumor cell line, and the Tf-conjugated NPs presented significantly higher antiproliferative activity than the nontargeted counterparts in all tested cell lines. Due to the promising antitumor activity of the Tf-decorated NPs, further studies were performed using the MDR cells (NCI/ADR-RES cell line) comparatively to one sensitive cell line (HeLa). The cytotoxicity of NPs was evaluated in 3D tumor spheroids and, similarly to the results achieved in the 2D assays, the Tf-conjugated NPs were more effective at reducing the spheroid's growth. The targeted Tf-NPs were also able to inhibit tumor cell migration, presented a higher cell internalization and induced a greater number of apoptotic events in both cell lines. Therefore, these findings evidenced the advantages of Tf-decorated NPs over the nontargeted counterparts, with the Tf-conjugated NPs containing an organoselenium compound representing a promising drug delivery system to overcome MDR and enhance the efficacy of cancer therapy.
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Nanotechnology has assumed a significant role over the last decade in the development of various technologies applied to health sciences. This becomes even more evident with its application in controlled drug delivery systems. In this context, peptoids are a promising class of compounds for application as nanocarriers in drug delivery systems. These compounds can be obtained efficiently and with highly functionalized structural diversity via the Ugi 4-component reaction (U-4CR). Herein, we report the design of the process control strategy for the future development of lipid-peptoid-based customized drug delivery system assemblies. Over 20 lipid-peptoid nanocomposites were synthesized via the U-4CR in good to excellent yields. These products were successfully submitted to the nanoparticle formation by the emulsification-evaporation process from lipophilic solution and analyzed via Dynamic Light Scattering (DLS). Several molecules generated nanoparticles with a size ≤200 nm, making them good candidates for drug delivery systems, such as in cancer treatment.
Assuntos
Nanocompostos , Nanopartículas , Peptoides , Peptoides/química , Sistemas de Liberação de Medicamentos , LipídeosRESUMO
Overview: Malignant brain tumors remain one of the greatest challenges faced by health professionals and scientists among the utmost lethal forms of cancer. Nanotheranostics can play a pivotal role in developing revolutionary nanoarchitectures with multifunctional and multimodal capabilities to fight cancer. Mitochondria are vital organelles to eukaryotic cells, which have been recognized as a significant target in cancer therapy where, by damaging the mitochondria, it will cause irreparable cell death or apoptosis. Methods: We designed and produced novel hybrid nanostructures comprising a fluorescent semiconductor core (AgInS2, AIS) and cysteine-modified carboxymethylcellulose (termed thiomer, CMC_Cys) conjugated with mitochondria-targeting peptides (KLA) forming a macromolecular shell for combining bioimaging and for inducing brain cancer cell (U-87 MG) death. Results: The optical and physicochemical properties of the nanoconjugates demonstrated suitability as photoluminescent nanostructures for cell bioimaging and intracellular tracking. Additionally, the results proved a remarkable killing activity towards glioblastoma cells of cysteine-bearing CMC conjugates coupled with KLA peptides through the half-maximal effective concentration values, approximately 70-fold higher compared to the conjugate analogs without Cys residues. Moreover, these thiomer-based pro-apoptotic drug nanoconjugates displayed higher lethality against U-87 MG cancer cells than doxorubicin, a model drug in chemotherapy, although extremely toxic. Remarkably, these peptidomimetic nanohybrids demonstrated a relative "protective effect" regarding healthy cells while maintaining high killing activity towards malignant brain cells. Conclusion: These findings pave the way for developing hybrid nanoarchitectures applied as targeted multifunctional platforms for simultaneous imaging and therapy against cancer while minimizing the high systemic toxicity and side-effects of conventional drugs in anticancer chemotherapy.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Corantes Fluorescentes/química , Mitocôndrias/efeitos dos fármacos , Nanotecnologia , Peptidomiméticos , Medicina de Precisão/métodos , Linhagem Celular Tumoral , HumanosRESUMO
Iron transport in the central nervous system (CNS) is a highly regulated process in which several important proteins participate to ensure this important metal reaches its sites of action. However, iron accumulation has been shown to be a common factor in different neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple Sclerosis, and Sanfilippo syndrome. This review is divided into four parts. The first part describes brain iron transport in homeostasis, mentioning the main proteins involved, whereas the second part contrasts the consequences of iron dysregulation, elaborating on its role in the aforementioned neurodegenerative diseases. The third part details the functions of the main proteins involved in brain iron homeostasis and their role in neurodegeneration. In the fourth part, in order to highlight the importance of transport proteins, the focus is set on human serum transferrin, the main iron transport protein. This final part describes perspectives about the mechanisms and chemical properties of human transferrin for the development of potential targeted drug delivery systems across the blood-brain barrier (BBB) or enhancers for the treatment of neurological diseases.
Assuntos
Barreira Hematoencefálica/metabolismo , Ferro/metabolismo , Doenças Neurodegenerativas/metabolismo , Transferrinas/metabolismo , Animais , Transporte Biológico , Barreira Hematoencefálica/patologia , Humanos , Doenças Neurodegenerativas/patologiaRESUMO
Natural polymer-based hybrid nanocomposites have been proposed as one of the most promising tools for biomedical applications, including disease treatment and diagnosis procedures. Xyloglucan nanocapsules can simultaneously load magnetic iron oxide nanoparticles and bioactive for a specific tissue, reducing the processes of degradation and metabolic inactivation of molecules with biological activity. In this work, magnetic nanocapsules of xyloglucan loaded with hydrophilic sulfated quercetin (MNXQ_SO3) were successfully synthesized by inverse miniemulsion process through interfacial polymerization. The polymeric shell formation of nanocapsules was evidenced by Fourier Transform Infrared spectroscopy and Transmission Electron Microscopy. The ferrofluid (Fe3O4@PAAS) incorporated into the xyloglucan nanocapsules was synthesized by hydrothermal method, using polyacrylic acid sodium salt as coating. Dynamic Light Scattering technique confirmed the nanomeric dimensions (202.3 nm) and the good colloidal stability (-40.2 mV) of MNXQ_SO3. The saturation magnetization analyses pointed out the superparamagnetic behavior of Fe3O4@PAAS (48 emu/g) and MNXQ_SO3 (4.2 emu/g). MNXQ_SO3 was able to modify the release profile of sulfated quercetin (67%) when compared to the free bioactive (100%), exhibiting a release profile compatible with the zero-order kinetic model. The results showed that the development of MNXQ_SO3 presents a new perspective for biomedical applications, including studies of targeted drug delivery.
Assuntos
Glucanos/química , Quercetina/síntese química , Sulfetos/química , Xilanos/química , Sistemas de Liberação de Medicamentos , Difusão Dinâmica da Luz , Cinética , Nanopartículas de Magnetita , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Quercetina/química , Quercetina/farmacologia , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A facile approach was developed to synthesize an innovative hyaluronic acid-modified carbon dot-doxorubicin nanoparticles drug delivery platform. CD44 targeted HA-modified carbon dots (HA-CDs) were synthesized as carrier by one-step hydrothermal treatment within one hour with citric acid and branch-PEI as core carbon source. HA not only functioned as carbon dot component but also as hydrophilic group and targeting ligand of this system. The as-prepared HA-CDs were then loaded with doxorubicin (HA-CD@p-CBA-DOX) via an acid-cleavable bond, which released drug in a pH-responsive manner. In in vitro experiments, HA-CD@p-CBA-DOX displayed good hemocompatibility and serum stability, while exhibited high cytotoxicity on 4T1 cells. The confocal laser scanning microscopy and flow cytometry results demonstrated that DOX-loaded nanoparticles were internalized by 4T1 cells via HA-mediated CD44-targeting effect. The enhanced in vivo tumor accumulation of HA-CD@p-CBA-DOX was testified by live imaging. Compared with free DOX, superior in vivo anti-tumor efficacy of HA-CD@p-CBA-DOX was observed in both heterotopic and orthotopic 4T1 cell tumor models. Furthermore, blood hematology and blood biochemistry analysis demonstrated that HA-CD@p-CBA-DOX did not induce noticeable toxicity, which further confirmed the good biocompatibility of HA-CD@p-CBA-DOX. The formulated HA-CD@p-CBA-DOX provides an alternative strategy for targeted breast cancer therapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carbono/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Nanopartículas/química , Animais , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Tecidual/fisiologiaRESUMO
The necessity to develop more efficient, biocompatible, patient compliance, and safer treatments in biomedical settings is receiving special attention using nanotechnology as a potential platform to design new drug delivery systems (DDS). Despite the broad range of nanocarrier systems in drug delivery, lack of biocompatibility, poor penetration, low entrapment efficiency, and toxicity are significant challenges that remain to address. Such practices are even more demanding when bioactive agents are intended to be loaded on a nanocarrier system, especially for topical treatment purposes. For the aforesaid reasons, the search for more efficient nano-vesicular systems, such as nanoliposomes, with a high biocompatibility index and controlled releases has increased considerably in the past few decades. Owing to the stratum corneum layer barrier of the skin, the in-practice conventional/conformist drug delivery methods are inefficient, and the effect of the administered therapeutic cues is limited. The current advancement at the nanoscale has transformed the drug delivery sector. Nanoliposomes, as robust nanocarriers, are becoming popular for biomedical applications because of safety, patient compliance, and quick action. Herein, we reviewed state-of-the-art nanoliposomes as a smart and sophisticated drug delivery approach. Following a brief introduction, the drug delivery mechanism of nanoliposomes is discussed with suitable examples for the treatment of numerous diseases with a brief emphasis on fungal infections. The latter half of the work is focused on the applied perspective and clinical translation of nanoliposomes. Furthermore, a detailed overview of clinical applications and future perspectives has been included in this review.
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A novel targeted drug delivery nanoparticle system based on poly(D,L-lactide-co-glycolide) acid (PLGA) for delivery of doxorubicin (DOX) was developed. DOX-PLGA NPs were obtained by the emulsification-solvent evaporation technique. Then, their surface was modified with poly(L-γ-glutamic acid) (γ-PGA) and finally conjugated to modified folic acid (FA) as a targeting ligand. The surface modification and FA conjugation were followed by UV-Vis and FT-IR spectroscopies. Morphology was observed by TEM/SEM. Particle size, PDI and zeta potential were measured using DLS studies. Encapsulation and loading efficiencies, and DOX release kinetics were determined. Specific uptake and cell viability of DOX-PLGA/γ-PGA-FA NPs were tested in HeLa cells. Quasi-spherical nanoparticles with a particle size lower than 600nm (DLS) were obtained. Spectroscopic techniques demonstrated the successful surface modification with γ-PGA and FA conjugation. Release profile of DOX-PLGA/γ-PGA-FA NPs showed a release of 55.4±0.6% after seven days, in an acidic environment. HeLa cells exhibited a decrease in viability when treated with DOX-PLGA/γ-PGA-AF NPs, and cellular uptake was attributed to FA receptor-mediated endocytosis. These results suggest that DOX-PLGA/γ-PGA-FA NPs are a potential targeted drug carrier for further applications in cancer therapy.
Assuntos
Nanopartículas , Doxorrubicina , Portadores de Fármacos , Ácido Fólico , Ácido Glutâmico , Humanos , Ácido Láctico , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX) into immunoliposomes where the human epidermal growth factor receptor 2 (HER2) antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR), and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly delayed in the combinational liposomal drug delivery group. This novel combinational therapy has great potential for the treatment of patients with HER2/MDR double positive breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fluorescência , Humanos , Lipossomos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacosRESUMO
A lot of effort has been devoted to achieving active targeting for cancer therapy in order to reach the right cells. Hence, increasingly it is being realized that active-targeted nanocarriers notably reduce off-target effects, mainly because of targeted localization in tumors and active cellular uptake. In this context, by taking advantage of the overexpression of transferrin receptors on the surface of tumor cells, transferrin-conjugated nanodevices have been designed, in hope that the biomarker grafting would help to maximize the therapeutic benefit and to minimize the side effects. Notably, active targeting nanoparticles have shown improved therapeutic performances in different tumor models as compared to their passive targeting counterparts. In this review, current development of nano-based devices conjugated with transferrin for active tumor-targeting drug delivery are highlighted and discussed. The main objective of this review is to provide a summary of the vast types of nanomaterials that have been used to deliver different chemotherapeutics into tumor cells, and to ultimately evaluate the progression on the strategies for cancer therapy in view of the future research.
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Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Receptores da Transferrina/antagonistas & inibidores , Transferrina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Nanotecnologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores da Transferrina/biossíntese , Transferrina/síntese química , Transferrina/químicaRESUMO
Cell backpacks, or micron-scale patches of a few hundred nanometers in thickness fabricated by layer-by-layer (LbL) assembly, are potentially useful vehicles for targeted drug delivery on the cellular level. In this work, echogenic liposomes (ELIPs) containing the anticancer drug doxorubicin (DOX) are embedded into backpacks through electrostatic interactions and LbL assembly. Poly(allylamine hydrochloride)/poly(acrylic acid) (PAH/PAA)n , and poly(diallyldimethylammonium chloride)/poly(styrene sulfonate) (PDAC/SPS)n film systems show the greatest ELIP incorporation of the films studied while maintaining the structural integrity of the vesicles. The use of ELIPs for drug encapsulation into backpacks facilitates up to three times greater DOX loading compared to backpacks without ELIPs. Cytotoxicity studies reveal that monocyte backpack conjugates remain viable even after 72 h, demonstrating promise as drug delivery vehicles. Because artificial vesicles can load many different types of drugs, ELIP containing backpacks offer a unique versatility for broadening the range of possible applications for cell backpacks.
Assuntos
Lipossomos/farmacologia , Monócitos/citologia , Animais , Cátions , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Recuperação de Fluorescência Após Fotodegradação , Lipossomos/ultraestrutura , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da PartículaRESUMO
Paclitaxel (PTX) is widely used as a first-line treatment for patients with metastatic breast cancer; however, its poor water solubility represents a major challenge for parenteral administration. The encapsulation of the PTX in drug-delivery systems with high affinity for tumor sites could improve the uptake and increase its therapeutic efficacy. In this work, long-circulating and pH-sensitive PEG-coated (SpHL-PTX) and PEG-folate-coated liposomes containing PTX (SpHL-FT-PTX) were prepared, and the physicochemical properties and in vitro cytotoxic activity were evaluated. Both formulations presented adequate physicochemical properties, including a mean diameter smaller than 200 nm, zeta potential values near the neutral range, and an encapsulation percentage higher than 93%. Moreover, SpHL-FT-PTX showed a good stability after storage for 100 days at 4 °C. The viability studies on breast cancer cell lines (MDA-MB-231 and MCF-7) demonstrated cytotoxic activity more pronounced for SpHL-FT-PTX than for SpHL-PTX or free drug for both tumor cell lines. This activity was reduced to a rate comparable to SpHL-PTX when the cells were previously treated with folic acid in order to saturate the receptors. In contrast, in the normal cell line (L929), cell viability was decreased only by free or liposomal PTX in the highest concentrations. A significantly higher selectivity index was obtained after SpHL-FT-PTX treatment compared to SpHL-PTX and free PTX. Therefore, the results of the present work suggest that SpHL-FT-PTX can be a promising formulation for the treatment of metastatic breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Lipídeos/administração & dosagem , Lipossomos , Paclitaxel/uso terapêutico , HumanosRESUMO
In this study, the methotrexate (MTX) was incorporated into the poly(ε-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4 days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-α and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Preparações de Ação Retardada/química , Metotrexato/administração & dosagem , Poliésteres/química , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Colágeno/análise , Citocinas/análise , Sistemas de Liberação de Medicamentos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/tratamento farmacológico , Próteses e ImplantesRESUMO
In this study, the methotrexate (MTX) was incorporated into the poly(e-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-a and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3731-3742, 2015.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Metotrexato/administração & dosagem , Poliésteres/química , Acetilglucosaminidase/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Proliferação de Células , Colágeno/química , Sistemas de Liberação de Medicamentos , Implantes de Medicamento , Liberação Controlada de Fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Metotrexato/farmacologia , Metotrexato/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/tratamento farmacológico , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Tecidual , Fator de Necrose Tumoral alfa/metabolismoRESUMO
O objetivo geral deste trabalho foi explorar a versatilidade de filmes multicamadas de polieletrólitos (PEM) e suas aplicações em sistemas de entrega de drogas e como filmes funcionais para aplicações biomédicas. Filmes PEM montados pela técnica de camada por camada (layer-by-layer, LbL), foram explorados em três aplicações principais. Na primeira, foi explorado o desenvolvimento de um protocolo de funcionalização em filmes de poli(alilamina)/poli (estireno sulfonato), PAH/SPS. Os parâmetros de construção do filme para biotinilação dos grupamentos amina do PAH foram otimizados e aplicados na captura e detecção do antígeno específico da próstata (PSA), na concentração de 100 a 0,1 ng/mL, usando pontos quânticos (Qdots). Em comparação com outros trabalhos, este sistema apresentou uma boa sensibilidade na detecção de PSA, dentro do limite de detecção clínica de 0,4 a 0,1 ng/mL. A segunda aplicação envolveu o desenvolvimento de filmes de sacrifício baseados nas interações naturais da mucina submandibular bovina e da lectina, jacalina (BSM/JAC). Filmes de BSM/JAC apresentaram estabilidade quando submetidos a uma ampla faixa de pH (pH 3--9) e em solução de alta força iônica (5 M NaCl). A dissolução dos filmes BSM/JAC pôde ser seletivamente desencadeada mediante à incubação em solução de melibiose, 37 °C, pH 7,4, sem apresentar citotoxicidade às células. Na última parte deste trabalho, a incorporação de lipossomos ecogênicos (ELIP) em mochilas celulares foi investigada. Mochilas celulares são "patches" de 7-10 µm de diâmetro que podem ser fabricados por meio de deposição alternada de polímeros utilizando--se a técnica de LbL, sobre uma matriz pré-moldada obtida por fotolitografia, a fim de criar um sistema composto por três multicamadas estratificadas: uma região de liberação, para promover o destacamento do substrato, uma região de carga de droga, e uma região adesiva às células. O uso de ELIP permitiu incorporação de até 9x mais doxorrubicina (DOX) se comparado com o fármaco livre em solução absorvido pelos dos filmes. A liberação de DOX pelos filmes foi monitorado por 25 dias. Mochilas contendo ELIP-DOX foram então aderidos a monócitos, e sua viabilidade monitorados por 72h. Mochilas vazias mostraram diminuir a proliferação de monócitos ao longo das 72 horas, enquanto mochilas carregadas com ELIP-DOX mostraram uma diminuição dramática na população celular, apontando uma potencialização dos efeitos da droga pela sua proximidade com as células
The overall goal of this thesis was to exploit the versatility of polyelectrolite multilayers (PEM) to be applied in drug delivery systems and biofunctionalizable films for biomedical applications. PEM films assembled by the layer-by-layer technique were explored in three main applications. In the first part of this work, the development of a functionalization protocol of poly(allylamine)/poly(styrene sulfonate), PAH/SPS was explored. The optimal film parameters to the use of biotinylated multilayers were applied for the capture and detection of prostate specific antigen (PSA) protein in the range of 100 to 0.1 ng/mL, by using quantum dots. Compared to previous work, this system presented a good sensitivity for PSA detection that is within the clinical limit range of 0.4 to 0.1 ng/mL. The second application involved the creation of a novel sacrificial multilayer film. Films based in natural interactions of bovine submaxillary mucin and the lectin jacalin, BSM/JAC were assembled. BSM/JAC films showed stability when underwent a wide rage of pH (pH 3 to 9) and high ionic strength (5 M NaCl) solutions. BSM/JAC dissolution could be triggered released by incubation in melibiose at 37 °C in pH 7.4 buffer, without cytotoxicity. In the last part of this work the incorporation of echogenic liposomes (ELIP) into cell backpacks was investigated. Cell backpacks are 7-10 µm diameter patches that can be fabricated through LbL polymer deposition onto a photopatterned array to create a stacked composite of three stratified multilayer systems: a releasable region for easy detachment from the substrate, a drug payload region, and a cell adhesive region. The use of ELIP allowed up to 9x more doxorubicin (DOX) loading when compared to free drug in solution adsorbed through the films. DOX release from films was monitored for over 25 days. ELIP-DOX backpacks were then attached to mouse monocytes and their viability monitored by 72h. Empty backpacks showed to decrease monocytes proliferation over the course of 72h, while ELIP-DOX backpacks showed a dramatic decrease in cell population, showing that DOX effects were enhancement in drug potency by its proximity
Assuntos
Biotecnologia/métodos , Preparações Farmacêuticas , Biomarcadores/metabolismo , Doxorrubicina/administração & dosagem , Lipossomos , Antígeno Prostático Específico/análise , Medicina RegenerativaRESUMO
Magnetic nanoparticles offer exciting new opportunities including the improvement of the quality of magnetic resonance imaging (MRI), hyperthermic treatment for malignant cells, site-specific drug delivery and also the recent research interest of manipulating cell membranes. The biological applications of these nanomaterials require these nanoparticles to have high magnetization values, size smaller than 20 nm, narrow particle size distribution and a special surface coating for both avoiding toxicity and allowing the coupling of biomolecules. In this review, we focus on the feasibility of radionuclide labeled magnetic nanoparticles, as drug carriers, and summarize recent advances in this field.
Nanopartículas magnéticas oferecem novas oportunidades interessantes, incuindo a melhora da qualidade da imagem de ressonância magnética (MRI), no tratamento hipertérmico para células malignas, na administração de medicamentos sítio-específicos e também no recente interesse da manipulação de membranas celulares. As aplicações biológicas desses nanomateriais requer que essas nanopartículas tenham valores altos de magnetização, tamanho menor que 20 nm, partículas de dimensão de distribuição restrita e um revestimento especial de superfície para evitar a toxicidade e permitir o acoplamento de biomoléculas. Nessa revisão, focalizamos na viabilidade de nanopartículas magnéticas marcadas com radionuclídeos, como transportadoras de medicamentos, e resumimos os recentes avanços nesse campo.