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1.
PLoS One ; 18(12): e0293700, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38117806

RESUMO

BACKGROUND: Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models. METHODS: Gene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin. RESULTS: TFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice. CONCLUSIONS: TfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.


Assuntos
Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quelantes , Expressão Gênica , Terapia de Alvo Molecular , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
2.
Ann Case Rep ; 8(5)2023.
Artigo em Inglês | MEDLINE | ID: mdl-37946711

RESUMO

Nontraumatic exertional syncope can be an ominous event reflecting profound arterial hypotension, cerebral hypoperfusion, and transient loss-of consciousness that occurs most commonly in patients with underlying cardiovascular disease. In contradistinction, transient loss-of-consciousness in "healthy adults" is typically vasovagal syncope related to exaggerated orthostatic cardiovascular responses attributed to a hyper-reactive autonomic nervous system. In the present report, a 34 yo male presents to the hospital emergency department (ED) for a sudden loss of consciousness and fall ultimately related to cardiac syncope ascribed to chronic recreational marijuana use complicated by coronary vasospasm.

3.
Clin Neuropsychol ; 37(4): 812-820, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36576117

RESUMO

Objective: A growing body of literature shows the unequivocal importance of incorporating diversity-related factors into the practice of clinical neuropsychology. Thus, it is imperative that we continue to seek and obtain updated training and knowledge on how culture and diversity intersect with our clinical roles throughout our careers, not merely to satisfy initial coursework requirements. Although most professional organizations pertaining to clinical psychology - and thereby neuropsychology - strongly encourage the pursuit of training in diversity-related factors, explicit requirements for such training across one's career are minimal. Method: The Asian Neuropsychological Association Advocacy Committee reviewed continuing education (CE) requirements for all US states. Results: We found that only 8 states mandated CE credits pertaining to diversity-related factors for the renewal of licensure. Discussion: Given how inseparable cultural competence is from any aspect of clinical work (and the harm that can be done if culture is not considered), it is essential that our field shift from aspirational guidance to firm requirements with regard to cultural competence and diversity-related training in psychology. Requiring CE units devoted to diversity-related factors represents one avenue to pursue this goal. This commentary outlines the current status of diversity-related CE for psychology licensure renewal and offers future directions for incorporating such training as a part of continuing professional development and education.


Assuntos
Educação Continuada , Neuropsicologia , Humanos , Testes Neuropsicológicos , Diversidade Cultural , Competência Cultural
4.
Med Phys ; 49(1): 129-143, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34748660

RESUMO

PURPOSE: Cardiovascular magnetic resonance (CMR) is a vital diagnostic tool in the management of cardiovascular diseases. The advent of advanced CMR technologies combined with artificial intelligence (AI) has the potential to simplify imaging, reduce image acquisition time without compromising image quality (IQ), and improve magnetic field uniformity. Here, we aim to implement two AI-based deep learning techniques for automatic slice alignment and cardiac shimming and evaluate their performance in clinical cardiac magnetic resonance imaging (MRI). METHODS: Two deep neural networks were developed, trained, and validated on pre-acquired cardiac MRI datasets (>500 subjects) to achieve automatic slice planning and shimming (implemented in the scanner) for CMR. To examine the performance of our automated cardiac planning (EasyScan) and AI-based shim (AI shim), two prospective studies were performed subsequently. For the EasyScan validation, 10 healthy subjects underwent two identical CMR protocols: with manual cardiac planning and with AI-based EasyScan to assess protocol scan time difference and accuracy of cardiac plane prescriptions on a 1.5 T clinical MRI scanner. For the AI shim validation, a total of 20 subjects were recruited: 10 healthy and 10 cardio-oncology patients with referrals for a CMR examination. Cine images were obtained with standard cardiac volume shim and with AI shim to assess signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), overall IQ (sharpness and MR image degradation), ejection fraction (EF), and absolute wall thickening. A hybrid statistical method using of nonparametric (Wilcoxon) and parametric (t-test) assessments was employed for statistical analyses. RESULTS: CMR protocol with AI-based plane prescriptions, EasyScan, minimized operator dependence and reduced overall scanning time by over 2 min (∼13 % faster, p < 0.001) compared to the protocol with manual cardiac planning. EasyScan plane prescriptions also demonstrated more accurate (less plane angulation errors from planes manually prescribed by a certified cardiac MRI technologist) cardiac planes than previously reported strategies. Additionally, AI shim resulted in improved B0 field homogeneity. Cine images obtained with AI shim revealed a significantly higher SNR (12.49%; p = 0.002) than those obtained with volume shim (volume shim: 32.90 ± 7.42 vs. AI shim: 37.01 ± 8.87) for the left ventricle (LV) myocardium. LV myocardium CNR was 12.48% higher for cine imaging with AI shim (149.02 ± 39.15) than volume shim (132.49 ± 33.94). Images obtained with AI shim resulted in sharper images than those obtained with volume shim (p = 0.012). The LVEF and absolute wall thickening also showed that differences exist between the two shimming methods. The LVEF by AI shim was shown to be slightly larger than LVEF by volume shim in two groups: 2.87% higher with AI shim for the healthy group and 1.70% higher with AI shim for the patient group. The LV absolute wall thickening (in mm) also showed that differences exist between shimming methods for each group with larger changes observed in the patient group (healthy: 3.31%, p = 0.234 and patient group: 7.29%, p = 0.059). CONCLUSIONS: CMR exams using EasyScan for cardiac planning demonstrated accelerated cardiac exam compared to the CMR protocol with manual cardiac planning. Improved and more uniform B0 magnetic field homogeneity also achieved using AI shim technique compared to volume shimming.


Assuntos
Inteligência Artificial , Imageamento por Ressonância Magnética , Coração/diagnóstico por imagem , Humanos , Imagem Cinética por Ressonância Magnética , Estudos Prospectivos , Reprodutibilidade dos Testes , Volume Sistólico
5.
J Clin Invest ; 131(20)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34520398

RESUMO

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.


Assuntos
Arginase/fisiologia , Neoplasias da Mama/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Tolerância Imunológica , Células Mieloides/enzimologia , Microambiente Tumoral , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , AMP Cíclico/fisiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL
6.
Theranostics ; 11(16): 7735-7754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335961

RESUMO

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Compostos Organometálicos/farmacologia , Osteoclastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Neoplasias Ósseas , Osso e Ossos/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacologia , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Compostos Organometálicos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteólise/patologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cancer Ther ; 20(6): 1183-1198, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33785647

RESUMO

Breast cancer bone metastases are common and incurable. Tumoral integrin ß3 (ß3) expression is induced through interaction with the bone microenvironment. Although ß3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of ß3+ tumor cells in murine bone metastases after docetaxel chemotherapy. ß3+ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n = 38). High tumoral ß3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral ß3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact ß3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in ß3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this ß3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvß3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that ß3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvß3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Integrina beta3/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Análise de Sobrevida
8.
Clin Cancer Res ; 27(7): 1974-1986, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33355244

RESUMO

PURPOSE: In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion-mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4ß1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments. EXPERIMENTAL DESIGN: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments. RESULTS: V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity. CONCLUSIONS: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.


Assuntos
Integrina alfa4beta1/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Nanopartículas/metabolismo , Animais , Camptotecina/uso terapêutico , Adesão Celular , Linhagem Celular Tumoral , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Melfalan/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/mortalidade , Inibidores da Topoisomerase I/uso terapêutico
9.
Theranostics ; 10(17): 7510-7526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685002

RESUMO

Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages in vitro and in vivo where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models. Methods: In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin ß3, and in vivo targeting and therapeutic potential was evaluated using αvß3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvß3-MI3-PD nanoparticles. Results: We observed that rhodamine, delivered by αvß3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvß3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin ß3 knock out tumors (PyMT-Bo1 ß3KO) were treated with αvß3-NP or αvß3-MI3-PD NP. M2 macrophages were significantly reduced with αvß3-MI3-PD nanoparticle therapy but not αvß3-NP treatment. Conclusion: These data suggest αvß3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Linhagem Celular Tumoral/transplante , Avaliação Pré-Clínica de Medicamentos , Feminino , Fluorocarbonos/administração & dosagem , Fluorocarbonos/química , Técnicas de Inativação de Genes , Humanos , Integrina alfaVbeta3 , Integrina beta3 , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Nanopartículas/química , Fagocitose , Cultura Primária de Células , Pró-Fármacos/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
10.
Invest Radiol ; 55(9): 573-577, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32694452
11.
J Nucl Cardiol ; 26(3): 986-997, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28608182

RESUMO

Robust thrombus imaging is an unresolved clinical unmet need dating back to the mid 1970s. While early molecular imaging approaches began with nuclear SPECT imaging, contrast agents for virtually all biomedical imaging modalities have been demonstrated in vivo with unique strengths and common weaknesses. Two primary molecular imaging targets have been pursued for thrombus imaging: platelets and fibrin. Some common issues noted over 40 years ago persist today. Acute thrombus is readily imaged with all probes and modalities, but aged thrombus remains a challenge. Similarly, anti-coagulation continues to interfere with and often negate thrombus imaging efficacy, but heparin is clinically required in patients suspected of pulmonary embolism, deep venous thrombosis or coronary ruptured plaque prior to confirmatory diagnostic studies have been executed and interpreted. These fundamental issues can be overcome, but an innovative departure from the prior approaches will be needed.


Assuntos
Imagem Molecular/história , Trombose/diagnóstico por imagem , História do Século XX , História do Século XXI , Humanos
13.
Theranostics ; 8(4): 1168-1179, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29464007

RESUMO

Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates. Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99mTc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A). Results:99mTc attenuation by LVAD titanium (1 mm) was 23%. 99mTc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99mTc-F4A probe was not displaced by F1A (120,000:1). Human plasma interfered with 99mTc-F1A binding to fibrin clot (p<0.05) in vitro, whereas, 99mTc-F4A targeting was unaffected. The pharmacokinetic half-life of 99mTc-F4A was 28% faster (124±41 min) than 99mTc-F1A (176±26 min) with both being bioeliminated through the urinary system with negligible liver or spleen biodistribution. In mice with carotid thrombus, 99mTc-F4A binding to the injured carotid was much greater (16.3±3.3 %ID/g, p=0.01) than that measured with an irrelevant negative control, 99mTc-I4A (3.4±1.6 %ID/g). In an LVAD mock flow-loop (1:1, PBS:human plasma:heparin) operating at maximal flow rate, 99mTc-F4A bound well to phantom clots in 2 min (p<0.05), whereas 99mTc-F1A had negligible targeting. Excised LVADs from patients undergoing pump exchange or heart transplant were rewired, studied in the mock flow loop, and found to have spatially variable fibrin accumulations in the inlet and outlet cannulas and bearings. Conclusions:99mTc-F4A is a high-avidity prototype probe for characterizing thrombus in LVADs that is anticipated to help optimize anticoagulation, reduce thromboembolic events, and minimize pump exchange.


Assuntos
Fibrina/metabolismo , Coração Auxiliar/efeitos adversos , Proteínas Recombinantes/metabolismo , Coloração e Rotulagem/métodos , Tecnécio/análise , Tecnécio/metabolismo , Trombose/diagnóstico , Animais , Meia-Vida , Insuficiência Cardíaca/terapia , Humanos , Camundongos , Ligação Proteica , Proteínas Recombinantes/farmacocinética
14.
Nat Commun ; 9(1): 275, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348537

RESUMO

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease.


Assuntos
Neoplasias Mamárias Experimentais/terapia , Mieloma Múltiplo/terapia , Compostos Organometálicos/administração & dosagem , Fotoquimioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Animais , Linhagem Celular , Resistencia a Medicamentos Antineoplásicos , Feminino , Integrina alfa4beta1 , Camundongos Endogâmicos C57BL , Camundongos SCID , Micelas , Terapia de Alvo Molecular , Nanopartículas , Ratos , Albumina Sérica Humana , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Theranostics ; 8(2): 563-574, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29290827

RESUMO

Eighty percent of lung cancers originate as subtle premalignant changes in the airway mucosal epithelial layer of bronchi and alveoli, which evolve and penetrate deeper into the parenchyma. Liquid-ventilation, with perfluorocarbons (PFC) was first demonstrated in rodents in 1966 then subsequently applied as lipid-encapsulated PFC emulsions to improve pulmonary function in neonatal infants suffering with respiratory distress syndrome in 1996. Subsequently, PFC nanoparticles (NP) were extensively studied as intravenous (IV) vascular-constrained nanotechnologies for diagnostic imaging and targeted drug delivery applications. Methods: This proof-of-concept study compared intratumoral localization of fluorescent paramagnetic (M) PFC NP in the Vx2 rabbit model using proton (1H) and fluorine (19F) magnetic resonance (MR) imaging (3T) following intratracheal (IT) or IV administration. MRI results were corroborated by fluorescence microscopy. Results: Dynamic 1H-MR and 19F-MR images (3T) obtained over 72 h demonstrated marked and progressive accumulation of M-PFC NP within primary lung Vx2 tumors during the first 12 h post IT administration. Marked 1H and 19F MR signal persisted for over 72 h. In contradistinction, IV M-PFC NP produced a modest transient signal during the initial 2 h post-injection that was consistent circumferential blood pool tumor enhancement. Fluorescence microscopy of excised tumors corroborated the MR results and revealed enormous intratumor NP deposition on day 3 after IT but not IV treatment. Rhodamine-phospholipid incorporated into the PFC nanoparticle surfactant was distributed widely within the tumor on day 3, which is consistent with a hemifusion-based contact drug delivery mechanism previously reported. Fluorescence microscopy also revealed similar high concentrations of M-PFC NP given IT for metastatic Vx2 lung tumors. Biodistribution studies in mice revealed that M-PFC NP given IV distributed into the reticuloendothelial organs, whereas, the same dosage given IT was basically not detected beyond the lung itself. PFC NP given IT did not impact rabbit behavior or impair respiratory function. PFC NP effects on cells in culture were negligible and when given IV or IT no changes in rabbit hematology nor serum clinical chemistry parameters were measured. Conclusion: IT delivery of PFC NP offered unique opportunity to locally deliver PFC NP in high concentrations into lung cancers with minimal extratumor systemic exposure.


Assuntos
Fluorocarbonos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Humanos , Pulmão/efeitos dos fármacos , Imageamento por Ressonância Magnética/métodos , Camundongos , Imagem Multimodal/métodos , Coelhos , Distribuição Tecidual
16.
ACS Nano ; 12(1): 24-43, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29257865

RESUMO

Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and diagnostics in the clinical setting are discussed. Finally, a strategic outlook of the future is discussed to highlight the need for next-generation cancer nanotechnology tools designed to address critical gaps in clinical cancer care.


Assuntos
Nanomedicina/métodos , Neoplasias/diagnóstico , Neoplasias/terapia , Animais , Humanos , Imunoterapia/métodos , Nanotecnologia/métodos , National Cancer Institute (U.S.) , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/radioterapia , Metástase Neoplásica/terapia , Neoplasias/radioterapia , Neoplasias/cirurgia , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento , Estados Unidos
17.
Precis Nanomed ; 1(2): 128-145, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31249994

RESUMO

While the in vivo efficacy of Sn-2 phosphatidylcholine prodrugs incorporated into targeted, non-pegylated lipid-encapsulated nanoparticles was demonstrated in prior preclinical studies, the microscopic details of cell prodrug internalization and trafficking events are unknown. Classic fluorescence microscopy, fluorescence lifetime imaging microscopy, and single-molecule super-resolution microscopy were used to investigate the cellular handling of doxorubicin-prodrug and AlexaFluor™-488-prodrug. Sn-2 phosphatidylcholine prodrugs delivered by hemifusion of nanoparticle and cell phospholipid membranes functioned as phosphatidylcholine mimics, circumventing the challenges of endosome sequestration and release. Phosphatidylcholine prodrugs in the outer cell membrane leaflet translocated to the inner membrane leaflet by ATP-dependent and ATP-independent mechanisms and distributed broadly within the cytosolic membranes over the next 12 h. A portion of the phosphatidylcholine prodrug populated vesicle membranes trafficked to the perinuclear Golgi/ER region, where the drug was enzymatically liberated and activated. Native doxorubicin entered the cells, passed rapidly to the nucleus, and bound to dsDNA, whereas DOX was first enzymatically liberated from DOX-prodrug within the cytosol, particularly in the perinuclear region, before binding nuclear dsDNA. Much of DOX-prodrug was initially retained within intracellular membranes. In vitro anti-proliferation effectiveness of the two drug delivery approaches was equivalent at 48 h, suggesting that residual intracellular DOX-prodrug may constitute a slow-release drug reservoir that enhances effectiveness. We have demonstrated that Sn-2 phosphatidylcholine prodrugs function as phosphatidylcholine mimics following reported pathways of phosphatidylcholine distribution and metabolism. Drug complexed to the Sn-2 fatty acid is enzymatically liberated and reactivated over many hours, which may enhance efficacy overtime.

18.
PLoS One ; 12(9): e0184250, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28873460

RESUMO

BACKGROUND: Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. AIM: To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). RESULTS: PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. CONCLUSION: IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dióxido de Carbono/uso terapêutico , Fluorocarbonos/uso terapêutico , Glioma/tratamento farmacológico , Oxigênio/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Neoplasias Encefálicas/patologia , Dióxido de Carbono/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Emulsões , Fluorocarbonos/farmacologia , Glioma/patologia , Camundongos Endogâmicos C57BL , Oxigênio/farmacologia , Radiossensibilizantes/farmacologia , Análise de Sobrevida , Hipóxia Tumoral/efeitos dos fármacos
19.
Cancer Res ; 77(22): 6299-6312, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28855208

RESUMO

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin ß3 (ß3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, ß3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, ß3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFß signaling through SMAD2/SMAD3 was necessary for breast cancer induction of ß3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvß3 (αvß3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvß3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvß3 at that metastatic site. Cancer Res; 77(22); 6299-312. ©2017 AACR.


Assuntos
Neoplasias Ósseas/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Integrina alfaVbeta3/genética , Integrina beta3/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Docetaxel , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Integrina beta3/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Terapia de Alvo Molecular/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Taxoides/administração & dosagem , Taxoides/química , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
20.
Theranostics ; 7(2): 377-389, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042341

RESUMO

Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvß3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvß3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvß3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvß3-No-Drug micelles while αvß3-Dxtl-PD or αvß3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvß3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvß3-Dxtl-PD micelles. Additionally, αvß3-Dxtl-PD decreased BAL eosinophil and αvß3+ CD45+ leukocytes relative to αvß3-No-Drug micelles, whereas αvß3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a clinically relevant rodent model.


Assuntos
Remodelação das Vias Aéreas , Inibidores da Angiogênese/administração & dosagem , Asma/tratamento farmacológico , Asma/patologia , Nanoestruturas/administração & dosagem , Animais , Asma/diagnóstico por imagem , Cicloexanos/administração & dosagem , Modelos Animais de Doenças , Docetaxel , Portadores de Fármacos/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Imageamento por Ressonância Magnética , Microscopia de Fluorescência , Pró-Fármacos/administração & dosagem , Pyroglyphidae/patogenicidade , Ratos , Sesquiterpenos/administração & dosagem , Taxoides/administração & dosagem , Resultado do Tratamento
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