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1.
Sci Adv ; 6(3): eaax3931, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998833

RESUMO

Development of effective tumor cell-targeted nanodrug formulations has been quite challenging, as many nanocarriers and targeting moieties exhibit nonspecific binding to cellular, extracellular, and intravascular components. We have developed a therapeutic nanoparticle formulation approach that balances cell surface receptor-specific binding affinity while maintaining minimal interactions with blood and tumor tissue components (termed "DART" nanoparticles), thereby improving blood circulation time, biodistribution, and tumor cell-specific uptake. Here, we report that paclitaxel (PTX)-DART nanoparticles directed to the cell surface receptor fibroblast growth factor-inducible 14 (Fn14) outperformed both the corresponding PTX-loaded, nontargeted nanoparticles and Abraxane, an FDA-approved PTX nanoformulation, in both a primary triple-negative breast cancer (TNBC) model and an intracranial model reflecting TNBC growth following metastatic dissemination to the brain. These results provide new insights into methods for effective development of therapeutic nanoparticles as well as support the continued development of the DART platform for primary and metastatic tumors.


Assuntos
Antineoplásicos/administração & dosagem , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia de Alvo Molecular , Nanopartículas , Nanomedicina Teranóstica , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Modelos Animais de Doenças , Matriz Extracelular , Feminino , Expressão Gênica , Humanos , Camundongos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro , Receptor de TWEAK/genética , Distribuição Tecidual , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nanomedicine ; 20: 102024, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176045

RESUMO

Therapeutic efficacy of nanoparticle-drug formulations for cancer applications is significantly impacted by the extent of intra-tumoral accumulation and tumor tissue penetration. We advanced the application of surface plasmon resonance to examine interfacial properties of various clinical and emerging nanoparticles related to tumor tissue penetration. We observed that amine-terminated or positively-charged dendrimers and liposomes bound strongly to tumor extracellular matrix (ECM) proteins, whereas hydroxyl/carboxyl-terminated dendrimers and PEGylated/neutrally-charged liposomes did not bind. In addition, poly(lactic-co-glycolic acid) (PLGA) nanoparticles formulated with cholic acid or F127 surfactants bound strongly to tumor ECM proteins, whereas nanoparticles formulated with poly(vinyl alcohol) did not bind. Unexpectedly, following blood serum incubation, this binding increased and particle transport in ex vivo tumor tissues reduced markedly. Finally, we characterized the protein corona on PLGA nanoparticles using quantitative proteomics. Through these studies, we identified valuable criteria for particle surface characteristics that are likely to mediate their tissue binding and tumor penetration.


Assuntos
Nanopartículas/química , Neoplasias/metabolismo , Ressonância de Plasmônio de Superfície , Animais , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Dendrímeros/química , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Lipossomos , Camundongos Nus , Nanopartículas/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ligação Proteica , Coroa de Proteína/química , Propriedades de Superfície , Tensoativos/química
4.
J Neurooncol ; 138(2): 241-250, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29453678

RESUMO

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/genética , Glioma/metabolismo , Mutação , Receptor de TWEAK/metabolismo , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Citocina TWEAK/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Gradação de Tumores , RNA Mensageiro/metabolismo , Estudos Retrospectivos
5.
J Control Release ; 267: 144-153, 2017 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-28887134

RESUMO

The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, 'sticky' microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as 'DART' therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor - an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Glioma/tratamento farmacológico , Nanopartículas/administração & dosagem , Receptor de TWEAK/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Encéfalo/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Proteínas da Matriz Extracelular/metabolismo , Glioma/metabolismo , Camundongos Endogâmicos C57BL , Nanopartículas/química , Poliésteres/administração & dosagem , Poliésteres/química , Poliésteres/farmacocinética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética
6.
Artigo em Inglês | MEDLINE | ID: mdl-27813323

RESUMO

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment of GBM including the tightly controlled interface between the bloodstream and central nervous system termed the 'neurovascular unit,' a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal of GBM therapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified as GBM targets include the transferrin receptor, low-density lipoprotein receptor-related protein, αv ß3 integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR), EGFR variant III, interleukin-13 receptor α chain variant 2, and fibroblast growth factor-inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the key GBM targets with the goal of advancing the understanding and development of targeted nanotherapeutics for GBM. WIREs Nanomed Nanobiotechnol 2017, 9:e1439. doi: 10.1002/wnan.1439 For further resources related to this article, please visit the WIREs website.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Nanopartículas/química , Humanos , Nanomedicina
7.
J Control Release ; 238: 139-148, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27460683

RESUMO

Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62nm, but less than 110nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non-PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration.


Assuntos
Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Neoplasias/metabolismo , Polietilenoglicóis/metabolismo , Paclitaxel Ligado a Albumina/administração & dosagem , Paclitaxel Ligado a Albumina/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Colágeno/metabolismo , Difusão , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , Portadores de Fármacos/análise , Combinação de Medicamentos , Feminino , Humanos , Ácido Láctico/análise , Ácido Láctico/metabolismo , Laminina/metabolismo , Camundongos , Camundongos Nus , Nanopartículas/análise , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/análise , Ácido Poliglicólico/análise , Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteoglicanas/metabolismo , Propriedades de Superfície
8.
Brain Res ; 1646: 543-550, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27369449

RESUMO

Diffusion within the extracellular and perivascular spaces of the brain plays an important role in biological processes, therapeutic delivery, and clearance mechanisms within the central nervous system. Recently, ultrasound has been used to enhance the dispersion of locally administered molecules and particles within the brain, but ultrasound-mediated effects on the brain parenchyma remain poorly understood. We combined an electron microscopy-based ultrastructural analysis with high-resolution tracking of non-adhesive nanoparticles in order to probe changes in the extracellular and perivascular spaces of the brain following a non-destructive pulsed ultrasound regimen known to alter diffusivity in other tissues. Freshly obtained rat brain neocortical slices underwent sham treatment or pulsed, low intensity ultrasound for 5min at 1MHz. Transmission electron microscopy revealed intact cells and blood vessels and evidence of enlarged spaces, particularly adjacent to blood vessels, in ultrasound-treated brain slices. Additionally, ultrasound significantly increased the diffusion rate of 100nm, 200nm, and 500nm nanoparticles that were injected into the brain slices, while 2000nm particles were unaffected. In ultrasound-treated slices, 91.6% of the 100nm particles, 20.7% of the 200nm particles, 13.8% of the 500nm particles, and 0% of the 2000nm particles exhibited diffusive motion. Thus, pulsed ultrasound can have meaningful structural effects on the brain extracellular and perivascular spaces without evidence of tissue disruption.


Assuntos
Espaço Extracelular/efeitos da radiação , Neocórtex/efeitos da radiação , Ondas Ultrassônicas , Animais , Difusão , Espaço Extracelular/metabolismo , Nanopartículas/administração & dosagem , Neocórtex/irrigação sanguínea , Neocórtex/metabolismo , Neocórtex/ultraestrutura , Ratos , Ratos Sprague-Dawley
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