RESUMO
The number of biologics in the therapeutic development pipeline is increasing including those delivered though inhalation (Morales, 2017; Fathe, 2016). Biologics comprise a broad variety of complex macromolecules with unique physicochemical characteristics. These distinctive characteristics control their pharmacological mechanisms of action, stability, and ultimately affect their processing, formulation, and delivery requirements. This review systematically covers crucial aspects of biologic powders formulations and dry powder inhalers which need to be taken into consideration to establish the drug loading and the payload to be delivered to reach the desired clinical dose.
Assuntos
Produtos Biológicos/administração & dosagem , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Administração por Inalação , Animais , Produtos Biológicos/farmacologia , Relação Dose-Resposta a Droga , Inaladores de Pó Seco , HumanosRESUMO
Pseudomonas aeruginosa is an opportunistic bacteria responsible for recurrent lung infections. Previously, we demonstrated that certain materials improved the activity of tobramycin (Tob) against P. aeruginosa biofilms in vitro. We aimed to develop prototype dry powder formulations comprising Tob and a mixture of excipients and test its aerodynamic properties and antimicrobial activity. First, we evaluated different combinations of excipients with Tob in solution against P. aeruginosa biofilms. We selected the compositions with the highest activity, to prepare dry powders by spray drying. The powders were characterized by morphology, bulk density, water content, and particle size distributions. Finally, the antimicrobial activity of the powders was tested. The combinations of Tob (64 µg/mL) with l-alanine and l-proline (at 10 and 20 mM; formulations 1 and 2, respectively) and with l-alanine and succinic acid (at 20 mM; formulation 3) showed the highest efficacies in vitro and were prepared as dry powders. Formulation 1 had the best aerodynamic performance as indicated by the fine particle fraction and the best in vitro activity against P. aeruginosa biofilms. Formulation 3 represents a good candidate for further optimization because it demonstrated good dispersibility potential and optimization of the particle size distribution may achieve high delivery efficiencies.
Assuntos
Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/administração & dosagem , Administração por Inalação , Alanina/química , Antibacterianos/química , Antibacterianos/farmacologia , Dessecação , Composição de Medicamentos , Inaladores de Pó Seco , Excipientes/química , Humanos , Tamanho da Partícula , Pós , Prolina/química , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/fisiologia , Ácido Succínico/química , Tobramicina/química , Tobramicina/farmacologiaRESUMO
With the growing interest in developing biologics for pulmonary delivery, systematic fast screening methods are needed for rapid development of formulations. Due to the labile nature of macromolecules, the development of stable, biologically active formulations with desired aerosol performance imposes several challenges both from a formulation and processing perspective. In this study, spray-freeze-drying was used to develop respirable protein powders. In order to systematically map the selected design space, lysozyme aqueous pre-formulations were prepared based on a constrained mixture design of experiment. The physicochemical properties of the resulting powders were characterized and the effects of formulation factors on aerosol performance and protein stability were systematically screened using a logic flow chart. Our results elucidated several relevant formulation attributes (density, total solid content, protein:sugars ratio) required to achieve a stable lysozyme powder with desirable characteristics for pulmonary delivery. A similar logical fast screening strategy could be used to delineate the appropriate design space for different types of proteins and guide the development of powders with pre-determined aerodynamic properties.
Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Muramidase/química , Administração por Inalação , Aerossóis , Anti-Infecciosos , Estabilidade de Medicamentos , Inaladores de Pó Seco , Liofilização/métodos , Tamanho da Partícula , PósRESUMO
Gap junctions, transmembrane protein channels that directly connect the cytoplasm of neighboring cells and enable the exchange of molecules between cells, are a promising new frontier for therapeutic delivery. Specifically, cell-derived lipid vesicles that contain functional gap junction channels, termed Connectosomes, have recently been demonstrated to substantially increase the effectiveness of small molecule chemotherapeutics. However, because gap junctions are present in nearly all tissues, Connectosomes have no intrinsic ability to target specific cell types, which potentially limits their therapeutic effectiveness. To address this challenge, here we display targeting ligands consisting of single-domain antibodies on the surfaces of Connectosomes. We demonstrate that these targeted Connectosomes selectively interact with cells that express a model receptor, promoting the selective delivery of the chemotherapeutic doxorubicin to this target cell population. More generally, our approach has the potential to boost cytoplasmic delivery of diverse therapeutic molecules to specific cell populations while protecting off-target cells, a critical step toward realizing the therapeutic potential of gap junctions.
Assuntos
Anticorpos Imobilizados/metabolismo , Micropartículas Derivadas de Células/metabolismo , Junções Comunicantes/metabolismo , Modelos Biológicos , Anticorpos de Domínio Único/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Anticorpos Imobilizados/química , Anticorpos Imobilizados/genética , Sobrevivência Celular/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/efeitos adversos , Junções Comunicantes/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Ligantes , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Fusão de Membrana , Microscopia de Fluorescência , Transporte Proteico , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/genética , Propriedades de SuperfícieRESUMO
Clofazimine (CFZ) is highly active against mycobacterium, including resistant Mycobacterium tuberculosis, but its therapeutic efficacy via the oral route is limited by severe adverse effects, poor aqueous solubility, and slow onset of action. Pulmonary delivery of CFZ is an attractive alternative to target mycobacterium-harboring alveolar macrophages. This study explores the use of air jet milling to develop a respirable, cost-effective CFZ formulation. Jet milled CFZ was readily dispersed from an off-the-shelf dry powder inhaler without the need for additional excipients or carrier particles. Additionally, milled CFZ was internalized by J774.A1 alveolar macrophages within 8 h, with evidence of intracellular biotransformation of the CFZ crystals and macrophage sequestration by 24 h. Less macrophage toxicity was noted in comparison to solubilized drug. Compared to macrophage uptake rate, dissolution of milled CFZ was limited, thereby potentially reducing systemic absorption and subsequent side effects. These results suggest that jet milling is an effective manufacturing method in the development of a CFZ formulation for pulmonary delivery and alveolar macrophage targeting.
Assuntos
Antituberculosos/química , Clofazimina/química , Excipientes/química , Antituberculosos/farmacologia , Clofazimina/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/metabolismoRESUMO
Gap junction (GJ) channels facilitate cell-cell communication through the exchange of chemical and mechanical signals, ensuring proper tissue development and homeostasis. The complex, disease stage-dependent role of connexins in breast cancer progression has been extensively studied over the past two decades. In the early stages of breast cancer, substantial evidence supports the role of GJ channels, formed by connexins at the interfaces between neighbouring cells, as suppressors of cell migration and proliferation. These findings suggest that materials that reintroduce connexins into the tumour cell environment have the potential to inhibit cell migration. Here, we report that exposure of highly metastatic MDA-MB-231 breast tumour cells to connexin-rich biovesicle materials potently suppresses cell migration. Specifically, these biovesicles, which can form GJ interfaces with cells, were extracted from the plasma membrane of donor cells engineered to express a high concentration of functional connexin 43 channels. These connexin-rich membrane materials dramatically reduced cell migration in both a transwell migration assay and a scratch closure assay. Collectively, these results suggest that using membrane materials to reintroduce connexins into the tumour cell environment provides a novel approach for combating cell migration and invasion.
Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular , Conexina 43/metabolismo , Junções Comunicantes/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Mama/patologia , Feminino , Junções Comunicantes/patologia , Humanos , Metástase NeoplásicaRESUMO
Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers. While all these routes avoid transit through the gastrointestinal tract, each has its own strengths and weaknesses that may be optimal for specific classes of compounds. Buccal and sublingual delivery enable rapid drug uptake through a relatively permeable barrier but are limited by small epithelial surface area, stratified epithelia, and the practical complexities of maintaining a drug delivery system in the mouth. Pulmonary delivery accesses the highly permeable and large surface area of the alveolar epithelium but must overcome the complexities of safe and effective delivery to the alveoli deep in the lung. Transdermal delivery offers convenient access to the body for extended-release delivery via the skin surface but requires the use of novel devices and formulations to overcome the skin's formidable stratum corneum barrier. New technologies and strategies advanced to overcome these challenges are reviewed, and critical views in future developments of each route are given.
Assuntos
Produtos Biológicos/administração & dosagem , Vias de Administração de Medicamentos , HumanosRESUMO
Transport of biomolecules, drugs, and other reagents across the cell's plasma membrane barrier is an inefficient and poorly controlled process, despite its fundamental importance to biotechnology, cell biology, and pharmaceutics. In particular, insufficient membrane permeability frequently limits the accumulation of drugs and reagents in the cytoplasm, undermining their efficacy. While encapsulating drugs in particles increases uptake by cells, inefficient release of drugs from these particles into the cytoplasm ultimately limits drug efficacy. In contrast, gap junctions provide a direct route to the cytoplasm that bypasses the plasma membrane. As transmembrane channels that physically connect the cytoplasm of adjacent cells, gap junctions permit transport of a diverse range of molecules, from ions and metabolites to siRNA, peptides, and chemotherapeutics. To utilize gap junctions for molecular delivery we have developed Connectosomes, cell-derived lipid vesicles that contain functional gap junction channels and encapsulate molecular cargos. Here we show that these vesicles form gap junction channels with cells, opening a direct and efficient route for the delivery of molecular cargo to the cellular cytoplasm. Specifically, we demonstrate that using gap junctions to deliver the chemotherapeutic doxorubicin reduces the therapeutically effective dose of the drug by more than an order of magnitude. Delivering drugs through gap junctions has the potential to boost the effectiveness of existing drugs such as chemotherapeutics, while simultaneously enabling the delivery of membrane-impermeable drugs and reagents.
Assuntos
Citoplasma/metabolismo , Portadores de Fármacos/química , Transporte Biológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Conexina 43/química , Doxorrubicina/química , Doxorrubicina/metabolismo , Junções Comunicantes/metabolismo , Humanos , Lipídeos/químicaRESUMO
BACKGROUND: Delivery of pharmacologically active compounds to the lung for systemic effects is well known and recently has entered a new era with several products achieving regulatory approval. This review focuses on the barriers to pulmonary delivery of biologics. METHODS: Lessons learned from the development of recently approved products will be reviewed to shed light on the current challenges that are faced when developing biological products for inhaled delivery. RESULTS: The text and tables presented herein consolidate the current data and ongoing research regarding biological, inhaled products. CONCLUSION: With this basis, we also review the future prospects for pulmonary delivery of biologics for systemic delivery and how the biological and physical barriers may be overcome.
Assuntos
Produtos Biológicos/administração & dosagem , Qualidade de Produtos para o Consumidor , Sistemas de Liberação de Medicamentos , Pulmão/química , Administração por Inalação , Animais , Humanos , Pulmão/metabolismoRESUMO
INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.
Assuntos
Implantes de Medicamento/farmacologia , Hipogonadismo/tratamento farmacológico , Testosterona/farmacologia , Animais , Hormônio Foliculoestimulante/sangue , Hipogonadismo/patologia , Hormônio Luteinizante/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Testosterona/sangueRESUMO
Breast cancer remains the second leading cause of cancer deaths for women in the U.S. The need for new and alternative strategies to treat this cancer is imperative. Here we show the optimization of our nanochannel delivery system (nDS) for constant and sustained delivery of docetaxel (DTX) for thetreatment of triple negative breast cancer. DTX is a highly hydrophobic drug, making it difficult to reach the therapeutic levels when released in aqueous solutions from our implantable delivery system. To overcome this challenge and test the release of DTX from nDS, we prepared DTX/2-hydroxypropyl ß-cyclodextrin (DTX/HPCD) inclusion complexes in different molar ratios. The 1:10 DTX/HPCD complex achieved 5 times higher solubility than the 1:2 complex and 3 times higher in vitrorelease of DTX than with free DTX. When released in SCID/Beige mice from nanochannel system, the DTX/HPCD complex showed reduced tumor growth, comparable to the standard bolus injections of DTX, indicating that the structural stability and biological activity of DTX were retained in the complex, after its diffusion through the nanochannel system.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Antineoplásicos/química , Preparações de Ação Retardada , Docetaxel , Feminino , Humanos , Camundongos , Camundongos SCID , Taxoides/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Primary or secondary hypogonadism results in a range of signs and symptoms that compromise quality of life and requires life-long testosterone replacement therapy. In this study, an implantable nanochannel system is investigated as an alternative delivery strategy for the long-term sustained and constant release of testosterone. In vitro release tests are performed using a dissolution set up, with testosterone and testosterone:2-hydroxypropyl-ß-cyclodextrin (TES:HPCD) 1:1 and 1:2 molar ratio complexes release from the implantable nanochannel system and quantify by HPLC. 1:2 TES:HPCD complex stably achieve 10-15 times higher testosterone solubility with 25-30 times higher in vitro release. Bioactivity of delivered testosterone is verified by LNCaP/LUC cell luminescence. In vivo evaluation of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels by liquid chromatography mass spectrometry (LC/MS) and multiplex assay is performed in castrated Sprague-Dawley rats over 30 d. Animals are treated with the nanochannel implants or degradable testosterone pellets. The 1:2 TES:HPCD nanochannel implant exhibits sustained and clinically relevant in vivo release kinetics and attains physiologically stable plasma levels of testosterone, LH, and FSH. In conclusion, it is demonstrated that by providing long-term steady release 1:2 TES:HPCD nanochannel implants may represent a major breakthrough for the treatment of male hypogonadism.
Assuntos
Implantes de Medicamento/administração & dosagem , Nanoestruturas/administração & dosagem , Testosterona/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Sistemas de Liberação de Medicamentos , Implantes de Medicamento/farmacologia , Hormônio Foliculoestimulante/sangue , Cinética , Medições Luminescentes , Hormônio Luteinizante/sangue , Masculino , Nanoestruturas/química , Orquiectomia , Ratos Sprague-Dawley , Testosterona/sangue , beta-Ciclodextrinas/químicaRESUMO
Metronomic chemotherapy supports the idea that long-term, sustained, constant administration of chemotherapeutics, currently not achievable, could be effective against numerous cancers. Particularly appealing are liposomal formulations, used to solubilize hydrophobic therapeutics and minimize side effects, while extending drug circulation time and enabling passive targeting. As liposome alone cannot survive in circulation beyond 48 h, sustaining their constant plasma level for many days is a challenge. To address this, we develop, as a proof of concept, an implantable nanochannel delivery system and ultra-stable PEGylated lapatinib-loaded liposomes, and we demonstrate the release of intact vesicles for over 18 d. Further, we investigate intravasation kinetics of subcutaneously delivered liposomes and verify their biological activity post nanochannel release on BT474 breast cancer cells. The key innovation of this work is the combination of two nanotechnologies to exploit the synergistic effect of liposomes, demonstrated as passive-targeting vectors and nanofluidics to maintain therapeutic constant plasma levels. In principle, this approach could maximize efficacy of metronomic treatments.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Nanotecnologia/métodos , Animais , CamundongosRESUMO
AIMS: Endothelial cells are dynamic cells tasked with selective transport of cargo from blood vessels to tissues. Here we demonstrate the potential for nanoparticle transport across endothelial cells in membrane-bound vesicles. MATERIALS & METHODS: Cell-free endothelial-derived biovesicles were characterized for cellular and nanoparticle content by electron microscopy. Confocal microscopy was used to evaluate biovesicles for organelle-specific proteins, and to monitor biovesicle engulfment by naive cells. RESULTS: Nanoparticle-laden biovesicles containing low-density polyethyleneimine nanoparticles appear to be predominately of endosomal origin, combining features of multivesicular bodies, lysosomes and autophagosomes. Conversely, high-density polyethyleneimine nanoparticles stimulate the formation of biovesicles associated with cellular apoptotic breakdown. Secreted LAMP-1-positive biovesicles are internalized by recipient cells, either of the same origin or of novel phenotype. CONCLUSION: Cellular biovesicles, rich in cellular signals, present an important mode of cell-to-cell communication either locally or through broadcasting of biological messages.
Assuntos
Comunicação Celular/fisiologia , Endossomos/química , Células Endoteliais/química , Células Endoteliais/fisiologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Vesículas Transportadoras/química , Materiais Biomiméticos/química , Sistema Livre de Células/química , Células Cultivadas , Humanos , Tamanho da PartículaRESUMO
Sustained release of a small molecule from a prototype implantable drug delivery device was monitored via MRI in an ex vivo tissue phantom over a period of two days. T1 mapping was used as a method to quantify analyte concentration. Continuous, controlled release was observed. The MRI methodology was thus found to be appropriate for device validation and quality assurance/control.
Assuntos
Bombas de Infusão Implantáveis , Meios de Contraste/química , Humanos , Imageamento por Ressonância Magnética , Imagens de FantasmasRESUMO
Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5 nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20 nm, we achieve sustained and constant plasma levels of leuprolide, interferon α-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70 days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions.
Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Nanoestruturas/ultraestrutura , Preparações Farmacêuticas/administração & dosagem , Animais , Cães , Desenho de Equipamento , Feminino , Humanos , Masculino , Membranas Artificiais , Camundongos , Nanoestruturas/química , Próteses e Implantes , Ratos , Ratos Sprague-DawleyRESUMO
Despite the clinical success of pancreatic islet transplantation, graft function is frequently lost over time due to islet dispersion, lack of neovascularization, and loss of physiological architecture. To address these problems, islet encapsulation strategies including scaffolds and devices have been developed, which produced encouraging results in preclinical models. However, islet loss from such architectures could represent a significant limitation to clinical use. Here, we developed and characterized a novel islet encapsulation silicon device, the NanoGland, to overcome islet loss, while providing a physiological-like environment for long-term islet viability and revascularization. NanoGlands, microfabricated with a channel size ranging from 3.6 nm to 60 µm, were mathematically modeled to predict the kinetics of the response of encapsulated islets to glucose stimuli, based on different channel sizes, and to rationally select membranes for further testing. The model was validated in vitro using static and perifusion testing, during which insulin secretion and functionality were demonstrated for over 30-days. In vitro testing also showed 70-83% enhanced islet retention as compared to porous scaffolds, here simulated through a 200 µm channel membrane. Finally, evidence of in vivo viability of human islets subcutaneously transplanted within NanoGlands was shown in mice for over 120 days. In this context, mouse endothelial cell infiltration suggesting neovascularization from the host were identified in the retrieved grafts. The NanoGland represents a novel, promising approach for the autotransplantation of human islets.
Assuntos
Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/citologia , Nanoestruturas/química , Nanotecnologia/instrumentação , Animais , Movimento Celular , Difusão , Células Endoteliais , Glucose/farmacologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Modelos Teóricos , Neovascularização Fisiológica , Silício/química , Transplante HeterólogoRESUMO
Combined use of gemcitabine (Gem) and LY-364947 (LY), a TGF-ß1 receptor inhibitor, has shown promise for the treatment of fibrotic pancreatic cancer, by reducing collagen production and improving tumor drug penetration. The preparation and optimization of novel Gem and LY formulations, including co-encapsulation in liposomes, require a validated method for the simultaneous quantification of both drugs, a method that had yet to be developed. Here we demonstrate an RP-HPLC protocol for the simultaneous detection of Gem and LY at 266 and 228 nm with retention times of 3.37 and 11.34 mins, respectively. The method, which uses a C18 column and a KH2PO4 (10 mM)-methanol mobile phase, was validated for linearity, precision, accuracy, limits of detection, and robustness. Co-loaded liposomes with both Gem and LY (Gem/LY liposomes) were developed to investigate the protocol applicability to pharmacokinetic analysis and formulation characterization. The method specificity was evaluated in presence of liposomal components in fetal bovine serum (FBS). Finally, the method was demonstrated by quantifying Gem/LY liposomal encapsulation efficiency and concentration liposomes-spiked FBS.
Assuntos
Antineoplásicos/análise , Cromatografia Líquida de Alta Pressão/métodos , Desoxicitidina/análogos & derivados , Lipossomos , Pirazóis/análise , Pirróis/análise , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Bovinos , Química Farmacêutica , Desoxicitidina/administração & dosagem , Desoxicitidina/análise , Desoxicitidina/farmacocinética , Estabilidade de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , GencitabinaRESUMO
Adequate drug delivery to tumors is hindered by barriers such as degradation and non-specific distribution. Nested incorporation of drug-containing nanoparticles within mesoporous silicon particles (MSVs), carriers rationally designed to enhance tumor transport, was hypothesized to result in pronounced and sustained antitumor efficacy. Paclitaxel (PTX)-containing poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) polymer micelles were favorably loaded within MSVs, after which drug release was significantly delayed. Antitumor efficacy analyses in mice bearing MDA-MB-468 breast tumors demonstrated significant tumor growth suppression following a single administration. Results highlight effective chemotherapeutic shuttling and site-specific controlled release afforded by MSVs, potentially translating towards improvements in patient outcomes and morbidity.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Neoplasias da Mama/metabolismo , Portadores de Fármacos/administração & dosagem , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Micelas , Nanopartículas/metabolismo , Distribuição Aleatória , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm(2)) that attain zero-order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO(2) and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high-yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants.