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1.
Front Bioeng Biotechnol ; 9: 794676, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926432

RESUMO

Apolipoprotein-based drug delivery is a promising approach to develop safe nanoparticles capable of targeted drug delivery for various diseases. In this work, we have synthesized a lipid-based nanoparticle (NPs) that we have called "Aposomes" presenting native apolipoprotein B-100 (apoB-100), the primary protein present in Low-Density Lipoproteins (LDL) on its surface. The aposomes were synthesized from LDL isolated from blood plasma using a microfluidic approach. The synthesized aposomes had a diameter of 91 ± 4 nm and a neutral surface charge of 0.7 mV ± mV. Protein analysis using western blot and flow cytometry confirmed the presence of apoB-100 on the nanoparticle's surface. Furthermore, Aposomes retained liposomes' drug loading capabilities, demonstrating a prolonged release curve with ∼80% cargo release at 4 hours. Considering the natural tropism of LDL towards the atherosclerotic plaques, we evaluated the biological properties of aposomes in a mouse model of advanced atherosclerosis. We observed a ∼20-fold increase in targeting of plaques when comparing aposomes to control liposomes. Additionally, aposomes presented a favorable biocompatibility profile that showed no deviation from typical values in liver toxicity markers (i.e., LDH, ALT, AST, Cholesterol). The results of this study demonstrate the possibilities of using apolipoprotein-based approaches to create nanoparticles with active targeting capabilities and could be the basis for future cardiovascular therapies.

2.
Sci Rep ; 11(1): 5107, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658580

RESUMO

In the field of oncology research, a deeper understanding of tumor biology has shed light on the role of environmental conditions surrounding cancer cells. In this regard, targeting the tumor microenvironment has recently emerged as a new way to access this disease. In this work, a novel extracellular matrix (ECM)-targeting nanotherapeutic was engineered using a lipid-based nanoparticle chemically linked to an inhibitor of the ECM-related enzyme, lysyl oxidase 1 (LOX), that inhibits the crosslinking of elastin and collagen fibers. We demonstrated that, when the conjugated vesicles were loaded with the chemotherapeutic epirubicin, superior inhibition of triple negative breast cancer (TNBC) cell growth was observed both in vitro and in vivo. Moreover, in vivo results displayed prolonged survival, minimal cytotoxicity, and enhanced biocompatibility compared to free epirubicin and epirubicin-loaded nanoparticles. This all-in-one nano-based ECM-targeting chemotherapeutic may provide a key-enabling technology for the treatment of TNBC.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Anticorpos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Epirubicina/administração & dosagem , Lipossomos/química , Nanopartículas/química , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Anticorpos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada/métodos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/enzimologia , Feminino , Humanos , Camundongos , Camundongos Nus , Proteína-Lisina 6-Oxidase/imunologia , Distribuição Tecidual , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nanomaterials (Basel) ; 10(11)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143238

RESUMO

Efficient communication is essential in all layers of the biological chain. Cells exchange information using a variety of signaling moieties, such as small molecules, proteins, and nucleic acids. Cells carefully package these messages into lipid complexes, collectively named extracellular vesicles (EVs). In this work, we discuss the nature of these cell carriers, categorize them by their origin, explore their role in the homeostasis of healthy tissues, and examine how they regulate the pathophysiology of several diseases. This review will also address the limitations of using EVs for clinical applications and discuss novel methods to engineer nanoparticles to mimic the structure, function, and features of EVs. Using lessons learned from nature and understanding how cells use EVs to communicate across distant sites, we can develop a better understanding of how to tailor the fundamental features of drug delivery carriers to encapsulate various cargos and target specific sites for biomedicine and bioengineering.

4.
Proc Natl Acad Sci U S A ; 117(31): 18401-18411, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690709

RESUMO

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tumores Neuroectodérmicos/tratamento farmacológico , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Xenoenxertos , Humanos , Camundongos , Neoplasias/genética , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/metabolismo , Fosfoproteínas/análise , Fosfoproteínas/genética , Fosforilação
5.
Sci Rep ; 10(1): 172, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932600

RESUMO

Despite recent advances in drug delivery, the targeted treatment of unhealthy cells or tissues continues to remain a priority. In cancer (much like other pathologies), delivery vectors are designed to exploit physical and biological features of unhealthy tissues that are not always homogenous across the disease. In some cases, shifting the target from unhealthy tissues to the whole organ can represent an advantage. Specifically, the natural organ-specific retention of nanotherapeutics following intravenous administration as seen in the lung, liver, and spleen can be strategically exploited to enhance drug delivery. Herein, we outline the development of a cell-based delivery system using macrophages as a delivery vehicle. When loaded with a chemotherapeutic payload (i.e., doxorubicin), these cellular vectors (CELVEC) were shown to provide continued release within the lung. This study provides proof-of-concept evidence of an alternative class of biomimetic delivery vectors that capitalize on cell size to provide therapeutic advantages for pulmonary treatments.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Biomimética , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Macrófagos/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Lipossomos , Pulmão/citologia , Masculino , Camundongos , Camundongos Nus , Distribuição Tecidual
6.
Circ Res ; 126(1): 25-37, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31647755

RESUMO

RATIONALE: Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. OBJECTIVE: Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. METHODS AND RESULTS: Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of -15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P=9.95122×10-6). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice. CONCLUSIONS: We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.


Assuntos
Aortite/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Placa Aterosclerótica/prevenção & controle , Sirolimo/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aortite/complicações , Aortite/patologia , Apolipoproteínas E/deficiência , Aterosclerose/patologia , Biomimética , Proteína C-Reativa/metabolismo , Microscopia Crioeletrônica , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas de Membrana/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Neovascularização Patológica/prevenção & controle , Especificidade de Órgãos , Fosfatidilcolinas/administração & dosagem , Distribuição Aleatória , Sirolimo/farmacologia , Sirolimo/uso terapêutico
7.
Biomater Sci ; 8(1): 333-341, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714542

RESUMO

In the last decades, several approaches were developed to design drug delivery systems to address the multiple biological barriers encountered after administration while safely delivering a payload. In this scenario, bio-inspired and bio-mimetic approaches have emerged as promising solutions to evade the mononuclear phagocytic system while simultaneously negotiating the sequential transport across the various biological barriers. Leukocytes freely circulate in the bloodstream and selectively target the inflamed vasculature in response to injury, infection, and cancer. Recently we have shown the use of biomimetic nanovesicles, called leukosomes, which combine both the physical and biological properties of liposomes and leukocytes, respectively, to selectively deliver drugs to the inflamed vasculature. Here we report the use of leukosomes to target and deliver doxorubicin, a model chemotherapeutic, to tumors in syngeneic murine models of breast cancer and melanoma. Exploiting the inflammatory pathway responsible for recruiting immune cells to the site of injury, leukosomes exhibited increased targeting of cancer vasculature and stroma. Furthermore, delivery of doxorubicin with leukosomes enabled significant tumor growth inhibition compared with free doxorubicin in both breast and melanoma tumors. This study demonstrates the promise of using biomimetic nanovesicles for effective cancer management in solid tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Melanoma/tratamento farmacológico , Nanopartículas/química , Animais , Materiais Biomiméticos/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Feminino , Estimativa de Kaplan-Meier , Leucócitos/química , Lipossomos/química , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Transplante Homólogo
8.
Nanoscale ; 11(28): 13576-13586, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31290914

RESUMO

Despite numerous advances in medical treatment, sepsis remains one of the leading causes of death worldwide. Sepsis is characterized by the involvement of all organs and tissues as a consequence of blood poisoning, resulting in organ failure and eventually death. Effective treatment remains an unmet need and novel approaches are urgently needed. The growing evidence of clinical and biological heterogeneity of sepsis suggests precision medicine as a possible key for achieving therapeutic breakthroughs. In this scenario, biomimetic nanomedicine represents a promising avenue for the treatment of inflammatory diseases, including sepsis. We investigated the role of macrophage-derived biomimetic nanoparticles, namely leukosomes, in a lipopolysaccharide-induced murine model of sepsis. We observed that treatment with leukosomes was associated with significantly prolonged survival. In vitro studies elucidated the potential mechanism of action of these biomimetic vesicles. The direct treatment of endothelial cells (ECs) with leukosomes did not alter the gene expression profile of EC-associated cell adhesion molecules. In contrast, the interaction of leukosomes with macrophages induced a decrease of pro-inflammatory genes (IL-6, IL-1b, and TNF-α), an increase of anti-inflammatory ones (IL-10 and TGF-ß), and indirectly an anti-inflammatory response on ECs. Taken together, these results showed the ability of leukosomes to regulate the inflammatory response in target cells, acting as a bioactive nanotherapeutic.


Assuntos
Anti-Inflamatórios , Materiais Biomiméticos , Células Endoteliais , Vesículas Extracelulares , Macrófagos , Nanopartículas/química , Sepse , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Vesículas Extracelulares/química , Vesículas Extracelulares/transplante , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Monocinas/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia
9.
Nanomaterials (Basel) ; 8(9)2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134564

RESUMO

Over the years, imaging and therapeutic modalities have seen considerable progress as a result of advances in nanotechnology. Theranostics, or the marrying of diagnostics and therapy, has increasingly been employing nano-based approaches to treat cancer. While first-generation nanoparticles offered considerable promise in the imaging and treatment of cancer, toxicity and non-specific distribution hindered their true potential. More recently, multistage nanovectors have been strategically designed to shield and carry a payload to its intended site. However, detection by the immune system and sequestration by filtration organs (i.e., liver and spleen) remains a major obstacle. In an effort to circumvent these biological barriers, recent trends have taken inspiration from biology. These bioinspired approaches often involve the use of biologically-derived cellular components in the design and fabrication of biomimetic nanoparticles. In this review, we provide insight into early nanoparticles and how they have steadily evolved to include bioinspired approaches to increase their theranostic potential.

10.
Adv Mater ; 30(15): e1702749, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29512198

RESUMO

The advancement of nanotechnology toward more sophisticated bioinspired approaches has highlighted the gap between the advantages of biomimetic and biohybrid platforms and the availability of manufacturing processes to scale up their production. Though the advantages of transferring biological features from cells to synthetic nanoparticles for drug delivery purposes have recently been reported, a standardizable, batch-to-batch consistent, scalable, and high-throughput assembly method is required to further develop these platforms. Microfluidics has offered a robust tool for the controlled synthesis of nanoparticles in a versatile and reproducible approach. In this study, the incorporation of membrane proteins within the bilayer of biomimetic nanovesicles (leukosomes) using a microfluidic-based platform is demonstrated. The physical, pharmaceutical, and biological properties of microfluidic-formulated leukosomes (called NA-Leuko) are characterized. NA-Leuko show extended shelf life and retention of the biological functions of donor cells (i.e., macrophage avoidance and targeting of inflamed vasculature). The NA approach represents a universal, versatile, robust, and scalable tool, which is extensively used for the assembly of lipid nanoparticles and adapted here for the manufacturing of biomimetic nanovesicles.


Assuntos
Microfluídica , Biomimética , Sistemas de Liberação de Medicamentos , Nanopartículas , Nanotecnologia
11.
Theranostics ; 8(4): 1131-1145, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29464004

RESUMO

Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases. Methods: Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes. For imaging applications, phospholipids modified with rhodamine and gadolinium were used. Leukosomes incubated with antibodies blocking lymphocyte function-associated antigen 1 (LFA-1) and CD45 were administered to explore their roles in targeting inflammation. In addition, relaxometric assessment of NPs was evaluated. Results: Liposomes and leukosomes were both spherical in shape with sizes ranging from 140-170 nm. Both NPs successfully integrated 8 and 13 µg of rhodamine and gadolinium, respectively, and demonstrated less than 4% variation in physicochemical features. Leukosomes demonstrated a 16-fold increase in breast tumor accumulation relative to liposomes. Furthermore, quantification of leukosomes in tumor vessels demonstrated a 4.5-fold increase in vessel lumens and a 14-fold increase in vessel walls. Investigating the targeting mechanism of action revealed that blockage of LFA-1 on leukosomes resulted in a 95% decrease in tumor accumulation. Whereas blockage of CD45 yielded a 60% decrease in targeting and significant increases in liver and spleen accumulation. In addition, when administered in mice with atherosclerotic plaques, leukosomes exhibited a 4-fold increase in the targeting of inflammatory vascular lesions. Lastly, relaxometric assessment of NPs demonstrated that the incorporation of membrane proteins into leukosomes did not impact the r1 and r2 relaxivities of the NPs, demonstrating 6 and 30 mM-1s-1, respectively. Conclusion: Our study demonstrates the ability of leukosomes to target activated vasculature and exhibit superior accumulation in tumors and vascular lesions. The versatility of the phospholipid backbone within leukosomes permits the incorporation of various contrast agents. Furthermore, leukosomes can potentially be loaded with therapeutics possessing diverse physical properties and thus warrant further investigation toward the development of powerful theranostic agents.


Assuntos
Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Endotélio Vascular/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Animais , Corantes Fluorescentes/farmacocinética , Gadolínio/farmacocinética , Leucócitos/química , Leucócitos/metabolismo , Proteínas de Membrana/isolamento & purificação , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Fosfolipídeos/isolamento & purificação , Fosfolipídeos/metabolismo , Ligação Proteica , Rodaminas/farmacocinética , Coloração e Rotulagem/métodos , Nanomedicina Teranóstica/métodos , Doenças Vasculares/diagnóstico , Doenças Vasculares/tratamento farmacológico
12.
Biomaterials ; 147: 155-168, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28946131

RESUMO

The engineering of future generations of nanodelivery systems aims at the creation of multifunctional vectors endowed with improved circulation, enhanced targeting and responsiveness to the biological environment. Moving past purely bio-inert systems, researchers have begun to create nanoparticles capable of proactively interacting with the biology of the body. Nature offers a wide-range of sources of inspiration for the synthesis of more effective drug delivery platforms. Because the nano-bio-interface is the key driver of nanoparticle behavior and function, the modification of nanoparticles' surfaces allows the transfer of biological properties to synthetic carriers by imparting them with a biological identity. Modulation of these surface characteristics governs nanoparticle interactions with the biological barriers they encounter. Building off these observations, we provide here an overview of virus- and cell-derived biomimetic delivery systems that combine the intrinsic hallmarks of biological membranes with the delivery capabilities of synthetic carriers. We describe the features and properties of biomimetic delivery systems, recapitulating the distinctive traits and functions of viruses, exosomes, platelets, red and white blood cells. By mimicking these biological entities, we will learn how to more efficiently interact with the human body and refine our ability to negotiate with the biological barriers that impair the therapeutic efficacy of nanoparticles.


Assuntos
Materiais Biomiméticos/química , Portadores de Fármacos/química , Nanopartículas/química , Vírus/química , Animais , Biomimética , Células Sanguíneas/química , Células Sanguíneas/fisiologia , Exossomos/química , Exossomos/fisiologia , Humanos , Tamanho da Partícula , Propriedades de Superfície , Fenômenos Fisiológicos Virais
13.
Sci Rep ; 7(1): 7991, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801676

RESUMO

A major challenge in regenerative medicine is to improve therapeutic cells' delivery and targeting using an efficient and simple protocol. Mesenchymal stem cells (MSC) are currently employed for the treatment of inflammatory-based diseases, due to their powerful immunosoppressive potential. Here we report a simple and versatile method to transiently overexpress the hyaluronic acid (HA) receptor, CD44, on MSC membranes, to improve their homing potential towards an inflammatory site without affecting their behavior. The effect of HA-coatings on murine MSC was functionally determined both, in vitro and in vivo as a consequence of the transient CD44 overexpression induced by HA. Data obtained from the in vitro migration assay demonstrated a two-fold increase in the migratory potential of HA-treated MSC compared to untreated cells. In an LPS-induced inflamed ear murine model, HA-treated MSC demonstrated a significantly higher inflammatory targeting as observed at 72 hrs as compared to untreated cells. This increased accumulation for HA-treated MSC yielded a substantial reduction in inflammation as demonstrated by the decrease in the expression of pro-inflammatory markers and by the induction of a pro-regenerative environment.


Assuntos
Movimento Celular , Ácido Hialurônico/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Cultura Primária de Células/métodos , Animais , Células Cultivadas , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos BALB C
14.
ACS Appl Mater Interfaces ; 9(28): 23441-23449, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28640590

RESUMO

Approaches to achieve site-specific and targeted delivery that provide an effective solution to reduce adverse, off target side effects are urgently needed for cancer therapy. Here, we utilized a Trojan-horse-like strategy to carry photosensitizer Chlorin e6 conjugated porous silicon multistage nanovectors with tumor homing mesenchymal stem cells for targeted photodynamic therapy and diagnosis. The inherent versatility of multistage nanovectors permitted the conjugation of photosensitizers to enable precise cell death induction (60%) upon photodynamic therapy, while simultaneously retaining the loading capacity to load various payloads, such as antitumor drugs and diagnostic nanoparticles. Furthermore, the mesenchymal stem cells that internalized the multistage nanovectors conserved their proliferation patterns and in vitro affinity to migrate and infiltrate breast cancer cells. In vivo administration of the mesenchymal stem cells carrying photosensitizer-conjugated multistage nanovectors in mice bearing a primary breast tumor confirmed their tropism toward cancer sites exhibiting similar targeting kinetics to control cells. In addition, this approach yielded in a > 70% decrease in local tumor cell viability after in vivo photodynamic therapy. In summary, these results show the proof-of-concept of how photosensitizer conjugated multistage nanovectors transported by stem cells can target tumors and be used for effective site-specific cancer therapy while potentially minimizing potential negative side effects.


Assuntos
Células-Tronco , Animais , Linhagem Celular Tumoral , Clorofilídeos , Camundongos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Nanomedicina Teranóstica
15.
Sci Rep ; 7(1): 2147, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28526874

RESUMO

Failure to remove a retrievable inferior vena cava (IVC) filter can cause severe complications with high treatment costs. Polydioxanone (PPDO) has been shown to be a good candidate material for resorbable IVC filters. However, PPDO is radioluscent under conventional imaging modalities. Thus, the positioning and integrity of these PPDO filters cannot be monitored by computed tomography (CT) or x-ray. Here we report the development of radiopaque PPDO IVC filters based on gold nanoparticles (AuNPs). Commercially available PPDO sutures were infused with AuNPs. Scanning electron microscopy analysis confirmed the presence of AuNP on the surface of PPDO. Micro-CT and x-ray images of the AuNP-infused PPDO sutures showed significant signal enhancement compared to untreated PPDO sutures. Elemental analysis showed that gold loading exceeded 2000 ppm. Tensile strength and in vitro cytotoxicity showed no significant difference between AuNP-infused and untreated PPDO. In a 10-week stability study, neither the gold content nor the radiopacity of the infused PPDO sutures significantly changed in the first 6 weeks. The increased attenuation of AuNP-infused PPDO sutures indicates their major advantage as a radiopaque resorbable filter material, as the radiopacity allows monitoring of the position and integrity of the filter, thereby increasing its safety and efficacy.


Assuntos
Ouro , Nanopartículas Metálicas , Filtros de Veia Cava , Sobrevivência Celular , Ouro/química , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Polidioxanona/química , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Radiografia , Suturas/efeitos adversos , Resistência à Tração , Veia Cava Inferior/cirurgia , Microtomografia por Raio-X
16.
Transplantation ; 100(8): 1629-38, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27257995

RESUMO

Transplantation is often the only choice many patients have when suffering from end-stage organ failure. Although the quality of life improves after transplantation, challenges, such as organ shortages, necessary immunosuppression with associated complications, and chronic graft rejection, limit its wide clinical application. Nanotechnology has emerged in the past 2 decades as a field with the potential to satisfy clinical needs in the area of targeted and sustained drug delivery, noninvasive imaging, and tissue engineering. In this article, we provide an overview of popular nanotechnologies and a summary of the current and potential uses of nanotechnology in cell and organ transplantation.


Assuntos
Transplante de Células/métodos , Nanomedicina/métodos , Transplante de Órgãos/métodos , Animais , Transplante de Células/efeitos adversos , Transplante de Células/tendências , Preparações de Ação Retardada , Difusão de Inovações , Portadores de Fármacos , Composição de Medicamentos/métodos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Imagem Molecular/métodos , Nanomedicina/tendências , Nanopartículas , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/tendências , Valor Preditivo dos Testes , Resultado do Tratamento
17.
Biomaterials ; 82: 168-77, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26761780

RESUMO

Recently, engineering the surface of nanotherapeutics with biologics to provide them with superior biocompatibility and targeting towards pathological tissues has gained significant popularity. Although the functionalization of drug delivery vectors with cellular materials has been shown to provide synthetic particles with unique biological properties, these approaches may have undesirable immunological repercussions upon systemic administration. Herein, we comparatively analyzed unmodified multistage nanovectors and particles functionalized with murine and human leukocyte cellular membrane, dubbed Leukolike Vectors (LLV), and the immunological effects that may arise in vitro and in vivo. Previously, LLV demonstrated an avoidance of opsonization and phagocytosis, in addition to superior targeting of inflammation and prolonged circulation. In this work, we performed a comprehensive evaluation of the importance of the source of cellular membrane in increasing their systemic tolerance and minimizing an inflammatory response. Time-lapse microscopy revealed LLV developed using a cellular coating derived from a murine (i.e., syngeneic) source resulted in an active avoidance of uptake by macrophage cells. Additionally, LLV composed of a murine membrane were found to have decreased uptake in the liver with no significant effect on hepatic function. As biomimicry continues to develop, this work demonstrates the necessity to consider the source of biological material in the development of future drug delivery carriers.


Assuntos
Materiais Biocompatíveis/toxicidade , Materiais Biomiméticos/toxicidade , Imunidade Inata/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Nanocápsulas/toxicidade , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C
18.
Small ; 12(11): 1479-88, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797709

RESUMO

Scaffolds functionalized with delivery systems for the release of growth factors is a robust strategy to enhance tissue regeneration. However, after implantation, macrophages infiltrate the scaffold, eventually initiating the degradation and clearance of the delivery systems. Herein, it is hypothesized that fully embedding the poly(d,l-lactide-co-glycolide acid) microspheres (MS) in a highly structured collagen-based scaffold (concealing) can prevent their detection, preserving the integrity of the payload. Confocal laser microscopy reveals that non-embedded MS are easily internalized; when concealed, J774 and bone marrow-derived macrophages (BMDM) cannot detect them. This is further demonstrated by flow cytometry, as a tenfold decrease is found in the number of MS engulfed by the cells, suggesting that collagen can cloak the MS. This correlates with the amount of nitric oxide and tumor necrosis factor-α produced by J774 and BMDM in response to the concealed MS, comparable to that found for non-functionalized collagen scaffolds. Finally, the release kinetics of a reporter protein is preserved in the presence of macrophages, only when MS are concealed. The data provide detailed strategies for fabricating three dimensional (3D) biomimetic scaffolds able to conceal delivery systems and preserve the therapeutic molecules for release.


Assuntos
Materiais Biomiméticos/química , Ácido Láctico/química , Macrófagos/metabolismo , Microesferas , Ácido Poliglicólico/química , Alicerces Teciduais/química , Adsorção , Animais , Endocitose , Genes Reporter , Mediadores da Inflamação/metabolismo , Cinética , Macrófagos/ultraestrutura , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Transdução de Sinais
19.
Colloids Surf B Biointerfaces ; 136: 694-703, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26513752

RESUMO

Familial adenomatous polyposis (FAP) is an inherited condition secondary to germline mutations in the APC gene, thus resulting in the formation of hundreds of colonic adenomas that eventually progress into colon cancer. Surgical removal of the colon remains the only treatment option to avoid malignancy, as long-term exposure to chemopreventive agents such as sulindac (a non-steroidal anti-inflammatory drug) and silymarin (phytoestrogen) is not feasible. Here, we have developed a multistage silicon-based drug delivery platform for sulindac and silymarin that preferentially interacts with colon cancer cells as opposed to normal intestinal mucosa. Preferential binding and internalization of these drugs into colon cancer cells was obtained using a targeting strategy against the protein meprin A, which we demonstrate is overexpressed in human colon cancer cells and in the small intestine of Apc(Min/+) mice. We propose that this delivery system could potentially be used to reduce drug-induced side effects in FAP patients, thus enabling long-term prevention of adenoma formation.


Assuntos
Anticarcinógenos/administração & dosagem , Neoplasias do Colo/prevenção & controle , Silimarina/administração & dosagem , Sulindaco/administração & dosagem , Células CACO-2 , Humanos
20.
Nanomedicine (Lond) ; 10(19): 3057-3075, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26419750

RESUMO

Controlling size, shape and uniformity of porous constructs remains a major focus of the development of porous materials. Over the past two decades, we have seen significant developments in the fabrication of new, porous-ordered structures using a wide range of materials, resulting in properties well beyond their traditional use. Porous materials have been considered appealing, due to attractive properties such as pore size length, morphology and surface chemistry. Furthermore, their utilization within the life sciences and medicine has resulted in significant developments in pharmaceutics and medical diagnosis. This article focuses on various classes of porous materials, providing an overview of principle concepts with regard to design and fabrication, surface chemistry and loading and release kinetics. Furthermore, predictions from a multiscale mathematical model revealed the role pore length and diameter could have on payload release kinetics.

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