RESUMO
Cellular and molecular-level interactions of nanoparticles with biological systems are a rapidly evolving field requiring an improved understanding of endocytic trafficking as the principal driver and regulator of signaling events and cellular responses. An understanding of these processes is vital to nanomedicine applications. Studies investigating the complex interplay of these processes and their relationship to targeted nanoparticles exploiting endocytic pathways are notably lacking. It is known that integrins traffic through the endosomal pathway and participate in diverse roles controlling signal transduction, cell migration, and proliferation. Here, it is shown that ultrasmall, nontoxic, core-shell silica nanoparticles (C-dots), surface-functionalized with cRGDY peptides, modestly activate integrin-signaling pathways, in turn, promoting the enhancement of cellular functions. First, nanomolar concentrations, two orders of magnitude higher than clinical trial doses, internalize within αvß3 integrin-expressing melanoma and endothelial cells, predominantly through an integrin receptor-dependent endocytic route. Second, integrin-mediated activation of focal adhesion kinase (FAK) and downstream signaling pathways occurs, in turn, upregulating phosphorylated protein expression levels and promoting concentration-dependent cellular migration and proliferative activity. Inhibiting FAK catalytic activity leads to decreased phosphorylation levels and cellular migration rates. These findings may inform the design of more effectively-targeted nanomedicines and provide insights into endocytic regulation of signal transduction.
Assuntos
Nanopartículas , Transdução de Sinais , Dióxido de Silício/química , Ciclo Celular , Endocitose , Células Endoteliais da Veia Umbilical Humana , Humanos , Integrinas/metabolismoRESUMO
The physicochemical design and synthesis of effective cancer-directed and particle-based nanotherapeutic imaging agents remains a challenging task. Of critical importance is the ability to demonstrate maximum delivery, retention, and treatment efficacy for platforms designed to deposit their cargo at sites of disease without attendant dose-limiting toxicity. In this work, we describe dual-modality nanoparticle drug conjugates (NDCs) which utilize protease sensitive linkers to attached drug compounds and imaging labels to a clinically translated class of ultrasmall silica nanoparticle (C' dots). We describe the synthesis and characterization of these linker-drug constructs. Linkers incorporating dipeptide enzyme substrates are attached to analogs of a prototypical epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), through a cleavable amide bond or para-aminobenzyloxycarbonyl (PABC) group. These constructs are conjugated onto C' dots leading to the desired NDCs. These NDCs exhibit fast and predictable release kinetics in the presence of model proteases, and are stable in various biological media. Finally, in vitro assays show NDCs to be highly active in reducing phosphorylated EGFR levels in H1650 cells, a human tumor-derived cell line. The data suggests that NDCs exhibit desirable properties that warrant further development toward oncological therapy.
Assuntos
Portadores de Fármacos/síntese química , Desenho de Fármacos , Nanopartículas/química , Dióxido de Silício/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Peptídeo Hidrolases/metabolismo , Fosforilação , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/química , Quinazolinas/metabolismoRESUMO
Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core-shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties. Most surprisingly, drawing upon its favorable physicochemical, pharmacokinetic, clearance, and target-specific dual-modality imaging properties in a "hit and run" approach, this conjugate eradicated HER2-expressing gastric tumors without any evidence of tumor regrowth, while exhibiting a wide therapeutic index. Therapeutic response mechanisms are accompanied by the activation of functional markers, as well as pathway-specific inhibition. Results highlight the potential clinical utility of this molecularly engineered particle drug-immune conjugate and underscore the versatility of the base platform as a carrier for conjugating an array of other immune products and payloads.
RESUMO
To address the key challenges in the development of next-generation drug delivery systems (DDS) with desired physicochemical properties to overcome limitations regarding safety, in vivo efficacy, and solid tumor penetration, an ultrasmall folate receptor alpha (FRα) targeted silica nanoparticle (C'Dot) drug conjugate (CDC; or folic acid CDC) was developed. A broad array of methods was employed to screen a panel of CDCs and identify a lead folic acid CDC for clinical development. These included comparing the performance against antibody-drug conjugates (ADCs) in three-dimensional tumor spheroid penetration ability, assessing in vitro/ex vivo cytotoxic efficacy, as well as in vivo therapeutic outcome in multiple cell-line-derived and patient-derived xenograft models. An ultrasmall folic acid CDC, EC112002, was identified as the lead candidate out of >500 folic acid CDC formulations evaluated. Systematic studies demonstrated that the lead formulation, EC112002, exhibited highly specific FRα targeting, multivalent binding properties that would mediate the ability to outcompete endogenous folate in vivo, enzymatic responsive payload cleavage, stability in human plasma, rapid in vivo clearance, and minimal normal organ retention organ distribution in non-tumor-bearing mice. When compared with an anti-FRα-DM4 ADC, EC112002 demonstrated deeper penetration into 3D cell-line-derived tumor spheroids and superior specific cytotoxicity in a panel of 3D patient-derived tumor spheroids, as well as enhanced efficacy in cell-line-derived and patient-derived in vivo tumor xenograft models expressing a range of low to high levels of FRα. With the growing interest in developing clinically translatable, safe, and efficacious DDSs, EC112002 has the potential to address some of the critical limitations of the current systemic drug delivery for cancer management.
Assuntos
Receptor 1 de Folato , Sistemas de Liberação de Fármacos por Nanopartículas , Neoplasias , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Receptor 1 de Folato/metabolismo , Receptor 1 de Folato/uso terapêutico , Ácido Fólico/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Dióxido de Silício/uso terapêuticoRESUMO
PURPOSE: Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. EXPERIMENTAL DESIGN: This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. RESULTS: Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. CONCLUSIONS: Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
Assuntos
Glioma , Nanopartículas , Animais , Linhagem Celular Tumoral , Doxorrubicina , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Humanos , Camundongos , Dióxido de Silício , Índice TerapêuticoRESUMO
BACKGROUND: Tissue necrosis, a consequence of inadequate tissue oxygenation, is a common post-operative complication. As current surgical assessments are often limited to visual and tactile feedback, additional techniques that can aid in the interrogation of tissue viability are needed to improve patient outcomes. In this bi-institutional pilot study, the performance of a novel snapshot hyperspectral imaging camera to detect superficial cutaneous oxygen saturation (StO2) was evaluated. METHODS: Healthy human volunteers were recruited at two participating centers. Cutaneous StO2 of the forearm was determined by a snapshot hyperspectral camera on two separate study days during occlusion-reperfusion of the brachial artery and after induction of local vasodilation. To calculate the blood StO2 at each pixel in the multispectral image, spectra were selected, and fitting was performed over wavelengths ranging from 470 to 950 nm. RESULTS: Quantitative detection of physiological changes in cutaneous StO2 levels was feasible in all sixteen volunteers. A significant (P<0.001) decrease in cutaneous StO2 levels from 78.3% (SD: 15.3) at baseline to 60.6% (SD: 19.8) at the end of occlusion phase was observed, although StO2 levels returned to baseline after five minutes. Mean cutaneous StO2 values were similar in the same subjects on separate study days (Pearson R2: 0.92 and 0.77, respectively) at both centers. Local vasodilation did not yield significant changes in cutaneous StO2 values. CONCLUSIONS: This pilot study demonstrated the feasibility of a snapshot hyperspectral camera for detecting quantitative physiological changes in cutaneous StO2 in normal human volunteers, and serves as a precursor for further validation in perioperative studies.
RESUMO
Importance: Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization. Objective: To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy. Design, Setting, and Participants: This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018. Interventions: Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine-aspartic acid-tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally. Main Outcomes and Measures: The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization. Results: Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves. Conclusions and Relevance: This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care. Trial Registration: ClinicalTrials.gov Identifier: NCT02106598.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Biópsia Guiada por Imagem/métodos , Melanoma/diagnóstico , Nanopartículas , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Dióxido de Silício/farmacologia , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Cintilografia , Estudos RetrospectivosRESUMO
Lutetium-177 (177Lu) radiolabeled ultrasmall (~6 nm dia.) fluorescent core-shell silica nanoparticles (Cornell prime dots or C' dots) were developed for improving efficacy of targeted radiotherapy in melanoma models. PEGylated C' dots were surface engineered to display 10-15 alpha melanocyte stimulating hormone (αMSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The 177Lu-DOTA-αMSH-PEG-C' dot product was radiochemically stable, biologically active, and exhibited high affinity cellular binding properties and internalization. Selective tumor uptake and favorable biodistribution properties were also demonstrated, in addition to bulk renal clearance, in syngeneic B16F10 and human M21 xenografted models. Prolonged survival was observed in the treated cohorts relative to controls. Dosimetric analysis showed no excessively high absorbed dose among normal organs. Correlative histopathology of ex vivo treated tumor specimens revealed expected necrotic changes; no acute pathologic findings were noted in the liver or kidneys. Collectively, these results demonstrated that 177Lu-DOTA-αMSH-PEG-C' dot targeted melanoma therapy overcame the unfavorable biological properties and dose-limiting toxicities associated with existing mono-molecular treatments. The unique and tunable surface chemistries of this targeted ultrasmall radiotherapeutic, coupled with its favorable pharmacokinetic properties, substantially improved treatment efficacy and demonstrated a clear survival benefit in melanoma models, which supports its further clinical translation.
Assuntos
Melanoma Experimental , Melanoma , Nanopartículas , Animais , Linhagem Celular Tumoral , Humanos , Melanoma/radioterapia , Dióxido de Silício , Distribuição Tecidual , alfa-MSH/metabolismoRESUMO
Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C' dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
Assuntos
Ferroptose/fisiologia , Osmose/fisiologia , Morte Celular/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Ferro/metabolismo , Células MCF-7 , Necrose/metabolismo , Necrose/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Células U937RESUMO
PURPOSE: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. EXPERIMENTAL DESIGN: Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. RESULTS: Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 µmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 µmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. CONCLUSIONS: Results underscore the clinical potential of DFO-Gef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desferroxamina/química , Desferroxamina/farmacologia , Sistemas de Liberação de Medicamentos , Gefitinibe/química , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Camundongos , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Dióxido de Silício/química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
An α particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C' dots, diameter â¼6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through α melanocyte-stimulating hormone peptides attached to the C' dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy α particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the α particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C' dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, MΦ and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic α-particle irradiation of melanoma using ultrasmall functionalized core-shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.
Assuntos
Partículas alfa/uso terapêutico , Portadores de Fármacos/química , Melanoma Experimental/radioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias Cutâneas/radioterapia , Microambiente Tumoral/efeitos da radiação , Actínio/administração & dosagem , Actínio/farmacocinética , Animais , Linhagem Celular Tumoral/transplante , Biologia Computacional , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imunidade Celular/genética , Imunidade Celular/efeitos da radiação , Masculino , Dose Máxima Tolerável , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Terapia de Alvo Molecular/métodos , Nanopartículas/química , RNA-Seq , Compostos Radiofarmacêuticos/farmacocinética , Receptor Tipo 1 de Melanocortina/antagonistas & inibidores , Receptor Tipo 1 de Melanocortina/metabolismo , Dióxido de Silício/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Distribuição Tecidual , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
PURPOSE: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. EXPERIMENTAL DESIGN: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. RESULTS: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. CONCLUSIONS: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dasatinibe/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Dióxido de Silício/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dasatinibe/química , Modelos Animais de Doenças , Glioblastoma/patologia , Radioisótopos do Iodo/química , Camundongos , Nanopartículas/química , Gradação de Tumores , Oligopeptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Proteínas Quinases/química , Radioisótopos/química , Zircônio/químicaRESUMO
BACKGROUND: Interpreting volume of activation maps of brain tumor patients remains difficult using blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) methods. A time-resolved fMRI may offer an informative strategy for investigating the possibility of functional reorganization by elucidating temporal variations in the activation of cortical structures . The aim of this study is to use time-resolved fMRI to investigate potential alterations in the spatially-varying and time-dependent hemodynamic response function within the supplementary motor area (SMA) and primary motor cortex (PMC) in the presence of an adjacent brain tumor, relative to normal control subjects. MATERIAL/METHODS: Fifteen patients and eight healthy volunteers were recruited. By utilizing a brief motor paradigm that exerts a differential effect on the activation of these structures, latency differences in the hemodynamic responses of such areas may be sensitively investigated. The present study determines the utility of this approach in brain tumor patients by examining the time to peak of the BOLD hemodynamic response within the SMA and PMC. RESULTS: In patients with glial tumors involving the PMC, the activation of the SMA was delayed and approached that of the PMC with time-to-peak difference between the PMC and SMA averaging 0.2 s. This delay in SMA activation was seen in all patients with glial tumors involving the PMC. CONCLUSIONS: The results suggest that in patients with high-grade brain tumors invading the PMC , the SMA may assume a greater role in the execution of primary motor activities, in addition to its role in executive motor planning.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Hemodinâmica , Córtex Motor/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Cell death can occur through numerous regulated mechanisms that are categorized by their molecular machineries and differing effects on physiology. Apoptosis and necrosis, for example, have opposite effects on tissue inflammation due to their different modes of execution. Another feature that can distinguish different forms of cell death is that they have distinct intrinsic effects on the cell populations in which they occur. For example, a regulated mechanism of necrosis called ferroptosis has the unusual ability to spread between cells in a wave-like manner, thereby eliminating entire cell populations. Here we discuss the ways in which cell death can propagate between cells in normal physiology and disease, as well as the potential exploitation of cell death propagation for cancer therapy.
Assuntos
Apoptose/fisiologia , Entose/fisiologia , Ferroptose/fisiologia , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Efeito Espectador/efeitos dos fármacos , Efeito Espectador/efeitos da radiação , Entose/efeitos dos fármacos , Entose/efeitos da radiação , Ferroptose/efeitos dos fármacos , Ferroptose/efeitos da radiação , Humanos , Modelos Animais , Neoplasias/terapia , Radioterapia/métodosRESUMO
PURPOSE: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival. EXPERIMENTAL DESIGN: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival. RESULTS: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases back toward normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time-to-progression or overall survival. CONCLUSIONS: These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available.
Assuntos
Quimiorradioterapia , Glioblastoma/diagnóstico por imagem , Neoplasia Residual/diagnóstico por imagem , Adulto , Idoso , Tamanho Celular/efeitos dos fármacos , Tamanho Celular/efeitos da radiação , Progressão da Doença , Fracionamento da Dose de Radiação , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Neoplasia Residual/radioterapia , Sódio/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiaçãoRESUMO
Although important advances have been achieved in the development of radiolabeled prostate-specific membrane antigen (PSMA)-targeting ligand constructs for both diagnosis and therapy of prostate cancer (PCa) over the past decade, challenges related to off-target effects and limited treatment responses persist. In this study, which builds upon the successful clinical translation of a series of ultrasmall, dye-encapsulating core-shell silica nanoparticles, or Cornell Prime Dots (C' dots), for cancer management, we sought to address these limitations by designing a dual-modality, PSMA-targeting platform that evades undesirable accumulations in the salivary glands, kidneys, and reticuloendothelial system, while exhibiting bulk renal clearance. This versatile PCa-targeted particle imaging probe offers significant clinical potential to improve future theranostic applications in a variety of patient care settings.
Assuntos
Rim/metabolismo , Nanopartículas/metabolismo , Tomografia por Emissão de Pósitrons/instrumentação , Dióxido de Silício/metabolismo , Animais , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Nanopartículas/química , Antígeno Prostático Específico/antagonistas & inibidores , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Dióxido de Silício/química , Nanomedicina TeranósticaRESUMO
Accurate detection and quantification of metastases in regional lymph nodes remain a vital prognostic predictor for cancer staging and clinical outcomes. As intratumoral heterogeneity poses a major hurdle to effective treatment planning, more reliable image-guided, cancer-targeted optical multiplexing tools are critically needed in the operative suite. For sentinel lymph node mapping indications, accurately interrogating distinct molecular signatures on cancer cells in vivo with differential levels of sensitivity and specificity remains largely unexplored. To address these challenges and demonstrate sensitivity to detecting micrometastases, we developed batches of spectrally distinct 6-nm near-infrared fluorescent core-shell silica nanoparticles, each batch surface-functionalized with different melanoma targeting ligands. Along with PET imaging, particles accurately detected and molecularly phenotyped cancerous nodes in a spontaneous melanoma miniswine model using image-guided multiplexing tools. Information afforded from these tools offers the potential to not only improve the accuracy of targeted disease removal and patient safety, but to transform surgical decision-making for oncological patients.
Assuntos
Melanoma/genética , Melanoma/cirurgia , Nanopartículas/química , Tamanho da Partícula , Dióxido de Silício/química , Cirurgia Assistida por Computador , Animais , Linhagem Celular Tumoral , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/patologia , Melanoma/diagnóstico por imagem , Camundongos , Imagem Multimodal , Nanopartículas/ultraestrutura , Imagem Óptica , Fenótipo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Biópsia de Linfonodo Sentinela , Suínos , Porco MiniaturaRESUMO
UNLABELLED: 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), a partially metabolized thymidine analog, has been used in preclinical and clinical settings for the diagnostic evaluation and therapeutic monitoring of tumor proliferation status. We investigated the use of (18)F-FLT for detecting and characterizing genetically engineered mouse (GEM) high-grade gliomas and evaluating the pharmacokinetics in GEM gliomas and normal brain tissue. Our goal was to develop a robust and reproducible method of kinetic analysis for the quantitative evaluation of tumor proliferation. METHODS: Dynamic (18)F-FLT PET imaging was performed for 60 min in glioma-bearing mice (n = 10) and in non-tumor-bearing control mice (n = 4) by use of a dedicated small-animal PET scanner. A 3-compartment, 4-parameter model was used to characterize (18)F-FLT kinetics in vivo. For compartmental analysis, the arterial input was measured by placing a region of interest over the left ventricular blood pool and was corrected for partial-volume averaging. The (18)F-FLT "trapping" and tissue flux model parameters were correlated with measured uptake (percentage injected dose per gram [%ID/g]) values at 60 min. RESULTS: (18)F-FLT uptake values (%ID/g) at 1 h in brain tumors were significantly greater than those in control brains (mean +/- SD: 4.33 +/- 0.58 and 0.86 +/- 0.22, respectively; P < 0.0004). Kinetic analyses of the measured time-activity curves yielded independent, robust estimates of tracer transport and metabolism, with compartmental model-derived time-activity data closely fitting the measured data. Except for tracer transport, statistically significant differences were found between the applicable model parameters for tumors and normal brains. The tracer retention rate constant strongly correlated with measured (18)F-FLT uptake values (r = 0.85, P < 0.0025), whereas a more moderate correlation was found between net (18)F-FLT flux and (18)F-FLT uptake values (r = 0.61, P < 0.02). CONCLUSION: A clinically relevant mouse glioma model was characterized by both static and dynamic small-animal PET imaging of (18)F-FLT uptake. Time-activity curves were kinetically modeled to distinguish early transport from a subsequent tracer retention phase. Estimated (18)F-FLT rate constants correlated positively with %ID/g measurements. Dynamic evaluation of (18)F-FLT uptake offers a promising approach for noninvasively assessing cellular proliferation in vivo and for quantitatively monitoring new antiproliferation therapies.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Didesoxinucleosídeos , Modelos Animais de Doenças , Glioma/diagnóstico por imagem , Glioma/patologia , Tomografia por Emissão de Pósitrons/métodos , Animais , Neoplasias Encefálicas/metabolismo , Didesoxinucleosídeos/farmacocinética , Glioma/metabolismo , Radioisótopos do Iodo/farmacocinética , Taxa de Depuração Metabólica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Distribuição TecidualRESUMO
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 UnidosRESUMO
The poor prognosis associated with malignant melanoma has not changed substantially over the past 30 years. Targeted molecular therapies, such as immunotherapy, have shown promise but suffer from resistance and off-target toxicities, underscoring the need for alternative therapeutic strategies that can be used in combination with existing protocols. Moreover, peptides targeting melanoma-specific markers, like the melanocortin-1 receptor (MC1-R), for imaging and therapy exhibit high renal uptake that limits clinical translation. In the current study, the application of ultrasmall fluorescent (Cy5) silica nanoparticles (C' dots), conjugated with MC1-R targeting alpha melanocyte stimulating hormone (αMSH) peptides on the polyethylene glycol (PEG) coated surface, is examined for melanoma-selective imaging. αMSH peptide sequences, evaluated for conjugation to the PEG-Cy5-C' dot nanoparticles, bound to MC1-R with high affinity and targeted melanoma in syngenetic and xenografted melanoma mouse models. Results demonstrated a 10-fold improvement in MC1-R affinity over the native peptide alone following surface attachment of the optimal αMSH peptide. Systematic in vivo studies further demonstrated favorable in vivo renal clearance kinetics as well as receptor-mediated tumor cell internalization of as-developed radiolabeled particle tracers in B16F10 melanoma bearing mice. These findings highlight the ability of αMSH-PEG-Cy5-C' dots to overcome previous hurdles that prevented clinical translation of peptide and antibody-based melanoma probes and reveal the potential of αMSH-PEG-Cy5-C' dots for melanoma-selective imaging, image-guided surgery, and therapeutic applications.