RESUMO
Nanoliposomes are one of the leading potential nano drug delivery systems capable of targeting chemotherapeutics to tumor sites because of their passive nano-targeting capability through the enhanced permeability and retention (EPR) effect for cancer patients. Recent advances in nano-delivery systems have inspired the development of a wide range of nanotargeted materials and strategies for applications in preclinical and clinical usage in the cancer field. Nanotargeted 188Re-liposome is a unique internal passive radiotheranostic agent for nuclear imaging and radiotherapeutic applications in various types of cancer. This article reviews and summarizes our multi-institute, multidiscipline, and multi-functional studied results and achievements in the research and development of nanotargeted 188Re-liposome from preclinical cells and animal models to translational clinical investigations, including radionuclide nanoliposome formulation, targeted nuclear imaging, biodistribution, pharmacokinetics, radiation dosimetry, radiation tumor killing effects in animal models, nanotargeted radionuclide and radio/chemo-combination therapeutic effects, and acute toxicity in various tumor animal models. The systemic preclinical and clinical studied results suggest 188Re-liposome is feasible and promising for in vivo passive nanotargeted radionuclide theranostics in future cancer care applications.
Assuntos
Lipossomos , Nanopartículas , Radioisótopos , Compostos Radiofarmacêuticos , Rênio , Pesquisa Translacional Biomédica , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Lipossomos/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/mortalidade , Neoplasias/terapia , Avaliação de Resultados em Cuidados de Saúde , Radiometria , Compostos Radiofarmacêuticos/química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Nanomedicina Teranóstica/métodos , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Pesquisa Translacional Biomédica/métodosRESUMO
Nanotargeted liposomes may be modified with targeting peptide on the surface of a prepared liposome to endow specificity and elevate targeting efficiency. The aim of this study was to develop a radioactive targeted nanoparticle, the 111In-cyclic RGDfK-liposome, and its advantage of recognizing the αVß3 integrin was examined. The cyclic RGDfK modified liposomes were demonstrated the ability to bind the αVß3 integrin expressed on the surface of human melanoma cell in vitro and in vivo. The effects of the cyclic RGDfK-liposome on the functioning of phagocytes was also examined, showing no considerable negative effects on the engulfment of bacteria and the generation of reactive oxygen species. Based upon these findings, the cyclic RGDfK- liposome is said to be a promising agent for tumor imaging.
Assuntos
Radioisótopos de Índio/química , Integrina alfaVbeta3/metabolismo , Lipossomos/química , Melanoma/metabolismo , Peptídeos Cíclicos/química , Animais , Adesão Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Peptídeos/química , Fagócitos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Microtomografia por Raio-XRESUMO
Epidermal growth factor receptor (EGFR) specific therapeutics is of great importance in cancer treatment. Fcy-hEGF fusion protein, composed of yeast cytosine deaminase (Fcy) and human EGF (hEGF), is capable of binding to EGFR and enzymatically convert 5-fluorocytosine (5-FC) to 1000-fold toxic 5-fluorocuracil (5-FU), thereby inhibiting the growth of EGFR-expressing tumor cells. To develop EGFR-specific therapy, 188Re-liposome-Fcy-hEGF was constructed by insertion of Fcy-hEGF fusion protein onto the surface of liposomes encapsulating of 188Re. Western blotting, MALDI-TOF, column size exclusion and flow cytometry were used to confirm the conjugation and bio-activity of 188Re-liposome-Fcy-hEGF. Cell lines with EGFR expression were subjected to treat with 188Re-liposome-Fcy-hEGF/5-FC in the presence of 5-FC. The 188Re-liposome-Fcy-hEGF/5-FC revealed a better cytotoxic effect for cancer cells than the treatment of liposome-Fcy-hEGF/5-FC or 188Re-liposome-Fcy-hEGF alone. The therapeutics has radio- and chemo-toxicity simultaneously and specifically target to EGFR-expression tumor cells, thereby achieving synergistic anticancer activity.
Assuntos
Citosina Desaminase/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Fluoruracila/farmacologia , Neoplasias/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citosina Desaminase/química , Fator de Crescimento Epidérmico/química , Flucitosina/metabolismo , Fluoruracila/metabolismo , Humanos , Lipossomos/química , Células MCF-7 , Neoplasias/patologia , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Rênio/químicaRESUMO
Hypopharyngeal cancer (HPC) accounts for the lowest survival rate among all types of head and neck cancers (HNSCC). However, the therapeutic approach for HPC still needs to be investigated. In this study, a theranostic 188Re-liposome was prepared to treat orthotopic HPC tumors and analyze the deregulated microRNA expressive profiles. The therapeutic efficacy of 188Re-liposome on HPC tumors was evaluated using bioluminescent imaging followed by next generation sequencing (NGS) analysis, in order to address the deregulated microRNAs and associated signaling pathways. The differentially expressed microRNAs were also confirmed using clinical HNSCC samples and clinical information from The Cancer Genome Atlas (TCGA) database. Repeated doses of 188Re-liposome were administrated to tumor-bearing mice, and the tumor growth was apparently suppressed after treatment. For NGS analysis, 13 and 9 microRNAs were respectively up-regulated and down-regulated when the cutoffs of fold change were set to 5. Additionally, miR-206-3p and miR-142-5p represented the highest fold of up-regulation and down-regulation by 188Re-liposome, respectively. According to Differentially Expressed MiRNAs in human Cancers (dbDEMC) analysis, most of 188Re-liposome up-regulated microRNAs were categorized as tumor suppressors, while down-regulated microRNAs were oncogenic. The KEGG pathway analysis showed that cancer-related pathways and olfactory and taste transduction accounted for the top pathways affected by 188Re-liposome. 188Re-liposome down-regulated microRNAs, including miR-143, miR-6723, miR-944, and miR-136 were associated with lower survival rates at a high expressive level. 188Re-liposome could suppress the HPC tumors in vivo, and the therapeutic efficacy was associated with the deregulation of microRNAs that could be considered as a prognostic factor.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Hipofaríngeas/radioterapia , Lipossomos/química , MicroRNAs/genética , Polietilenoglicóis/química , Radioisótopos/administração & dosagem , Radioisótopos/uso terapêutico , Rênio/administração & dosagem , Rênio/uso terapêutico , Animais , Cápsulas , Linhagem Celular Tumoral , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/patologia , Camundongos , Radioisótopos/química , Rênio/química , Análise de SobrevidaRESUMO
Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA-200 (miR-200) has been reported to inhibit metastasis in cancer cells. Herein, pH-sensitive and peptide-modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR-200, respectively. These peptides include one cell-penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria-targeting peptide. The peptide-modified nanoparticles are further coated with a pH-sensitive PEG-lipid derivative with an imine bond. These specially-designed nanoparticles exhibit pH-responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR-200 by SLN further increases the cytotoxicity of irinotecan-loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/ß-catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC-bearing mice, the in vivo results further indicate that irinotecan and miR-200 in pH-responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate ß-catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH-responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.
Assuntos
Neoplasias Colorretais/metabolismo , Irinotecano/uso terapêutico , MicroRNAs/administração & dosagem , MicroRNAs/uso terapêutico , Nanopartículas/química , Animais , Apoptose/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Endocitose/fisiologia , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Marcação In Situ das Extremidades Cortadas , Irinotecano/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
BACKGROUND: The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial-mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells. RESULTS: Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways. CONCLUSION: This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib.
Assuntos
Afatinib/química , Antineoplásicos/química , Lipídeos/química , MicroRNAs/química , Nanopartículas/química , Peptídeos/química , Polímeros/química , Afatinib/farmacologia , Afatinib/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.
Assuntos
Autofagia/efeitos dos fármacos , Lipossomos/química , Mitocôndrias/efeitos dos fármacos , Compostos Radiofarmacêuticos/toxicidade , Animais , Antígeno Ca-125/sangue , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Nanomedicina , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/radioterapia , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/uso terapêutico , Rênio/química , Transplante HeterólogoRESUMO
N,N-Bis(2-mercaptoethyl)-N',N'-diethylenediamine (BMEDA) is used in the preparation of the (188)Re-BMEDA-liposome as a chelator to deliver rhenium 188 into liposomes. Although the safety of the (188)Re-BMEDA-liposome had been established, the use of BMEDA in preparing the liposome is of interest; however, an assessment of its safety is warranted. In this present work, we report on the acute toxicity study of BMEDA in beagles to identify doses causing no adverse effect and doses causing life-threatening toxicity. In a single dose 14-day systemic toxicity study conducted in beagles, BMEDA was without compound-related adverse effects at doses of up to 2mg/kg in a series of clinical observations and clinical pathology examinations. The results of these studies could aid in choosing doses for repeat-dose studies and in the selection of starting doses for Phase 1 human studies.
Assuntos
Etilenodiaminas/administração & dosagem , Etilenodiaminas/toxicidade , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Testes de Toxicidade Aguda , Animais , Cães , Relação Dose-Resposta a Droga , Feminino , Injeções Intravenosas , Lipossomos , Masculino , Radioisótopos/administração & dosagem , Rênio/administração & dosagemRESUMO
The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 (188Re) to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles' plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0-t and AUC0-∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.
Assuntos
Etilenodiaminas/administração & dosagem , Etilenodiaminas/farmacocinética , Administração Intravenosa , Animais , Cromatografia Líquida , Cães , Feminino , Lipossomos , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
Nanoliposomes are good drug delivery systems that allow the encapsulation of drugs into vesicles for their delivery. The objective of this study is to investigate the therapeutic efficacy of a new radio-therapeutics of (188)Re-labeled pegylated liposome in a C26 murine colon carcinoma solid tumor model. The safety of (188)Re-liposome was evaluated before radiotherapy treatment. The anti-tumor effect of (188)Re-liposome was assessed by tumor growth inhibition, survival ratio and ultrasound imaging. Apoptotic marker in tumor was also evaluated by the TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) method after injection of (188)Re-liposome. The group treated with (188)Re-liposome displayed slight loss in body weight and decrease in white blood cell (WBC) count 7 to 14 days post-injection. With respect to therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI = 0.140; 80 day) than those treated with anti-cancer drug 5-FU (MGI = 0.195; 69 day) and untreated control mice (MGI = 0.413; 48 day). The ultrasound imaging showed a decrease in both tumor volume and number of blood vessels. There were significantly more apoptotic nuclei (TUNEL-positive) in (188)Re-liposome-treated mice at 8 h after treatment than in control mice. These results evidenced the potential benefits achieved by oncological application of the radio-therapeutics (188)Re-liposome for adjuvant cancer treatment.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Etilenodiaminas/uso terapêutico , Lipossomos/uso terapêutico , Compostos Organometálicos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Etilenodiaminas/administração & dosagem , Etilenodiaminas/toxicidade , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Injeções Intravenosas , Marcação por Isótopo , Lipossomos/administração & dosagem , Lipossomos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Análise de Sobrevida , Resultado do Tratamento , UltrassonografiaRESUMO
(188)Re/(186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine-labeled pegylated liposome ((188)Re-BMEDA-liposome) has been proven as a promising candidate for cancer therapy in tumor-rodent models. (188)Re-BMEDA complexes should be prepared for the radiolabeling of liposomes. This article describes the acute toxicity of BMEDA in Imprinting Control Region (ICR) mice. Treated mice were administered with BMEDA at dose levels of 3, 6, 9, and 12 mg/kg, with a dose volume of 10 mL/kg. The control mice were administered 10 mL/kg of vehicle control. The mice were observed for 14 days. Observations included mortality, clinical signs, total body-weight gains, food consumption, and gross necropsy findings. BMEDA exerted no adverse toxic effects in ICR mice at dose levels 3 mg/kg, which are up to 360,000 times higher than the intended human dose. The lethal-dose (LD(50)) value of BMEDA was 8.13 and 8.68 mg/kg in male and female mice, respectively.
Assuntos
Etilenodiaminas/toxicidade , Compostos Organometálicos/toxicidade , Compostos Radiofarmacêuticos/toxicidade , Animais , Etilenodiaminas/administração & dosagem , Feminino , Injeções Intravenosas , Dose Letal Mediana , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Compostos Organometálicos/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Testes de Toxicidade AgudaRESUMO
Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. The objective of this study was to investigate acute radiotoxicity of ¹88Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (¹88Re-BMEDA-liposome) in Sprague-Dawley rats. Rats were administered with ¹88Re-BMEDA-liposome, normal saline as blank or non-radioactive liposome as vehicle control via intravenous injection and observed for 14 days. Examinations were conducted with respect to mortality, clinical signs, food consumption, body weight and hematological and biochemical analyses. In addition, gross necropsy, histopathological examinations and cytogenetic analyses were also performed. None of the rats died and no clinical sign was observed during the 14-day study period. Rats administered with ¹88Re-BMEDA-liposome at dosage of 185 MBq displayed a significant weight loss compared with the control from study day (SD) 1 to SD 4, and the white blood cell count reduced to 5-10% of initial value (female: 18.55 ± 6.58 to 0.73 ± 0.26 x 10³ µl⻹; male: 14.52 ± 5.12 to 1.43 ± 0.54 x 10³ µl⻹) 7 days-post injection, but were found to have recovered on SD 15. There were no significant differences in biochemical parameters and histopathological assessments between the ¹88Re-BMEDA-liposome-treated and control groups. The frequencies of dicentric chromosomes were associated with dosage of ¹88Re-BMEDA-liposome. The information generated from this study on acute toxicity will serve as a safety reference for further subacute toxicity study in rats and human clinical trials.
Assuntos
Rênio/uso terapêutico , Animais , Quelantes/administração & dosagem , Quelantes/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Etilenodiaminas , Feminino , Injeções Intravenosas , Lipossomos/administração & dosagem , Lipossomos/química , Masculino , Compostos Organometálicos , Polietilenoglicóis/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Rênio/administração & dosagem , Testes de Toxicidade Aguda/métodosRESUMO
Gold nanostars (AuNSs), with unique physicochemical properties, are thought to be a promising agent for photothermal therapy (PTT). In this study, we prepared PEGylated gold nanostars (pAuNSs) using the HEPES-reduction method. The high photothermal conversion efficiency (â¼80%) and photothermal stability of pAuNSs were demonstrated in vitro and in vivo. 111In-DTPA-pAuNSs were prepared as a radioactive surrogate for the biodistribution studies of pAuNSs. In both microSPECT/CT images and the biodistribution study, the tumor-to-muscle (T/M) ratio reached a maximum at 24 h post intravenous injection of 111In-DTPA-pAuNSs. The high linear correlation between the 111In radioactivity and the gold content in the tumors (R2 0.86-0.99) indicated that 111In-DTPA-pAuNSs were appropriate for noninvasively tracking pAuNSs in vivo after systemic administration. Histological examination after silver enhancement staining clearly illustrated that the accumulated pAuNSs in the tumors were mainly located on the luminal surface of vessels. The mice bearing a SKOV-3 xenograft exhibited remarkable therapeutic efficacy with negligible organ damage after receiving pAuNS-mediated photothermal therapy. Our findings suggested that pAuNSs, together with their radioactive surrogate 111In-DTPA-pAuNSs, are promising for applications in image-guided photothermal therapy.
Assuntos
Ouro/farmacocinética , Nanopartículas Metálicas/uso terapêutico , Neoplasias/terapia , Fototerapia/métodos , Polietilenoglicóis/farmacocinética , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Feminino , Ouro/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Background: Head and neck cancer (HNC) is a major cause of morbidity and mortality and has a poor treatment outcome. Irinotecan, a topoisomerase-I inhibitor, induces cell death by decreasing the religation of double-strand DNA. However, epithelial-mesenchymal transition (EMT), therapy resistance, and systemic toxicity caused by available antineoplastic agents hinder the efficacy and safety of HNC treatment. Chemotherapy combined with gene therapy shows potential application in circumventing therapy resistance and EMT. miR-200 exerts a remarkable suppressing effect on EMT-associated genes. Herein, liposomes and solid lipid nanoparticles (SLNs) modified with a pH-sensitive, self-destructive polyethylene glycol (PEG) shell and different peptides were designed as irinotecan and miR-200 nanovectors to enhance tumor-specific accumulation. These peptides included one ligand targeting the angiogenic tumor neovasculature, one mitochondrion-directed apoptosis-inducing peptide, and one cell-penetrating peptide (CPP) with high potency and selectivity toward cancer cells. Methods: Physicochemical characterization, cytotoxicity analysis, cellular uptake, regulation mechanisms, and in vivo studies on miR-200- and irinotecan-incorporated nanoparticles were performed to identify the potential antitumor efficacy and biosafety issues involved in HNC treatment and to elucidate the underlying signaling pathways. Results: We found that the cleavable PEG layer responded to low extracellular pH, and that the CPP and targeting peptides were exposed to improve the uptake and release of miR-200 and irinotecan into HNC human tongue squamous carcinoma (SAS) cells. The apoptosis of SAS cells treated with the combinatorial therapy was significantly induced by regulating various pathways, such as the Wnt/ß-catenin, MDR, and EMT pathways. The therapeutic efficacy and safety of the proposed co-treatment outperformed the commercially available Onivyde and other formulations used in a SAS tumor-bearing mouse model in this study. Conclusion: Chemotherapy and gene therapy co-treatment involving pH-sensitive and targeting peptide-modified nanoparticles may be an innovative strategy for HNC treatment.
Assuntos
Ácidos/química , Peptídeos Penetradores de Células/farmacologia , Irinotecano/farmacologia , MicroRNAs/administração & dosagem , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Neoplasias da Língua/terapia , Animais , Apoptose , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Terapia Genética/métodos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Mitocôndrias/metabolismo , Nanopartículas/química , Neovascularização Patológica/metabolismo , Neoplasias da Língua/genética , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Inibidores da Topoisomerase I/farmacologia , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ((188)Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality (188)Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC((o-->infinity)) of (188)Re-DXR-liposome in blood, ascites and tumor was 9.3-, 4.2- and 4.7-fold larger than that of (188)Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated (188)Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after (188)Re-DXR-liposome (22.2 MBq of (188)Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of (188)Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; P<.05) in mice than radiotherapeutics of (188)Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel (188)Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications.
Assuntos
Ascite/terapia , Neoplasias do Colo/terapia , Doxorrubicina/análogos & derivados , Doxorrubicina/administração & dosagem , Polietilenoglicóis/uso terapêutico , Radioisótopos/uso terapêutico , Rênio/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Animais , Autorradiografia , Neoplasias do Colo/diagnóstico por imagem , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Estabilidade de Medicamentos , Marcação por Isótopo , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos BALB C , Nanotecnologia , Polietilenoglicóis/farmacocinéticaRESUMO
Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.
Assuntos
Neoplasias do Colo/diagnóstico por imagem , Etilenodiaminas/farmacocinética , Compostos Organometálicos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Autorradiografia , Portadores de Fármacos , Etilenodiaminas/síntese química , Processamento de Imagem Assistida por Computador , Injeções Intraperitoneais , Marcação por Isótopo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Compostos Organometálicos/síntese química , Polietilenoglicóis/química , Compostos Radiofarmacêuticos/síntese química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
Nanoliposomes are useful carriers in drug delivery. Radiolabeled nanoliposomes have potential applications in radiotherapy and diagnostic imaging. In this study, the biodistribution and pharmacokinetics of 188Re-BMEDA-labelled pegylated liposomes (RBLPL) and unencapsulated 188Re-BMEDA administered by the i.v. route in murine C26-colon tumour-bearing mice were investigated. MicroSPECT/CT images were performed to evaluate the distribution and tumor targeting of RBLPL in mice. For the biodistribution study, the highest uptake of liposome in tumors was 3.62% +/- 0.73% at 24 h after RBLPL administration, and the tumor to muscle ratio of RBLPL was 7.1-fold higher than that of 188Re-BMEDA. With image analysis, the highest SUV in tumor was 2.81 +/- 0.26 at 24 h after injection of RBLPL. The Pearson correlation analysis showed a positive correlation of tumor targeting or uptake of RBLPL between biodistribution and microSPECT semi-quantification imaging analysis (r = 0.633). The results of the pharmacokinetics revealed that the area under the tissue concentration-time curve (AUC) of RBLPL was 4.7-fold higher than that of unencapsulated 188Re-BMEDA. These results suggested the potential benefit and advantage of 188Re-labeled nanoliposomes for imaging and treatment of malignant diseases.
Assuntos
Neoplasias do Colo/metabolismo , Etilenodiaminas/administração & dosagem , Etilenodiaminas/farmacocinética , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Modelos Animais de Doenças , Estabilidade de Medicamentos , Etilenodiaminas/química , Marcação por Isótopo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/química , Radioisótopos , Compostos Radiofarmacêuticos/química , Rênio/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND PURPOSE: Cancer stem cells exhibit distinctive cellular metabolism compared with the more differentiated counterparts or normal cells. We aimed to investigate the impact of a novel radionuclide anti-cancer agent (188)Re-Liposome on stemness markers' expression and cellular metabolism in an ovarian cancer model. MATERIAL AND METHODS: A 2×2 factorial experiment was designed in which factor 1 represented the drug treatment comparing (188)Re-BMEDA, a free form of (188)Re, with (188)Re-Liposome, a nanoparticle-encapsulated form of (188)Re. Factor 2 represented the delivery route, comparing intravenous with intraperitoneal delivery. RESULTS: Intraperitoneal delivery of (188)Re-Liposome predominantly killed the CSCs-like cells in tumours and switched metabolism from glycolysis to oxidative phosphorylation. Further, intraperitoneal delivery of (188)Re-Liposome treatment was able to block epithelial-to-mesenchymal transition (EMT) and reactivate p53 function. Collectively, these molecular changes led to a striking tumour-killing effect. CONCLUSIONS: Radionuclides encapsulated in liposomes may represent a novel treatment for ovarian cancer when delivered intraperitoneally (a type of loco-regional delivery). In the future, this concept may be further extended for the treatment of several relevant cancers that have been proved to be suitable for loco-regional delivery of therapeutic agents, such as colon cancer, gastric cancer, and pancreatic cancer.
Assuntos
Glicólise , Neoplasias Ovarianas/radioterapia , Fosforilação Oxidativa , Radioisótopos/administração & dosagem , Rênio/administração & dosagem , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Humanos , Lipossomos , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Tolerância a Radiação , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Lipossomos , MicroRNAs/genética , Nanopartículas/química , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Rênio/farmacologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Rênio/química , Rênio/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma. MATERIALS AND METHODS: The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats. RESULTS: By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group. CONCLUSION: The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, (188)Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.