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1.
ACS Nano ; 14(8): 10127-10140, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32806051

RESUMO

Glioblastoma (GBM) is resistant to immune checkpoint inhibition due to its low mutation rate, phosphatase and tensin homologue (PTEN)-deficient immunosuppressive microenvironment, and high fraction of cancer stem-like cells (CSCs). Nanomedicines fostering immunoactivating intratumoral signals could reverse GBM resistance to immune checkpoint inhibitors (ICIs) for promoting curative responses. Here, we applied pH-sensitive epirubicin-loaded micellar nanomedicines, which are under clinical evaluation, to synergize the efficacy of anti-PD1antibodies (aPD1) against PTEN-positive and PTEN-negative orthotopic GBM, the latter with a large subpopulation of CSCs. The combination of epirubicin-loaded micelles (Epi/m) with aPD1 overcame GBM resistance to ICIs by transforming cold GBM into hot tumors with high infiltration of antitumor immune cells through the induction of immunogenic cell death (ICD), elimination of immunosuppressive myeloid-derived suppressor cells (MSDCs), and reduction of PD-L1 expression on tumor cells. Thus, Epi/m plus aPD1 eradicated both PTEN-positive and PTEN-negative orthotopic GBM and provided long-term immune memory effects. Our results indicate the high translatable potential of Epi/m plus aPD1 for the treatment of GBM.

2.
Sci Adv ; 6(26): eabb8133, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32637625

RESUMO

A major critical issue in systemically administered nanomedicines is nonspecific clearance by the liver sinusoidal endothelium, causing a substantial decrease in the delivery efficiency of nanomedicines into the target tissues. Here, we addressed this issue by in situ stealth coating of liver sinusoids using linear or two-armed poly(ethylene glycol) (PEG)-conjugated oligo(l-lysine) (OligoLys). PEG-OligoLys selectively attached to liver sinusoids for PEG coating, leaving the endothelium of other tissues uncoated and, thus, accessible to the nanomedicines. Furthermore, OligoLys having a two-armed PEG configuration was ultimately cleared from sinusoidal walls to the bile, while OligoLys with linear PEG persisted in the sinusoidal walls, possibly causing prolonged disturbance of liver physiological functions. Such transient and selective stealth coating of liver sinusoids by two-arm-PEG-OligoLys was effective in preventing the sinusoidal clearance of nonviral and viral gene vectors, representatives of synthetic and nature-derived nanomedicines, respectively, thereby boosting their gene transfection efficiency in the target tissues.

3.
Mol Pharm ; 17(6): 1835-1847, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315193

RESUMO

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with the potential to cross the blood-brain barrier; however, the concentrations necessary for a cytotoxic effect against cancer cells exceed the concentrations achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the three-dimensional (3D) models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration; however, if transport across the blood-brain barrier is sufficient to reach the therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

4.
J Control Release ; 321: 132-144, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32032656

RESUMO

Tumor resistance to tyrosine kinase inhibitors (TKIs) is an inexorable clinical event. The manipulation of adaptive changes in cancer cells while inhibiting the signaling pathways could be an effective strategy for overcoming TKI resistance toward reducing tumor relapse and prolonging survival. Here, we tested this approach by using polymeric nanomedicines delivering the pan-kinase inhibitor staurosporine (STS) to treat renal cell carcinoma (RCC) resistant to the multi-targeted TKI sunitinib. STS blocked the activity of TKI-resistant protein kinases and strongly inhibited adaptive dynamics in RCC cells promoted by MDR1 and GLUT1 to overcome sunitinib resistance. Co-delivery of STS and epirubicin directed to eliminate fast-proliferating cancer cells through the same nanomedicine platform enabled safe and potent in vivo efficacy in mouse models of RCC, overcoming sunitinib resistance and suppressing the development of metastasis. These results indicate our approach as a promising strategy for effectively managing TKI resistance.

5.
ACS Nano ; 13(11): 12732-12742, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31647640

RESUMO

Despite the rigidity of double-stranded DNA (dsDNA), its packaging is used to construct nonviral gene carriers due to its availability and the importance of its double-helix to elicit transcription. However, there is an increasing demand for more compact-sized carriers to facilitate tissue penetration, which may be easily fulfilled by using the more flexible single-stranded DNA (ssDNA) as an alternative template. Inspired by the adeno-associated virus (AAV) as a prime example of a transcriptionally active ssDNA system, we considered a methodology that can capture unpaired ssDNA within the polyplex micelle system (PM), an assembly of DNA and poly(ethylene glycol)-b-poly(l-lysine) (PEG-PLys). A micellar assembly retaining unpaired ssDNA was prepared by unpairing linearized pDNA with heat and performing polyion complexation on site with PEG-PLys. The PM thus formed had a compact and spherical shape, which was distinguishable from the rod-shaped PM formed from dsDNA, and still retained its ability to activate gene expression. Furthermore, we demonstrated that its capacity to encapsulate DNA was much higher than AAV, thereby potentially allowing the delivery of a larger variety of protein-encoding DNA. These features permit the ssDNA-loaded PM to easily penetrate the size-restricting stromal barrier after systemic application. Further, they can elicit gene expression in tumor cell nests of an intractable pancreatic cancer mouse model to achieve antitumor effects through suicide gene therapy. Thus, single-stranded DNA-packaged PM is appealing as a potential gene vector to tackle intractable diseases, particularly those with target delivery issues due to size-restriction barriers.

6.
Nat Commun ; 10(1): 1894, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31019193

RESUMO

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.


Assuntos
Antineoplásicos/metabolismo , Neoplasias Encefálicas/terapia , Regulação Neoplásica da Expressão Gênica , Nanoestruturas/química , Oligonucleotídeos/genética , Neoplasias Pancreáticas/terapia , RNA Interferente Pequeno/genética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Carbocianinas/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Corantes Fluorescentes/química , Humanos , Injeções Intravenosas , Masculino , Camundongos , Nanoestruturas/administração & dosagem , Oligonucleotídeos/síntese química , Oligonucleotídeos/metabolismo , Oligonucleotídeos/farmacocinética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Polietilenoglicóis/química , Polilisina/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/síntese química , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacocinética , Eletricidade Estática , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
7.
ACS Nano ; 13(2): 2357-2369, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30699292

RESUMO

Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (•OH), and •OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.

8.
J Control Release ; 295: 268-277, 2019 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-30639386

RESUMO

Cancer stem-like cells (CSCs) treatment is a plausible strategy for enhanced cancer therapy. Here we report a glucose-installed sub-50-nm nanocarrier for the targeted delivery of small interfering RNA (siRNA) to CSCs through selective recognition of the glucose ligand to the glucose transporter 1 (GLUT1) overexpressed on the CSC surface. The siRNA nanocarrier was constructed via a two-step assembling process. First, a glucose-installed poly(ethylene glycol)-block-poly(l-lysine) modified with lipoic acid (LA) at the ω-end (Glu-PEG-PLL-LA) was associated with a single siRNA to form a unimer polyion complex (uPIC). Second, a 20 nm gold nanoparticle (AuNP) was decorated with ~65 uPICs through AuS bonding. The glucose-installed targeted nanoparticles (Glu-NPs) exhibited higher cellular uptake of siRNA payloads in a spheroid breast cancer (MBA-MB-231) cell culture compared with glucose-unconjugated control nanoparticles (MeO-NPs). Notably, the Glu-NPs became more efficiently internalized into the CSC fraction, which was defined by aldehyde dehydrogenase (ALDH) activity assay, than the other fractions, probably due to the higher GLUT1 expression level on the CSCs. The Glu-NPs elicited significantly enhanced gene silencing in a CSC-rich orthotopic MDA-MB-231 tumor tissue following systemic administration to tumor-bearing mice. Ultimately, the repeated administrations of polo-like kinase 1 (PLK1) siRNA-loaded Glu-NPs significantly suppressed the growth of orthotopic MDA-MB-231 tumors. These results demonstrate that Glu-NP is a promising nanocarrier design for CSC-targeted cancer treatment.


Assuntos
Neoplasias da Mama/terapia , Transportador de Glucose Tipo 1/genética , Ouro/química , Nanopartículas Metálicas/química , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi , Animais , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose/química , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico
9.
J Control Release ; 264: 127-135, 2017 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-28842317

RESUMO

Breast cancer recurrence and resistance are associated with cancer stem-like cell (CSC) sub-populations. As conventional therapies fail to treat CSCs, institution of novel therapeutic strategies capable of eradicating both cancer cells and CSCs is central for achieving effective treatments with long-term survival. Here, we studied the ability of polymeric micelles cooperatively loading the cytotoxic drug epirubicin (Epi) and the CSC inhibitor staurosporine (STS) to treat breast tumors, particularly when tumors relapsed after chemotherapy. The STS/Epi-loaded micelles (STS/Epi/m) demonstrated potent therapeutic efficacy against both naïve orthotopic 4T1-luc breast tumors and their recurrent Epi-resistant counterparts, significantly prolonging survival. This efficacy enhancement of STS/Epi/m was correlated with the ability of the micelles to suppress the CSC-associated sub-populations of breast cancer, i.e. the aldehyde dehydrogenase-positive (ALDH+) population and the CD44+/CD24- fraction, in Epi-resistant cells and tumors. These results demonstrated STS/Epi/m as a promising strategy for effective management of breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Micelas , Estaurosporina/administração & dosagem , Aldeído Desidrogenase , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas , Polímeros/administração & dosagem , Carga Tumoral/efeitos dos fármacos
10.
J Control Release ; 261: 275-286, 2017 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-28666729

RESUMO

Recalcitrant head and neck squamous cell carcinoma (HNSCC) usually relapses after therapy due to the enrichment of drug resistant cancer stem-like cells (CSCs). Nanomedicines have shown potential for eradicating both cancer cells and CSCs by effective intratumoral navigation for reaching particular cell populations and controlling drug delivery. The installation of ligands on nanomedicines is an attractive approach for improving the delivery to CSCs within tumors, though the development of CSC-selective ligand-receptor systems has been challenging. Herein, we found that the CSC subpopulation in HNSCC cells overexpresses αvß5 integrins, which is preferentially expressed in tumor neovasculature and cancer cells, and can be effectively targeted by using cyclic Arg-Gly-Asp (cRGD) peptide. Thus, in this study, we propose installing cRGD peptide on micellar nanomedicines incorporating cisplatin for improving their activity against CSCs and enhancing survival. Both cisplatin-loaded micelles (CDDP/m) and cRGD-installed CDDP/m (cRGD-CDDP/m) were effective against HNSCC SAS-L1-Luc cells in vitro, though cRGD-installed CDDP/m was more potent than CDDP/m against the CSC fraction. In vivo, the cRGD-CDDP/m also showed significant antitumor activity against HNSCC orthotopic tumors, i.e. SAS-L1 and HSC-2. Moreover, cRGD-CDDP/m rapidly accumulated into the lymph node metastasis of SAS-L1 tumors, effectively inhibiting their growth, and prolonging mice survival. These findings indicate cRGD-installed nanomedicines as an advantageous strategy for targeting CSCs in HNSCC, and particularly, cRGD-CDDP/m as a significant therapeutic strategy against regionally advanced HNSCC.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Peptídeos Cíclicos/química , Animais , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas , Células-Tronco Neoplásicas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço
11.
ACS Nano ; 10(6): 5643-55, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27093466

RESUMO

Nanomedicines capable of control over drug functions have potential for developing resilient therapies, even against tumors harboring recalcitrant cancer stem cells (CSCs). By coordinating drug interactions within the confined inner compartment of core-shell nanomedicines, we conceived multicomponent nanomedicines directed to achieve synchronized and synergistic drug cooperation within tumor cells as a strategy for enhancing efficacy, overcoming drug resistance, and eradicating CSCs. The approach was validated by using polymeric micellar nanomedicines co-incorporating the pan-kinase inhibitor staurosporine (STS), which was identified as the most potent CSC inhibitor from a panel of signaling-pathway inhibitors, and the cytotoxic agent epirubicin (Epi), through rationally contriving the affinity between the drugs. The micelles released both drugs simultaneously, triggered by acidic endosomal pH, attaining concurrent intracellular delivery, with STS working as a companion for Epi, down-regulating efflux transporters and resistance mechanisms induced by Epi. These features prompted the nanomedicines to eradicate orthotopic xenografts of Epi-resistant mesothelioma bearing a CSC subpopulation.


Assuntos
Antineoplásicos/administração & dosagem , Nanomedicina , Células-Tronco Neoplásicas , Linhagem Celular Tumoral , Epirubicina/administração & dosagem , Humanos , Micelas
12.
Biomaterials ; 82: 221-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26763736

RESUMO

Systemic delivery of messenger RNA (mRNA) is technically challenging because mRNA is highly susceptible to enzymatic degradation in the blood circulation. In this study, we used a nanomicelle-based platform, prepared from mRNA and poly(ethylene glycol) (PEG)-polycation block copolymers. A cholesterol (Chol) moiety was attached to the ω-terminus of the block copolymer to increase the stability of the nanomicelle by hydrophobic interaction. After in vitro screening, polyaspartamide with four aminoethylene repeats in its side chain (PAsp(TEP)) was selected as the cationic segment of the block copolymer, because it contributes to enhance nuclease resistance and high protein expression from the mRNA. After intravenous injection, PEG-PAsp(TEP)-Chol nanomicelles showed significantly enhanced blood retention of mRNA in comparison to nanomicelles without Chol. We used the nanomicelles for treating intractable pancreatic cancer in a subcutaneous inoculation mouse model through the delivery of mRNA encoding an anti-angiogenic protein (sFlt-1). PEG-PAsp(TEP)-Chol nanomicelles generated efficient protein expression from the delivered mRNA in tumor tissue, resulting in remarkable inhibition of the tumor growth, whereas nanomicelles without Chol failed to show a detectable therapeutic effect. In conclusion, the stabilized nanomicelle system led to the successful systemic delivery of mRNA in therapeutic application, holding great promise for the treatment of various diseases.


Assuntos
Colesterol/química , Terapia Genética/métodos , Nanocápsulas/química , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , RNA Mensageiro/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Nanocápsulas/administração & dosagem , Nanocápsulas/ultraestrutura , Neoplasias Pancreáticas/genética , Tamanho da Partícula , Resultado do Tratamento
13.
J Control Release ; 220(Pt B): 783-91, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26474676

RESUMO

Lymph node metastasis (LNM) is correlated with decreased survival, indicating high tumor malignancy and being a potential source for subsequent fatal metastases. Targeted therapies inhibiting the formation of LNM, while eliminating established metastatic foci, could provide synergistic effects by reducing the incidence and growth of metastasis. Based on the inhibitory activity of cRGD peptide against the development of metastasis, and the LNM targeting ability of systemically injected drug-loaded polymeric micelles, herein, we studied the capability of cRGD-installed polymeric micelles incorporating the platinum anticancer drug (1,2-diaminocylohexane)platinum(II) (DACHPt) for cooperatively inhibiting the formation and progression of LNM. As cRGD-installed DACHPt-loaded micelles (cRGD-DACHPt/m) presented similar size, drug loading and surface charge to non-conjugated micelles (MeO-DACHPt/m), the differences in the biological performance of the micelles were endorsed to the effect of the ligand. In a syngeneic melanoma model, both MeO-DACHPt/m and cRGD-DACHPt/m showed comparable antitumor activity against the primary tumors and the established metastatic foci in lymph nodes. However, cRGD-DACHPt/m significantly enhanced the efficacy against LNM draining from primary tumors through the effective inhibition of the spreading of cancer cells. This improved inhibition was associated with the ability of cRGD-DACHPt/m to reduce the migration of melanoma cells, which was higher than that of MeO-DACHPt/m, free cRGD and their combination. These results support our strategy of using cRGD-installed micelles for attaining cooperative therapies against LNM exploiting the inhibitory function of the peptide and the cytotoxic effect of the micelles.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos , Melanoma Experimental/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Polímeros/química , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Química Farmacêutica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metástase Linfática , Melanoma Experimental/metabolismo , Melanoma Experimental/secundário , Camundongos Endogâmicos C57BL , Micelas , Compostos Organoplatínicos/química , Compostos Organoplatínicos/metabolismo , Tamanho da Partícula , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Propriedades de Superfície , Fatores de Tempo
14.
J Control Release ; 189: 1-10, 2014 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-24956488

RESUMO

Nanocarriers have been used for specific delivery of therapeutic agents to solid tumors based on the enhanced permeability and retention in cancerous tissues. Despite metastasis is the main reason of cancer-related death and a priority for nanocarrier-based therapies, the targeting ability of nanocarriers to the metastatic disease is poorly understood, especially for preangiogenic micrometastases as nanocarriers usually use the malignant neovasculature for enhancing their accumulation. Thus, herein, we studied the ability of micellar nanocarriers incorporating (1,2-diaminocyclohexane)platinum(II) (DACHPt) for treating liver metastases of bioluminescent murine colon adenocarcinoma C-26, during overt and preangiogenic metastatic stages. After intravenous injection, DACHPt-loaded micelles (DACHPt/m) effectively inhibited the tumor growth in both metastatic tumor models. While the anticancer activity of the micelles against overt metastases was associated with their selective accumulation in cancerous tissues having neovasculature, the ability of DACHPt/m to target preangiogenic metastases was correlated with the inflammatory microenvironment of the niche. This targeting capability of polymeric micelles to preangiogenic metastasis may provide a novel approach for early diagnosis and treatment of metastases.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Micrometástase de Neoplasia/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Inflamação , Neoplasias Hepáticas/secundário , Camundongos Endogâmicos BALB C , Micelas , Compostos Organoplatínicos/química , Polímeros/administração & dosagem , Polímeros/química
15.
Biomaterials ; 33(18): 4722-30, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22444644

RESUMO

Homo-poly{N'-[N-(2-aminoethyl)-2-aminoehtyl]aspartamide} [PAsp(DET), H] was attempted to integrate into poly (ethylene glycol) (PEG)-b-PAsp(DET)] (B) formulated polyplex micelle with the aim of enhancing cell transfection efficiency for PEGylated polyplex micelle via H integration. In vitro evaluations verified H integration of potent stimulation in enhancing cell-transfecting activity of PEGylated polyplex micelles via promoted cellular uptake and facilitated endosome escape. In vivo anti-angiogenic tumor suppression evaluations validated the feasibility of H integration in promoting gene transfection to the affected cells via systemic administration, where loaded anti-angiogenic gene remarkably expressed in the tumor site, thereby imparting significant inhibitory effect on the growth of vascular endothelial cells, ultimately leading to potent tumor growth suppression. These results demonstrated potency of H integration for enhanced transfection activity and potential usage in systemic applications, which could have important implications on the strategic use of H integration in the non-viral gene carrier design.


Assuntos
Terapia Genética/métodos , Micelas , Nanopartículas/química , Neoplasias Pancreáticas/terapia , Polietilenoglicóis/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Camundongos , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/efeitos adversos
16.
Mol Ther ; 20(4): 769-77, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22314292

RESUMO

Malignant pleural mesothelioma (MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor (uPAR). We here examined the potential of our new and powerful recombinant Sendai virus (rSeV), which shows uPAR-specific cell-to-cell fusion activity (rSeV/dMFct14 (uPA2), named "BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate (PDTC) or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I (RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/nuclear factor-κB (NF-κB) axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.


Assuntos
Mesotelioma/metabolismo , Mesotelioma/terapia , Vírus Oncolíticos/fisiologia , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/terapia , Vírus Sendai/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Mesotelioma/genética , Camundongos , Vírus Oncolíticos/genética , Neoplasias Pleurais/genética , RNA Interferente Pequeno , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vírus Sendai/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Neoplasia ; 12(11): 906-14, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21076616

RESUMO

We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs) activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacies of this method: 1) in more clinically relevant situations including metastatic diseases, 2) on other tumor types and other animal species, and 3) on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP)-activated bone marrow-derived DCs (rSeV/dF-GFP-DC), consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I) (rSeV/dF-RIGIC-DC), an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies.


Assuntos
Células Dendríticas/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias da Próstata/imunologia , Vírus Sendai/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imunoterapia Adotiva/métodos , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Mutação , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , RNA Helicases/genética , RNA Helicases/metabolismo , Ratos , Vírus Sendai/genética , Transdução de Sinais/imunologia
18.
Mol Ther ; 18(10): 1778-86, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20606645

RESUMO

Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named "BioKnife"] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-ß (IFN-ß) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-ß (BioKnife-IFNß), cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-ß, and in turn, IFN-ß significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNß may have significant potential to improve the survival of GM patients in a clinical setting.


Assuntos
Glioblastoma/terapia , Interferon beta/metabolismo , Vírus Oncolíticos/fisiologia , Vírus Sendai/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Interferon beta/genética , Imagem por Ressonância Magnética , Camundongos , Camundongos Nus , Vírus Oncolíticos/genética , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Ratos , Ratos Endogâmicos F344 , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vírus Sendai/genética , Ativador de Plasminogênio Tipo Uroquinase/genética
19.
J Immunol ; 183(7): 4211-9, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19734206

RESUMO

We recently demonstrated efficient antitumor immunity against murine tumors using dendritic cells (DCs) activated by recombinant Sendai viruses (rSeVs), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacy of this method in preventing metastatic diseases. In this study, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV (rSeV/dF) using a murine model of lung metastasis. Bolus and i.v. administration of DCs harboring rSeV/dF-expressing GFP without pulsation of tumor Ag (DC-rSeV/dF-GFP) 2 days before tumor inoculation showed efficient prevention against lung metastasis of c1300 neuroblastoma, but not of RM-9 prostatic cancer. We found that the timing of DC therapy was critical for the inhibition of pulmonary metastasis of RM-9, and that the optimal effect of DCs was seen 28 days before tumor inoculation. Interestingly, the antimetastatic effect was sustained for over 3 mo, even when administered DCs were already cleared from the lung and organs related to the immune system. Although NK cell activity had already declined to baseline at the time of tumor inoculation, Ab-mediated depletion studies revealed that CD4+ cells as well as the presence of, but not the activation of, NK cells were crucial to the prevention of lung metastasis. These results are the first demonstration of efficient inhibition of lung metastasis via bolus administration of virally activated DCs that was sustained and NK/CD4+ cell-dependent, and may suggest a potentially new mechanism of DC-based immunotherapy for advanced malignancies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Vírus Sendai/imunologia , Animais , Proliferação de Células , Citotoxicidade Imunológica/genética , Células Dendríticas/virologia , Neoplasias Pulmonares/patologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Neuroblastoma/imunologia , Terapia Viral Oncolítica , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/virologia , Vírus Sendai/genética , Fatores de Tempo , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
20.
PLoS One ; 4(8): e6674, 2009 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-19688095

RESUMO

BACKGROUND: Limitations of the clinical efficacy of dendritic cell (DC)-based immunotherapy, as well as difficulties in their industrial production, are largely related to the limited number of autologous DCs from each patient. We here established a possible breakthrough, a simple and cytokine-based culture method to realize a log-scale order of functional murine DCs (>1,000-fold), which cells were used as a model before moving to human studies. METHODOLOGY/PRINCIPAL FINDINGS: Floating cultivation of lineage-negative hematopoietic progenitors from bone marrow in an optimized cytokine cocktail (FLT3-L, IL-3, IL-6, and SCF) led to a stable log-scale proliferation of these cells, and a subsequent differentiation study using IL-4/GM-CSF revealed that 3-weeks of expansion was optimal to produce CD11b+/CD11c+ DC-like cells. The expanded DCs had typical features of conventional myeloid DCs in vitro and in vivo, including identical efficacy as tumor vaccines. CONCLUSIONS/SIGNIFICANCE: The concept of DC expansion should make a significant contribution to the progress of DC-based immunotherapy.


Assuntos
Citocinas/fisiologia , Células Dendríticas/citologia , Animais , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Teste de Cultura Mista de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL
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