scholarly journals Protein nanocages that penetrate airway mucus and tumor tissue

2017 ◽  
Vol 114 (32) ◽  
pp. E6595-E6602 ◽  
Author(s):  
Xinglu Huang ◽  
Jane Chisholm ◽  
Jie Zhuang ◽  
Yanyu Xiao ◽  
Gregg Duncan ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Surface Density ◽  
Tumor Tissue ◽  
Lung Tumor ◽  
Dependent Manner ◽  
Therapeutic Benefits ◽  
Intracellular Release ◽  
Mucus Gel

Reports on drug delivery systems capable of overcoming multiple biological barriers are rare. We introduce a nanoparticle-based drug delivery technology capable of rapidly penetrating both lung tumor tissue and the mucus layer that protects airway tissues from nanoscale objects. Specifically, human ferritin heavy-chain nanocages (FTn) were functionalized with polyethylene glycol (PEG) in a unique manner that allows robust control over PEG location (nanoparticle surface only) and surface density. We varied PEG surface density and molecular weight to discover PEGylated FTn that rapidly penetrated both mucus barriers and tumor tissues in vitro and in vivo. Upon inhalation in mice, PEGylated FTn with optimized PEGylation rapidly penetrated the mucus gel layer and thus provided a uniform distribution throughout the airways. Subsequently, PEGylated FTn preferentially penetrated and distributed within orthotopic lung tumor tissue, and selectively entered cancer cells, in a transferrin receptor 1-dependent manner, which is up-regulated in most cancers. To test the potential therapeutic benefits, doxorubicin (DOX) was conjugated to PEGylated FTn via an acid-labile linker to facilitate intracellular release of DOX after cell entry. Inhalation of DOX-loaded PEGylated FTn led to 60% survival, compared with 10% survival in the group that inhaled DOX in solution at the maximally tolerated dose, in a murine model of malignant airway lung cancer. This approach may provide benefits as an adjuvant therapy combined with systemic chemo- or immunotherapy or as a stand-alone therapy for patients with tumors confined to the airways.

Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

2020 ◽  
Vol 17 (3) ◽  
pp. 229-245
Author(s):  
Gang Wang ◽  
Junjie Wang ◽  
Rui Guan
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Oral Delivery ◽  
Safe Delivery ◽  
Drug Delivery Vehicles ◽  
Therapeutic Benefits ◽  
Delivery Vehicles ◽  
The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

scholarly journals Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model

2021 ◽  
Vol 11 (1) ◽  
pp. 266-283
Author(s):  
Ahmed A. H. Abdellatif ◽  
Riaz A. Khan ◽  
Ahmad H. Alhowail ◽  
Abdulmajeed Alqasoumi ◽  
Sultan M. Sajid ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Silver Nanoparticles ◽  
Cell Lines ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Drug Uptake ◽  
Emission Spectrometry ◽  
Dependent Manner

Abstract Drug uptake and distribution through cell–receptor interactions are of prime interest in reducing the adverse effects and increasing the therapeutic effectiveness of delivered formulations. This study aimed to formulate silver nanoparticles (AgNPs) conjugated to somatostatin analogs for specific delivery through somatostatin receptors (SSTRs) expressed on cells and by nebulizing the prepared AgNPs formulations into lung cells for in vivo application. AgNPs were prepared using the citrate reduction method, yielding AgNPs–CTT, which was further chemically conjugated to octreotide (OCT) to form AgNPs–OCT through an amide linkage. The AgNPs–OCT formulation was coated using alginate to yield a carrier, AgNPs–OCT–Alg, feasible for drug delivery through nebulization. AgNPs were uniform in size with an acceptable range of zeta potential. Furthermore, the concentrations of AgNP formulations were found safe for the model cell lines used, and cell proliferation was significantly reduced in a dose-dependent manner (p < 0.05). In the healthy lung tissues, AgNPs–OCT–Alg accumulated at a concentration of 0.416 ± 5.7 mg/kgtissue, as determined via inductively coupled plasma optical emission spectrometry. This study established the accumulation of AgNPs, specifically the AgNPs–OCT–Alg, in lung tissues, and substantiated the active, specific, and selective targeting of SSTRs at pulmonary sites. The anticancer efficacy of the formulations was in vitro tested and confirmed in the MCF-7 cell lines. Owing to the delivery suitability and cytotoxic effects of the AgNPs–OCT–Alg formulation, it is a potential drug delivery formulation for lung cancer therapy in the future.

scholarly journals gro-beta, a -C-X-C- chemokine, is an angiogenesis inhibitor that suppresses the growth of Lewis lung carcinoma in mice.

1995 ◽  
Vol 182 (6) ◽  
pp. 2069-2077 ◽  
Author(s):  
Y Cao ◽  
C Chen ◽  
J A Weatherbee ◽  
M Tsang ◽  
J Folkman
Keyword(s):  
Growth Factor ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Lung Tumor ◽  
Angiogenesis Inhibitor ◽  
Endothelial Cell Proliferation ◽  
Dependent Manner ◽  
Lewis Lung

We have found that two chemokines, recombinant gro-alpha and gro-beta, specifically inhibit growth factor-stimulated proliferation of capillary endothelial cells in a dose-dependent manner, whereas gro-gamma has no inhibitory effect. In vivo, gro-beta inhibits blood vessel formation in the chicken chorioallantoic membrane assay. It is sufficiently potent to effectively suppress basic fibroblast growth factor-induced corneal neovascularization after systemic administration in mice. Further, gro-beta significantly inhibits the growth of murine Lewis lung carcinoma in syngeneic C57B16/J and immunodeficient nude mice without toxicity. In vitro, Lewis lung carcinoma cells are completely insensitive to recombinant gro-beta at high concentrations that significantly inhibit endothelial cell proliferation. This finding supports the conclusion that gro-beta inhibits Lewis lung tumor growth by suppression of tumor-induced neovascularization.

scholarly journals Gecko Crude Peptides Induce Apoptosis in Human Liver Carcinoma CellsIn Vitroand Exert Antitumor Activity in a Mouse Ascites H22 Xenograft Model

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ying Song ◽  
Jian-Gang Wang ◽  
Rui-Fang Li ◽  
Yan Li ◽  
Zhao-Chu Cui ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Xenograft Model ◽  
Liver Carcinoma ◽  
High Dose ◽  
Dependent Manner ◽  
Cancer Model ◽  
Mouse Ascites ◽  
Necrosis Factor

Aim. To investigate the anti-tumor effects and mechanisms of gecko crude peptides (GCPs)in vitroandin vivo.Methods. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was applied to measure the effects of GCPs on the HepG2 cell viability. Fluorescence morphology was used to identify apoptotic cells. A xenograft H22 liver cancer model was established in Kunming mice. The tumor-bearing mice were treated with daily intraperitoneal injections of normal saline (NS group) or GCPs (80, 40 or 20 mg/kg) for 10 days, or once per two days with 2 mg/kg doxorubicin (ADR group;n=10each). Serum tumor necrosis factor (TNF-α) and interleukin (IL)-6 were quantified using ELISA assay.Results. GCPs significantly inhibited the growth of HepG2 cells and induced typical apoptotic morphological features through increasing bcl-2/bax ratio in a dose- and time-dependent mannerin vitro. The tumor weights of the ADR group, GCPs (H) group, GCPs (M) group, GCPs (L) group were smaller compared to the NS group. While the white blood cell count, thymus index, spleen index were higher in the high dose GCPs group than the NS group (P<0.05), the VEGF expression in tumor tissue and serum TNF-αand IL-6 levels in the GCPs groups were lower than the NS group (P<0.05).

Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo

2011 ◽  
Vol 114 (3) ◽  
pp. 689-694 ◽  
Author(s):  
Weijun Wang ◽  
Alex Ghandi ◽  
Leonard Liebes ◽  
Stan G. Louie ◽  
Florence M. Hofman ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Survival Time ◽  
Topoisomerase I ◽  
Malignant Gliomas ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Systemic Delivery ◽  
Series Of Experiments

Object Irinotecan (CPT-11), a topoisomerase I inhibitor, is a cytotoxic agent with activity against malignant gliomas and other tumors. After systemic delivery, CPT-11 is converted to its active metabolite, SN-38, which displays significantly higher cytotoxic potency. However, the achievement of therapeutically effective plasma levels of CPT-11 and SN-38 is seriously complicated by variables that affect drug metabolism in the liver. Thus the capacity of CPT-11 to be converted to the active SN38 intratumorally in gliomas was addressed. Methods For in vitro studies, 2 glioma cell lines, U87 and U251, were tested to determine the cytotoxic effects of CPT-11 and SN-38 in a dose-dependent manner. In vivo studies were performed by implanting U87 intracranially into athymic/nude mice. For a period of 2 weeks, SN-38, CPT-11, or vehicle was administered intratumorally by means of an osmotic minipump. One series of experiments measured the presence of SN-38 or CPT-11 in the tumor and surrounding brain tissues after 2 weeks' exposure to the drug. In a second series of experiments, after 2 weeks' exposure to the drug, the animals were maintained, in the absence of drug, until death. The survival curves were then calculated. Results The results show that the animals that had CPT-11 delivered intratumorally by the minipump expressed SN-38 in vivo. Furthermore, both CPT-11 and SN-38 accumulated at higher levels in tumor tissues compared with uninvolved brain. Intratumoral delivery of CPT-11 or SN-38 extended the average survival time of tumor-bearing animals from 22 days to 46 and 65 days, respectively. Conclusions These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

scholarly journals Treatment with sodium butyrate has therapeutic benefits for Machado-Joseph disease through the induction of autophagy

2021 ◽  
Author(s):  
Maxinne Watchon ◽  
Katherine J. Robinson ◽  
Luan Luu ◽  
Kristy C. Yuan ◽  
Albert Lee ◽  
...  
Keyword(s):  
Sodium Butyrate ◽  
Trinucleotide Repeat ◽  
Swimming Performance ◽  
Protein Aggregates ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Machado Joseph Disease

AbstractMachado-Joseph disease (MJD) is a fatal neurodegenerative disease caused by expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of neurotoxic ataxin-3 protein aggregates, neurodegeneration and motor deficits. Here we investigated the therapeutic potential of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model MJD. MJD SH-SY5Y cells were found to contain ataxin-3 oligomeric species and protein aggregates. Interestingly, treatment with SB decreased the size of detergentinsoluble ataxin-3 aggregates in vitro. Further investigation revealed that SB treatment increased activity of the autophagy protein quality control pathway in the MJD cells and decreased presence of ataxin-3 oligomers in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo through induction of autophagy and improving swimming performance in transgenic MJD zebrafish. Co-treating the MJD zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB, suggesting that the improved swimming performance was autophagy-dependent. Furthermore, intraperitoneal injection of SB to wild type mice resulted in increased levels of neuronal LC3B levels, indicating induction of autophagy within the brain. Collectively, our findings suggest that SB can induce activity of the autophagy pathway and can produce beneficial effects in vitro and in vivo. We propose that treatment with sodium butyrate warrants further investigation for the treatment of neurodegenerative diseases underpinned by proteinopathy mechanisms, including MJD.

scholarly journals Polyethylenimine-Based Theranostic Nanoplatform for Glioma-Targeting SPECT Imaging and Anticancer Drug Delivery

2020 ◽  
Author(s):  
Lingzhou Zhao ◽  
Jingyi Zhu ◽  
Jiali Gong ◽  
Ningning Song ◽  
Shan Wu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Anticancer Drug ◽  
Biological Properties ◽  
Spect Imaging ◽  
Dependent Manner ◽  
Rat Glioma ◽  
Anticancer Drug Delivery ◽  
Targeting Peptide

Abstract Background Glioma is the deadliest brain cancer in adults because the blood-brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma (SPECT) imaging and anticancer drug delivery. Results This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol ( m PEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99m Tc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac 2 O), the CTX-modified PEI ( m PEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The m PEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the m PEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99m Tc via DTPA, the 99m Tc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging. Conclusions These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

A Heparin-Based Inhibitor of Heparanase Blocks Myeloma Growth In Vivo by Targeting the Tumor Microenvironment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1502-1502
Author(s):  
Yang Yang ◽  
Telisha Swain ◽  
Annamaria Naggi ◽  
Giangiacomo Torri ◽  
Benito Casu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Tissue ◽  
Single Agent ◽  
Cell Activity ◽  
Dependent Manner ◽  
Myeloma Cells

Abstract Heparanase is an enzyme that cleaves heparan sulfate chains of proteoglycans and promotes the growth and metastasis of many types of human tumors. Our previous work demonstrates that enzymatically active heparanase is present in the bone marrow of myeloma patients and is associated with a poor prognosis, substantially enhances tumor growth and spontaneous metastasis to bone in an animal model of myeloma, and increases the synthesis and shedding of syndecan-1 by myeloma cells, this in turn contributes to myeloma progression by elevating levels of syndecan-1 in the tumor microenvironment. Thus, we hypothesized that inhibitors of heparanase activity would have a dramatic impact on the growth of myeloma tumors. To test this we used a chemically modified form of heparin that is 100% N-acetylated and 25% glycol-split (designated 100NA,RO-H). This form heparin is a potent inhibitor of heparanase enzyme activity but lacks anticoagulant activity thus enabling use of relatively high doses of the drug in vivo. Delivery of the 100NA,RO-H to animals bearing established myeloma tumors dramatically blocked tumor growth and progression in a dose-dependent manner(P&lt;0.04). To understand the mechanism of action of 100NA,RO-H, a series of experiments were performed on tumor tissue harvested from the animals. Results demonstrate that the modified heparin significantly inhibits proliferation of cells within the tumor (33 ± 8/mm2 Ki-67 positive cells in treated vs. 688 ± 164/mm2 positive cells in controls, P = 0.002). 100NA,RO-H also dramatically inhibits angiogenesis as compared to controls as assessed by CD34 staining of tumor tissue. This anti-angiogenic effect may be due at least in part to its regulation of hepatocyte growth factor and/or vascular endothelial growth factor, two angiogenic factors that are detected by immunohistochemistry at high levels in controls but virtually absent from tumors of animals treated with 100NA,RO-H. In vitro studies demonstrate that 100NA,RO-H blocks syndecan-1 shedding from cells, consistent with the role of heparanase in promoting syndecan-1 shedding. In addition, in contrast to our finding that 100NA,RO-H blocks tumor growth in vivo, it only slightly inhibited proliferation, cell cycle progression and growth factor signaling in myeloma cells growing in vitro. Thus, the compound does not appear to have substantial direct effects on tumor cells. Although it is not yet clear if all of the effects of 100NA,RO-H are due to its anti-heparanase activity, we conclude that this modified heparin disrupts the myeloma tumor microenvironment thereby blocking in vivo growth and progression of the cancer. Therefore, its use as a single agent or in combination with agents having direct anti-tumor cell activity may constitute a potent new anti-myeloma therapy.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

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