11 research outputs found
Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression
Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues
Morphological Effects of CuO Nanostructures on Fibrillation of Human Serum Albumin
The
influence of different morphologies of nanostructures on amyloid
fibrillation has been investigated by monitoring the fibrillation
of human serum albumin (HSA) in the presence of rod-, sphere-, flower-,
and star-shaped copper oxide (CuO) nanostructures. The different morphologies
of CuO have been synthesized from an aqueous solution-based precipitation
method using various organic acids, viz., acetic acid, citric acid,
and tartaric acid. The fibrillation process of HSA has been examined
using various biophysical techniques, e.g., Thioflavin T fluorescence,
Congo red binding studies through UV spectroscopy, circular dichroism
spectroscopy, and fluorescence microscopy. The monolayer protein coverage
on the CuO nanostructures has been established through DLS studies,
and the well-fitted Langmuir isotherm model has been used to interpret
the differential adsorption behavior of HSA molecules on the CuO nanostructures.
The nanostar-shaped CuO, by virtue of their higher specific surface
area (94.45 m<sup>2</sup> g<sup>–1</sup>), presence of high
indexed facets {211} and high positive surface charge potential (+16.2
mV at pH 7.0) was found to show the highest adsorption of the HSA
monomers and thus was more competent to inhibit the formation of HSA
fibrils compared to the other nanostructures of CuO
Effect of functionalized magnetic MnFe<sub>2</sub>O<sub>4</sub> nanoparticles on fibrillation of human serum albumin
Pathogenesis of amyloid-related diseases is related to nonnative folding of proteins with the formation of insoluble deposits in the extracellular space of various tissues. Having the unique properties of small size, large surface area, biodegradability, and relative nontoxicity, magnetic nanoparticles have drawn a lot of attention in biomedical applications. Herein, we demonstrate the effect of bare and differently functionalized magnetic MnFe<sub>2</sub>O<sub>4</sub> nanoparticles on fibrillation of human serum albumin in vitro. The process has been monitored using Thioflavin T fluorescence, Congo red binding assay, circular dichroism, fluorescence microscopy, and transmission electron microscopy. From our experimental results, amine functionalized MnFe<sub>2</sub>O<sub>4</sub> nanoparticles are found to inhibit formation of fibrils more effectively than bare ones, while carboxylated nanoparticles do not have a significant effect on fibrillation. This study has explored the prospects of using specific magnetic nanoparticles with appropriate modification to control self-assembly of proteins and may act as a precursor in therapeutic applications
Synthesis of biocompatible multicolor luminescent carbon dots for bioimaging applications
Water-soluble carbon dots (C-dots) were prepared through microwave-assisted pyrolysis of an aqueous solution of dextrin in the presence of sulfuric acid. The C-dots produced showed multicolor luminescence in the entire visible range, without adding any surface-passivating agent. X-ray diffraction and Fourier transform infrared spectroscopy studies revealed the graphitic nature of the carbon and the presence of hydrophilic groups on the surface, respectively. The formation of uniformly distributed C-dots and their luminescent properties were, respectively, revealed from transmission electron microscopy and confocal laser scanning microscopy. The biocompatible nature of C-dots was confirmed by a cytotoxicity assay on MDA-MB-468 cells and their cellular uptake was assessed through a localization study
Effect of Functionalized Magnetic MnFe<sub>2</sub>O<sub>4</sub> Nanoparticles on Fibrillation of Human Serum Albumin
Pathogenesis
of amyloid-related diseases is related to nonnative folding of proteins
with the formation of insoluble deposits in the extracellular space
of various tissues. Having the unique properties of small size, large
surface area, biodegradability, and relative nontoxicity, magnetic
nanoparticles have drawn a lot of attention in biomedical applications.
Herein, we demonstrate the effect of bare and differently functionalized
magnetic MnFe<sub>2</sub>O<sub>4</sub> nanoparticles on fibrillation
of human serum albumin <i>in vitro</i>. The process has
been monitored using Thioflavin T fluorescence, Congo red binding
assay, circular dichroism, fluorescence microscopy, and transmission
electron microscopy. From our experimental results, amine functionalized
MnFe<sub>2</sub>O<sub>4</sub> nanoparticles are found to inhibit formation
of fibrils more effectively than bare ones, while carboxylated nanoparticles
do not have a significant effect on fibrillation. This study has explored
the prospects of using specific magnetic nanoparticles with appropriate
modification to control self-assembly of proteins and may act as a
precursor in therapeutic applications
Micellear Gold Nanoparticles as Delivery Vehicles for Dual Tyrosine Kinase Inhibitor ZD6474 for Metastatic Breast Cancer Treatment
The therapeutic index
of poorly water-soluble drugs is often hampered
due to poor pharmacokinetics, reduced blood retention, and lack of
effective drug concentrations in the tumor region. In order to overcome
these issues, drugs are often delivered by use of delivery vehicles
to provide an enhanced therapeutic index. Gold nanoparticles synthesized
in micellar networks of amphiphilic block copolymer (AuNM) provide
an efficient nanocarrier for tissue- and site-specific drug delivery
owing to their low cytotoxicity and immunogenicity. AuNM is formed
by exploiting the properties of both inorganic Au material and an
amphiphilic polymer of polyÂ(ethylene glycol)-<i>block</i>-polyÂ(propylene glycol)-<i>block</i>-polyÂ(ethylene glycol)
(PEG–PPG–PEG). We further functionalized AuNM with the
FDA-approved dual tyrosine kinase inhibitor ZD6474 and studied the
physicochemical properties of the conjugate ZD6474–AuNM. Both
AuNM and ZD6474–AuNM, with a diameter of ∼70 nm, were
very stable at physiological pH. Conversely, at an acidic pH of 5.2,
a slow sustained-release profile of ZD6474 was evident from AuNM,
which could provide a method of facilitating release of the drug in
an acidic tumor environment. In vitro, in triple-negative breast cancer
cells, ZD6474–AuNM inhibited tumor cell proliferation, migration,
and invasion and induced apoptosis. There was no detectable lysis
of red blood cells observed when they were treated with AuNM and ZD6474–AuNM,
confirming hemocompatibility. To reinforce the possibility of AuNM
serving as a delivery vehicle, AuNM was conjugated with the IR680
dye for tracking, and this conjugate was systemically delivered in
female nude mice bearing MDA-MB-231 human breast cancer xenografts.
Fluorescence signal was retained in the tumor region in a temporal
manner as compared to other organs, indicating passive retention of
AuNM in the tumor locale. Moreover, delivery of ZD6474–AuNM
in nude mice bearing MDA-MB-231 xenografts led to decreased tumor
size as compared to the control group. The promising safety, targeting,
and therapeutic results of systemic delivery of ZD6474 by AuNM provide
an attractive alternative method for treating patients with metastatic
breast cancer
Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes
Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes
Akt overexpression in cancer causes
resistance to traditional chemotherapeutics.
Silencing Akt through siRNA provides new therapeutic options; however,
poor <i>in vivo</i> siRNA pharmacokinetics impede translation.
We demonstrate that acidic milieu-sensitive multilamellar gold niosomes
(Nio-Au) permit targeted delivery of both Akt-siRNA and thymoquinone
(TQ) in tamoxifen-resistant and Akt-overexpressing MCF7 breast cancer
cells. Octadecylamine groups of functionalized gold nanoparticles
impart cationic attribute to niosomes, stabilized through polyethylene
glycol. TQ’s aqueous insolubility renders its encapsulation
within hydrophobic core, and negatively charged siRNA binds in hydrophilic
region of cationic niosomes. These niosomes were exploited to effectively
knockdown Akt, thereby sensitizing cells to TQ. Immunoblot studies
revealed enhanced apoptosis by inducing p53 and inhibiting MDM2 expression,
which was consistent with <i>in vivo</i> xenograft studies.
This innovative strategy, using Nio-Au to simultaneously deliver siRNA
(devoid of any chemical modification) and therapeutic drug, provides
an efficacious approach for treating therapy-resistant cancers with
significant translational potential
Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy
Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrite nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in the peripheral and subsequent inner layers of multilayered nanocarriers. In vitro and in vivo studies evaluated the nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced the cellular levels of Bcl2 and p53, while increasing the levels of Bim. This delivery system successfully embodies the sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers
The effect of phloretin on synaptic proteins and adult hippocampal neurogenesis in Aβ (1-42)-injected male Wistar rats
Objectives: Considering the deleterious effect of Aβ1-42, a study was designed to evaluate the effect of phloretin on altered synaptic proteins and adult hippocampal neurogenesis in Aβ1-42-injected Wistar rats. Methods: The rats were pretreated with 5 mg/kg p.o dose of phloretin and donepezil (positive control) for 28 days, followed by intrahippocampal injections of aggregated Aβ1-42. After termination, perfused brains were isolated and subjected to Western blot and immunohistochemistry (IHC) analysis. Key findings: The Western blot revealed that Aβ1-42-injected rats had significantly low levels of synaptophysin as compared to sham control. Phloretin pretreatment significantly protected the presynaptic protein synaptophysin against the effects of Aβ1-42. There were no significant changes in the levels of PSD95 between different groups. The IHC findings showed that Aβ1-42 significantly reduced the Ki67 and DCX in the dentate gyrus as compared to sham control. However, phloretin significantly improved the number of Ki67- and DCX-positive neurons in the dentate gyrus region as compared to Aβ1-42 group. Conclusions: This study demonstrated the protective effect of phloretin on synaptophysin and adult neuronal proliferating cells in Aβ1-42-injected rats. The encouraging findings highlight the potential of phloretin as a dietary supplement targeting key therapeutic mechanisms in neurodegenerative disorders such as AD.</p