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1.
Nanotechnology ; 35(24)2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38408368

RESUMEN

The crossing of the blood-brain barrier (BBB) for conventional anticancer drugs is still a big challenge in treating glioma. The biomimetic nanoparticle delivery system has attracted increasing attention and has a promising future for crossing the BBB. Herein, we construct a multifunctional biomimetic nanoplatform using the erythrocyte membrane (EM) with the tumor-penetrating peptide iRGD (CRGDK/RGPD/EC) as a delivery, and the inner core loaded with the chemotherapeutic drug temozolomide (TMZ). The resulting biomimetic nanoparticle has perfect biocompatibility and stealth ability, which will provide more chances to escape the reticuloendothelial system (RES) entrapment, and increase the opportunity to enter the tumor site. Moreover, the decorated iRGD has been extensively used to actively targeting and deliver therapeutic agents across the BBB into glioma tissue. We show that this biomimetic delivery of TMZ with a diameter of 22 nm efficiently slowed the growth of glioblastoma multiforme (GBM) and increased the survival rate of the 30 d from 0% to 100%.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Membrana Eritrocítica , Biomimética , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico
2.
Mol Divers ; 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38878213

RESUMEN

Identifying tumor cells can be challenging due to cancer's complex and heterogeneous nature. Here, an efficacious phosphorescent probe that can precisely highlight tumor cells has been created. By combining the ruthenium(II) complex with oligonucleotides, we have developed a nanosized functional ruthenium(II) complex (Ru@DNA) with dimensions ranging from 300 to 500 nm. Our research demonstrates that Ru@DNA can readily traverse biomembranes via ATP-dependent endocytosis without carriers. Notably, the nanosized ruthenium(II) complex exhibits rapid and selective accumulation within tumor cells, possibly attributed to the nanoparticles' enhanced permeation and retention (EPR) effect. Ru@DNA can also effectively discern and label the transplanted cancer cells in the zebrafish model. Moreover, Ru@DNA is efficiently absorbed into the intestine and further distributed in the pancreas. Our findings underscore the potential of Ru@DNA as a DNA-based nanodevice derived from a functional ruthenium(II) complex. This innovative nanodevice holds promise as an efficient phosphorescent probe for both in vitro and in vivo imaging of living tumor cells.

3.
Nanomedicine ; 48: 102636, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36549553

RESUMEN

In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20-30 µg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.


Asunto(s)
Antineoplásicos , Neoplasias , Fotoquimioterapia , Humanos , Ácido Aminolevulínico/farmacología , Ácido Aminolevulínico/uso terapéutico , Antineoplásicos/farmacología , Doxorrubicina/farmacología , Neoplasias/patología , Polímeros/química , Línea Celular Tumoral
4.
Int J Mol Sci ; 24(12)2023 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-37373227

RESUMEN

Over the past few decades, the enhanced permeability and retention (EPR) effect of nanomedicine has been a crucial phenomenon in targeted cancer therapy. Specifically, understanding the EPR effect has been a significant aspect of delivering anticancer agents efficiently to targeted tumors. Although the therapeutic effect has been demonstrated in experimental models using mouse xenografts, the clinical translation of the EPR effect of nanomedicine faces several challenges due to dense extracellular matrix (ECM), high interstitial fluid pressure (IFP) levels, and other factors that arise from tumor heterogeneity and complexity. Therefore, understanding the mechanism of the EPR effect of nanomedicine in clinics is essential to overcome the hurdles of the clinical translation of nanomedicine. This paper introduces the basic mechanism of the EPR effect of nanomedicine, the recently discussed challenges of the EPR effect of nanomedicine, and various strategies of recent nanomedicine to overcome the limitations expected from the patients' tumor microenvironments.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Animales , Ratones , Nanomedicina/métodos , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Permeabilidad , Microambiente Tumoral
5.
Pak J Med Sci ; 39(1): 236-240, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36694750

RESUMEN

Objective: To investigate the effect of hypertension on the (enhanced permeability and retention, EPR) effect induced by polymer nanomicelles in renal cell carcinoma in vitro. Methods: A total of 80 patients with renal cell carcinoma treated at the Department of Urology Surgery in the Dept. of Urology of the Affiliated Hospital of Hebei University from Oct. 2019 to Oct. 2020, were analyzed retrospectively. The hypertension group (experimental group) included 40 patients, and the normal blood pressure group (control group) included 40 patients. The diagnosis of renal clear cell carcinoma was confirmed by preoperative auxiliary examinations, such as ultrasonography and CT combined with postoperative pathological analysis. All patients underwent laparoscopic radical nephrectomy for renal cell carcinoma. Polymer nanomicelles (loaded with prolonium iodide) were perfused into the resected kidney specimens within the specified time. The iodine enrichment of polymer nanomicelles in renal tumors was assessed by CT scanning. The peak EPR effect and the time to the peak were statistically compared between the two groups. Results: No significant differences were found in age, sex, location of kidney disease, tumor location or tumor size between the two groups (p> 0.05). The peak (χ̄±S) of the EPR effect in experimental group was 3.60±0.95 ug/cm3 and 3.01±0.96 ug/cm3 in control group, respectively. There was significant difference between the two groups (p< 0.05). The time to the peak of the EPR effect was 3.76±0.75 h in experimental group and 3.82±0.93 hour in control group, respectively. No statistically significant difference was found in the time to the peak of the EPR effect between the two groups (p> 0.05). Conclusion: Hypertension has a certain effect on the EPR effect induced by polymer nanomicelles in renal cell carcinoma in vitro.

6.
Semin Cancer Biol ; 69: 77-90, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-31962173

RESUMEN

Cancer has thwarted as a major health problem affecting the global population. With an alarming increase in the patient population suffering from diverse varieties of cancers, the global demographic data predicts sharp escalation in the number of cancer patients. This can be expected to reach 420 million cases by 2025. Among the diverse types of cancers, the most frequently diagnosed cancers are the breast, colorectal, prostate and lung cancer. From years, conventional treatment approaches like surgery, chemotherapy and radiation therapy have been practiced. In the past few years, increasing research on molecular level diagnosis and treatment of cancers have significantly changed the realm of cancer treatment. Lately, uses of advanced chemotherapy and immunotherapy like treatments have gained significant progress in the cancer therapy, but these approaches have several limitations on their safety and toxicity. This has generated lot of momentum for the evolution of new drug delivery approaches for the effective delivery of anticancer therapeutics, which may improve the pharmacokinetic and pharmacodynamic effect of the drugs along with significant reduction in the side effects. In this regard, the protein-based nano-medicines have gained wider attention in the management of cancer. Proteins are organic macromolecules essential, for life and have quite well explored in developing the nano-carriers. Furthermore, it provides passive or active tumour cell targeted delivery, by using protein based nanovesicles or virus like structures, antibody drug conjugates, viral particles, etc. Moreover, by utilizing various formulation strategies, both the animal and plant derived proteins can be converted to produce self-assembled virus like nano-metric structures with high efficiency in targeting the metastatic cancer cells. Therefore, the present review extensively discusses the applications of protein-based nano-medicine with special emphasis on intracellular delivery/drug targeting ability for anticancer drugs.


Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanomedicina , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Proteínas/administración & dosificación , Animales , Humanos , Nanopartículas/química , Neoplasias/patología , Proteínas/química
7.
Nanomedicine ; 42: 102533, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35150904

RESUMEN

Molecular ultrasound imaging is a promising strategy for non-invasive and precise cancer diagnosis. Previously reported ultrasound contrast agents (UCAs) are mostly microbubbles or nanobubbles (NBs) larger than 200 nm, leading to less efficient tumor delivery. Here we synthesized NBs with a small size (~49 nm) and modified the NB surface with alanine-alanine-asparagine (NB-A) or arginine-glycine-aspartic acid peptide (NB-R) for concurrent active targeting towards legumain in tumor cells and integrin in tumor neovasculature. In vitro, the NB-A and NB-R presented echogenicity comparable with SonoVue MBs and showed specific binding with tumors cells and endothelial cells, respectively. In vivo, the combined NB-A/NB-R accumulated in tumor tissues selectively and provided ultrasound signals with prolonged duration and that were significantly stronger than non-targeted NBs, single-targeted NBs and SonoVue MBs. Overall, the dual targeted NBs served as efficient UCAs for specific imaging of breast cancer, and hold great potential for general cancer diagnosis/monitoring in the future.


Asunto(s)
Neoplasias de la Mama , Alanina , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Medios de Contraste/química , Cisteína Endopeptidasas , Células Endoteliales/metabolismo , Femenino , Humanos , Integrinas , Ratones , Ratones Endogámicos BALB C , Microburbujas , Imagen Molecular/métodos , Ultrasonografía/métodos
8.
Int J Mol Sci ; 24(1)2022 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-36614071

RESUMEN

Predicting the ability of nanoparticles (NP) to access the tumor is key to the success of chemotherapy using nanotherapeutics. In the present study, the ability of the dual NP-based theranostic system to accumulate in the tumor was evaluated in vivo using intravital microscopy (IVM) and MRI. The system consisted of model therapeutic doxorubicin-loaded poly(lactide-co-glycolide) NP (Dox-PLGA NP) and novel hybrid Ce3/4+-doped maghemite NP encapsulated within the HSA matrix (hMNP) as a supermagnetic MRI contrasting agent. Both NP types had similar sizes of ~100 nm and negative surface potentials. The level of the hMNP and PLGA NP co-distribution in the same regions of interest (ROI, ~2500 µm2) was assessed by IVM in mice bearing the 4T1-mScarlet murine mammary carcinoma at different intervals between the NP injections. In all cases, both NP types penetrated into the same tumoral/peritumoral regions by neutrophil-assisted extravasation through vascular micro- and macroleakages. The maximum tumor contrasting in MRI scans was obtained 5 h after hMNP injection/1 h after PLGA NP injection; the co-distribution level at this time reached 78%. Together with high contrasting properties of the hMNP, these data indicate that the hMNP and PLGA NPs are suitable theranostic companions. Thus, analysis of the co-distribution level appears to be a useful tool for evaluation of the dual nanoparticle theranostics, whereas assessment of the leakage areas helps to reveal the tumors potentially responsive to nanotherapeutics.


Asunto(s)
Nanopartículas , Neoplasias , Humanos , Ratones , Animales , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Albúmina Sérica Humana , Doxorrubicina , Neoplasias/terapia , Portadores de Fármacos , Línea Celular Tumoral
9.
Cancer Sci ; 112(8): 2939-2947, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34032331

RESUMEN

Antibody drugs have become the mainstream of cancer treatment due to advances in cancer biology and Ab engineering. However, several barriers to Ab therapy have also been identified. These include various mechanisms for Ab drug resistance, such as heterogeneity of antigen expression in tumor cells and reduction in antitumor immunity due to expression diversity, polymorphism of Fc receptors (FcR) in effector cells, and reduced function of effector cells. Countermeasures to each resistance mechanism are being investigated. This review focuses on barriers that impede the delivery of Ab drugs due to features of the solid tumor microenvironment. Unlike hematological malignancies, in which the target tumor cells are in blood vessels, clinical solid tumors contain cancer stroma, which interferes with the delivery of Ab drugs. In addition, the cancer mass itself interferes with the penetration of Ab drugs. In this article, I will consider the etiology of cancer stroma and propose a new Ab drug development strategy for solid cancer treatment centering on cancer stromal targeting (CAST) therapy using anti-insoluble fibrin Ab-drug conjugate (ADC), which can overcome the cancer stroma barrier. The recent success of ADCs, chimeric antigen receptor T cells (CAR-Ts), and Bi-specific Abs is changing the category of Ab drugs from molecular-targeted drugs based on growth signal inhibition to cancer-specific targeted therapies. Therefore, at the end of this review, I argue that it is time to reorient the concept of Ab drug development.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores Fc/genética , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/farmacología , Diseño de Fármacos , Resistencia a Antineoplásicos , Humanos , Modelos Moleculares , Neoplasias/genética , Neoplasias/inmunología , Polimorfismo Genético , Ingeniería de Proteínas , Microambiente Tumoral/efectos de los fármacos
10.
Bioorg Med Chem Lett ; 53: 128417, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34710623

RESUMEN

Human serum albumin (HSA), which is distributed throughout the blood, is used as a carrier for transporting drugs to tumors based on the enhanced permeability and retention (EPR) effect. To develop an agent for the in vivo radiolabeling of endogenous albumin, we designed and synthesized novel hydroxamamide (Ham)-based technetium-99m (99mTc) complexes, which contained a monovalent or bivalent 4-(4-iodophenyl)butyric acid (IA) derivative as an albumin binder (ALB) moiety ([99mTc]AB2 and [99mTc]ALB2, respectively), and evaluated their utility for in vivo tumor imaging. In an in vitro HSA-binding assay, [99mTc]AB2 and [99mTc]ALB2 showed greater binding to HSA than [99mTc]BHam, a 99mTc-Ham complex without an ALB moiety. In an in vivo biodistribution assay, [99mTc]ALB2 showed marked blood and tumor retention (25.13 and 4.61% injected dose (ID)/g, respectively, at 1 h postinjection), suggesting that the EPR effect had been induced. However, [99mTc]AB2 showed no marked blood or tumor retention (4.16 and 0.75% ID/g, respectively, at 1 h postinjection), probably because the affinity of the monovalent IA derivative for albumin was insufficient to induce the EPR effect. These findings indicated that the multivalent interactions of [99mTc]ALB2 had enhanced its affinity for albumin. 99mTc-complexes containing multivalent ALB moieties may be useful for tumor imaging.


Asunto(s)
Ácidos Hidroxámicos/química , Neoplasias/diagnóstico por imagen , Compuestos de Organotecnecio/química , Albúmina Sérica Humana/química , Animales , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Tecnecio
11.
Proc Natl Acad Sci U S A ; 115(45): 11454-11459, 2018 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-30348798

RESUMEN

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.


Asunto(s)
Neoplasias del Colon/diagnóstico por imagen , Complejos de Coordinación/farmacocinética , Radioisótopos de Galio/farmacocinética , Glioblastoma/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Medios de Contraste/química , Medios de Contraste/farmacocinética , Complejos de Coordinación/sangre , Complejos de Coordinación/química , Dendrímeros/química , Fluorodesoxiglucosa F18/química , Radioisótopos de Galio/sangre , Radioisótopos de Galio/química , Glioblastoma/patología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos con 1 Anillo , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/patología , Neoplasias de la Próstata/patología
12.
Molecules ; 26(12)2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34207832

RESUMEN

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA-TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.


Asunto(s)
Antineoplásicos/farmacología , Alcaloides Indólicos/farmacología , Nanopartículas/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Alcaloides Indólicos/química , Maleatos/química , Maleatos/farmacología , Ratones , Ratones Endogámicos BALB C , Micelas , Poliestirenos/química , Poliestirenos/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
13.
J Cell Physiol ; 235(5): 4814-4823, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31663620

RESUMEN

CD8+ T cells play a vital role in cancer immunotherapy and can be shaped by metabolism. Avasimibe is an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor, which has been clinically verified safe in other phase Ⅲ clinical trials. It can potentiate the killing function of CD8+ T cells by modulating cholesterol metabolism. Doxorubicin (DOX) is an anticancer drug widely used in many cancers to induce tumor cell apoptosis. Unfortunately, DOX also can induce toxic and side effects in many organs, compromising its usage and efficacy. Herein, we report the combinational usage of avasimibe and a safe pH sensitive nano-drug delivery system composing of DOX and metal-organic frameworks nanoparticles (MNPs). Our findings demonstrated that DOX-MNPs treatment inhibited tumor growth with good safety profile and avasimibe treatment combined DOX-MNPs treatment exhibited a better efficacy than monotherapies in 4T1 breast cancer therapy.


Asunto(s)
Acetamidas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Portadores de Fármacos , Inmunoterapia , Nanopartículas del Metal , Sulfonamidas/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Citotoxicidad Inmunológica/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/toxicidad , Composición de Medicamentos , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Biochem Biophys Res Commun ; 525(2): 313-318, 2020 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-32087973

RESUMEN

For achieving efficient cancer treatment, it is important to elucidate the mechanism responsible for the accumulation of nanoparticles in tumor tissue. Recent studies suggest that nanoparticles are not delivered merely through gaps between tumor endothelial cells. We previously reported that the maturation of the vascular structure by the vascular endothelial cell growth factor receptor 2 (VEGFR2) using a previously developed siRNA delivery technology (RGD-MEND) significantly enhanced the accumulation of nanoparticles in types of cancers that area vessel-rich (renal cell carcinoma). This result was completely inconsistent with the generally accepted theory of the enhanced permeability and retention (EPR) effect. We hypothesized that a caveolin-1 (Cav1)-mediated transcellular route would be involved with the penetration of nanoparticles into tumor vasculature. To reveal the exact mechanism responsible for this enhancement, we observed the delivery of long-circulating liposomes (LPs) after Cav1 was co-suppressed by RGD-MEND with VEGFR2. The enhanced delivery of LPs by siRNA against VEGFR2 (siVEGFR2) was accompanied by the elevated expression of the Cav1 protein. In addition, Cav1 knockdown by siRNA against Cav1 (siCav1) canceled the enhanced delivery of LPs by siVEGFR2. The injection of siCav1 had no effect on the formation of alpha smooth muscle actin or vascular endothelial cell adhesion molecules. These results suggest that a Cav1-induced transcellular route and not a paracellular route, at least partially, contributes to the accumulation of nanoparticles in tumors.


Asunto(s)
Caveolina 1/fisiología , Liposomas/metabolismo , Neoplasias/metabolismo , Transcitosis , Animales , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/metabolismo , Caveolina 1/efectos de los fármacos , Humanos , Nanopartículas/metabolismo , Neoplasias/irrigación sanguínea , ARN Interferente Pequeño/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
15.
Nanomedicine ; 24: 102122, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31706037

RESUMEN

The flavoenzyme D-amino acid oxidase (DAAO) represents a potentially good option for cancer enzyme prodrug therapy as it produces H2O2 using D-amino acids as substrates, compounds present at low concentration in vivo and that can be safely administered to regulate H2O2 production. We optimized the cytotoxicity of the treatment by: i) using an efficient enzyme variant active at low O2 and D-alanine concentrations (mDAAO); ii) improving the stability and half-life of mDAAO and the enhanced permeability and retention effect by PEGylation; and iii) inhibiting the antioxidant cellular system by a heme oxygenase-1 inhibitor (ZnPP). A very low amount of PEG-mDAAO (10 mU, 50 ng of enzyme) induces cytotoxicity on various tumor cell lines. Notably, PEG-mDAAO seems well suited for in vivo evaluation as it shows the same cytotoxicity at air saturation (21%) and 2.5% O2, a condition resembling the microenvironment found in the central part of tumors.


Asunto(s)
Basidiomycota/enzimología , D-Aminoácido Oxidasa , Proteínas Fúngicas , Polietilenglicoles , Ingeniería de Proteínas , Animales , Basidiomycota/genética , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , D-Aminoácido Oxidasa/química , D-Aminoácido Oxidasa/genética , D-Aminoácido Oxidasa/farmacología , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/farmacología , Neoplasias/metabolismo , Neoplasias/patología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología
16.
Small ; 15(48): e1901930, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31259483

RESUMEN

Preferential accumulation of nanoparticles in a tumor is realized commonly by combined effects of active and passive targeting. However, passive targeting based on an enhanced permeation and retention (EPR) effect is not sufficient to observe clear tumor fluorescence images in most of the in vivo experiments using tumor-bearing mice. Herein, polyglycerol-functionalized nanodiamonds (ND-PG) conjugated with cyanine dye (Cy7) are synthesized and it is found that the resulting ND-PG-Cy7 is preferentially accumulated in the tumor, giving clear fluorescence in in vivo and ex vivo fluorescence images. One of the plausible reasons is the longer in vivo blood circulation time of ND-PG-Cy7 (half-life: 58 h determined by the pharmacokinetic analysis) than that of other nanoparticles (half-life: <20 h in most of the previous reports). In a typical example, the fluorescence intensity of tumors increases due to continuous tumor accumulation of ND-PG-Cy7, even more than one week postinjection. This may be owing to the stealth effect of PG that was reported previously, avoiding recognition and excretion by reticuloendothelial cells, which are abundant in liver and spleen. In fact, the fluorescence intensities from the liver and spleen is similar to those from other organs, while the tumor exhibits much stronger fluorescence in the ex vivo image.


Asunto(s)
Benzotiazoles/química , Carbocianinas/química , Glicerol/química , Rayos Infrarrojos , Nanodiamantes/química , Neoplasias/diagnóstico por imagen , Polímeros/química , Animales , Fluorescencia , Proteínas Fluorescentes Verdes/metabolismo , Células HeLa , Humanos , Hidrodinámica , Ratones Endogámicos BALB C , Ratones Desnudos , Nanodiamantes/ultraestructura , Imagen Óptica , Electricidad Estática , Factores de Tiempo
17.
Biotechnol Bioeng ; 116(5): 1201-1219, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30636289

RESUMEN

This paper presents the development of a vascularized breast tumor and healthy or tumorigenic liver microenvironments-on-a-chip connected in series. This is the first description of a vascularized multi tissue-on-a-chip microenvironment for modeling cancerous breast and cancerous/healthy liver microenvironments, to allow for the study of dynamic and spatial transport of particles. This device enables the dynamic determination of vessel permeability, the measurement of drug and nanoparticle transport, and the assessment of the associated efficacy and toxicity to the liver. The platform is utilized to determine the effect of particle size on the spatiotemporal diffusion of particles through each microenvironment, both independently and in response to the circulation of particles in varying sequences of microenvironments. The results show that when breast cancer cells were cultured in the microenvironments they had a 2.62-fold higher vessel porosity relative to vessels within healthy liver microenvironments. Hence, the permeability of the tumor microenvironment increased by 2.35- and 2.77-fold compared with a healthy liver for small and large particles, respectively. The extracellular matrix accumulation rate of larger particles was 2.57-fold lower than smaller particles in a healthy liver. However, the accumulation rate was 5.57-fold greater in the breast tumor microenvironment. These results are in agreement with comparable in vivo studies. Ultimately, the platform could be utilized to determine the impact of the tissue or tumor microenvironment, or drug and nanoparticle properties, on transport, efficacy, selectivity, and toxicity in a dynamic, and high-throughput manner for use in treatment optimization.


Asunto(s)
Neoplasias de la Mama/metabolismo , Dispositivos Laboratorio en un Chip , Neoplasias Hepáticas/metabolismo , Nanopartículas/química , Neovascularización Patológica/metabolismo , Microambiente Tumoral , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/patología , Línea Celular Tumoral , Matriz Extracelular/química , Femenino , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/patología , Neovascularización Patológica/patología , Tamaño de la Partícula
18.
Mol Ther ; 26(1): 70-83, 2018 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-29241971

RESUMEN

Metastasis is the cause of most (>90%) cancer deaths and currently lacks effective treatments. Approaches to understanding the biological process, unraveling the most effective molecular target(s), and implementing nanotechnology to increase the therapeutic index are expected to facilitate cancer therapy against metastasis. Here, we demonstrate the potential advantages of bringing these three approaches together through the rational design of a small interfering RNA (siRNA) that targets p70S6K in cancer stem cells (CSCs) in combination with dendrimer nanotechnology-based siRNA delivery. Our results demonstrated that the generation 6 (G6) poly(amidoamine) dendrimer can be used as a nanovector to effectively deliver p70S6K siRNA by forming uniform dendriplex nanoparticles that protect the siRNA from degradation. These nanoparticles were able to significantly knock down p70S6K in ovarian CSCs, leading to a marked reduction in CSC proliferation and expansion without obvious toxicity toward normal ovarian surface epithelial cells. Furthermore, treatment with the p70S6K siRNA/G6 dendriplexes substantially decreased mesothelial interaction, migration and invasion of CSCs in vitro, as well as tumor growth and metastasis in vivo. Collectively, these results suggest that p70S6K constitutes a promising therapeutic target, and the use of siRNA in combination with nanotechnology-based delivery may constitute a new approach for molecularly targeted cancer therapy to treat metastasis.


Asunto(s)
Dendrímeros , Técnicas de Transferencia de Gen , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/genética , ARN Interferente Pequeño/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Animales , Adhesión Celular , Movimiento Celular/genética , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Neoplasias Ováricas/patología , Interferencia de ARN , Estabilidad del ARN , ARN Interferente Pequeño/administración & dosificación , Recurrencia , Nanomedicina Teranóstica
19.
Prostate ; 78(9): 655-663, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29572902

RESUMEN

BACKGROUND: The SH-group at Cys-34 of human serum albumin (HSA) is a unique and accessible functional group that can be exploited for efficient linkage of a maleimide containing cytotoxic drug derivative to albumin. The specific maleimide chemistry used for production of the maleimide-linked albumin drug (MAD) is critical, however, to minimize the plasma concentration of "free" cytotoxic drug spontaneously released from albumin carrier thus decreasing dose-limiting host toxicity while enhancing the plasma half-life from minutes to days (ie, pharmacokinetic effect) and tissue concentration of the MAD in the extracellular cellular fluid at sites of cancer (ie, EPR effect). METHODS: To accomplish this goal, a chemical synthesis was developed using 2-fluoro-5-maleimidobenzoic acid to stably link the potent cytotoxic chemically modified analogue of the naturally occurring sesquiterpene γ-lactone, thapsigargin, 8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin (12ADT), to Cys-34 of albumin to produce 12ADT-MAD. RESULTS: Using FITC-labeling, LC/MS analysis, and in vitro growth and clonogenic survival assays on a series of 6 human prostate cancer lines (LNCaP, LAPC-4, VCap, CWR22Rv 1, PC3, and Du145), we documented that 12ADT-MAD is endocytosed by prostate cancer cells where it is degraded into its amino acids liberating cysteinyl-maleimide-12ADT which is both chemically stable at the acidic pH of 5.5 present in the endosome while retaining its high killing ability (IC50 50 nM) via SERCA inhibition. CONCLUSIONS: Based upon these positive in vitro validation results, the in vivo efficacy versus host toxicity of this 12-ADT-MAD approach is presently being evaluated against a series of patient derived androgen responsive and castration resistant human xenografts in immune-deficient mice.


Asunto(s)
Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos/métodos , Lactonas/farmacocinética , Maleimidas/farmacología , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Sesquiterpenos/farmacocinética , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , Citotoxinas/uso terapéutico , Líquido Extracelular/química , Líquido Extracelular/efectos de los fármacos , Humanos , Lactonas/síntesis química , Lactonas/química , Lactonas/uso terapéutico , Masculino , Maleimidas/síntesis química , Maleimidas/química , Maleimidas/uso terapéutico , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/secundario , Albúmina Sérica Humana/farmacología , Albúmina Sérica Humana/uso terapéutico , Sesquiterpenos/síntesis química , Sesquiterpenos/química , Sesquiterpenos/uso terapéutico
20.
Biochem Biophys Res Commun ; 498(1): 86-91, 2018 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-29470987

RESUMEN

One approach to increasing pharmacotherapy effects is administering drugs at times of day when they are most effective and/or best tolerated. Circadian variation in expression of pharmacokinetics- and pharmacodynamics-related genes was shown to contribute to dosing time-dependent differences in therapeutic effects of small molecule drugs. However, influence of dosing time of day on effects of high molecular weight formulations, such as drugs encapsulated in liposomes, has not been studied in detail. This study demonstrates that blood pressure rhythm affects dosing time-dependent variation in effects of high molecular weight formulations. Systolic blood pressure in sarcoma 180-bearing mice showed significant 24-h oscillation. Intratumoral accumulation of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA), an indicator of tumor vascular permeability, varied with dosing time of day, matching phases of blood pressure circadian rhythm. Furthermore, intratumoral accumulation of liposome-encapsulated oxaliplatin (Lipo-L-OHP) increased with increases in systolic blood pressure. Our findings suggest that circadian blood pressure oscillations may be an important factor to consider in dosing strategies for macromolecular drugs and liposomes in cancer therapy.


Asunto(s)
Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Composición de Medicamentos , Sustancias Macromoleculares/metabolismo , Sarcoma/metabolismo , Animales , Permeabilidad Capilar/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Liposomas , Masculino , Ratones Endogámicos ICR , Compuestos Organoplatinos/metabolismo , Oxaliplatino , Sarcoma/patología , Albúmina Sérica Bovina/metabolismo , Sístole/efectos de los fármacos , Factores de Tiempo
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