Folate Receptor Overexpressed HeLa Cells Research Articles

Magnetic mesoporous silica nanoparticles mediated redox and pH dual-responsive target drug delivery for combined magnetothermal therapy and chemotherapy

A combination of multiple therapies is conducive to the treatment efficacy of cancer. Chemotherapy combined with magnetothermal therapy provides an outstanding synergy for cancer treatment. In this study, magnetic mesoporous silica nanoparticles (MMSN) were developed as a multipurpose nanoplatform for doxorubicin (DOX) delivery and magnetothermal treatment of cancer simultaneously. The MMSN were composed of Fe3O4 and mesoporous silica as core and shell. The folic acid (FA) linked chitosan (CS) was conjugated at the outlets of MMSN (MMSN-SS-FA) using disulfide bonds to avert the premature release of the drug in mesopores of MMSN, target folate receptor-overexpressed cancer cells and increase the safety and physiological stability of MMSN. The temperature of the MMSN suspension could be elevated from 37 °C to 45 °C at the concentration of 1 mg/mL under an alternating magnetic field (AMF), which exceeded the tumor ablating temperature. The in vitro drug release proved that the DOX/MMSN-SS-FA displayed the redox/pH/AMF multiple-responsive release. The cellular uptake results indicated that the MMSN-SS-FA could target folate receptor-overexpressed HeLa cells. The DOX/MSNS-SS-FA with AMF had the highest cytotoxicity at the equivalent drug concentration towards HeLa cells with a combination index (CI) of 0.276, demonstrating the synergistic treatment effect of chemotherapy and magnetic-thermal therapy. Meanwhile, the DOX/MMSN-SS-FA+AMF showed the strongest tumor inhibitory effect of 84 % on tumor growth. Therefore, the constructed MMSN-SS-FA with good biocompatibility and biosafety can act as multifunctional nano-platforms for tumor treatment.

Design and construction of multifunctional hyperbranched polymers coated magnetite nanoparticles for both targeting magnetic resonance imaging and cancer therapy

Magnetic drug targeting is a drug delivery strategy that can be used to improve the therapeutic efficiency on tumor cells and reduce the side effects on normal cells and tissues. The aim in this study is designing a novel multifunctional drug delivery system based on superparamagnetic nanoparticles for cancer therapy. Magnetic nanoparticles were synthesized by coprecipitation of iron oxide followed by coating with poly citric acid (PCA) dendritic macromolecules via bulk polymerization strategy. It was further surface-functionalized with poly(ethylene glycol) (PEG) and then to achieve tumor cell targeting property, folic acid was further incorporated to the surface of prepared carriers via a facile coupling reaction between the hydroxyl end group of the PEG and the carboxyl group of folic acid. The so prepared nanocarriers (Fe3O4@PCA-PEG-FA) were characterized by X-ray diffraction, TEM, TGA, FT-IR, DLS and VSM techniques. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. Transmission electron microscopy and dynamic light scattering were also performed which revealed that size of nanocarriers was lying in the range of 10–49nm. Quercetin loading and release profiles of prepared nanocarriers showed that up to 83% of loaded drug was released in 250h. Fluorescent microscopy showed that the cellular uptake by folate receptor-overexpressing HeLa cells of the quercetin-loaded Fe3O4@PCA-PEG-FA nanoparticles was higher than that of non-folate conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. Also, T2-weighted MRI images of Fe3O4@PCA-PEG-FA nanoparticles showed that the magnetic resonance signal is enhanced significantly with increasing nanoparticle concentration in water and they also served as MRI contrast agents with relaxivities of 3.4mM−1s−1 (r1) and 99.8mM−1s−1 (r2). The results indicate that this multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.

Stability, Pharmacokinetics, Biodistribution and Safety Assessment of Folate-Conjugated Pullulan Acetate Nanoparticles as Cervical Cancer Targeted Drug Carriers.

It is recognized that the stability and journey in the body of nanoparticles are important issues for drug formulations. In this study, we prepared folate-conjugated pullulan acetate nanoparticles (FPANs) and epirubicin loaded FPANs (FPA/EPI) using dialysis method. The storage stability of FPANs and FPA/EPI at 4 degrees C could be up to 3 months. Using folate receptor overexpressed Hela cells, dose dependent cellular uptake and receptor-mediated endocytosis of FPA/EPI were confirmed. From the in vivo pharmacokinetics test, compared to free EPI, half-life time (t½) of FPA/EPI was extended 1.57 times and the area under-the-curve (AUC) increased 3.95 times as well. In addition, biodistribution data showed that, EPI concentration in tumor in FPA/EPI group was 2.01 times higher than that in free EPI group after 96 h; The concentration of drug in liver treated by FPA/EPI was 5.7-11.6 times, while in heart, kidney, especially in stomach and intestine were much lower than those in free EPI group from 24 to 96 h. Furthermore, blank FPANs showed no apparent acute toxicity at dose up to 125 mg/kg. All results suggested that FPA/EPI showed a promising potential on treating cervical carcinoma and its metastatic hepatocellular carcinoma in future because of the high stability, less toxicity and tumor targeting.

Autofluorescent and pH-responsive mesoporous silica for cancer-targeted and controlled drug release

A new autofluorescent and pH-sensitive multifunctional drug release system is developed in this contribution by layer-by-layer assembly of chitosan (CHI)/dialdehyde starch (DAS) polyelectrolyte multilayers (PEM) onto mesoporous silica nanoparticles (MSN) surface. The formed mesoporous silica composites can be used as drug delivery carriers, which have very slow drug release rate at pH 7.4, but have very fast drug release rate at pH 5.0 owing to the breakage of CN bonds of the CHI/DAS multilayers under acidic condition. As a proof of concept, folic acid (FA) has been conjugated to the outer surface of the mesoporous silica composites by the amide reaction in order to deliver target anticancer drug, and it is found that cellular uptake of the folate conjugated doxorubicin-loaded nanoparticles in folate receptor-overexpressing HeLa cells is much higher than that of non-folate receptor-overexpressing A549 cells, indicating that successful targeting drug release has realized.

Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect, and the pH-sensitive and ligand-mediated delivery of loaded drug

Folate-conjugated micelles were fabricated from amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate and methacrylic acid as the hydrophobic block. Doxorubicin (DOX), a model drug that contains an amine group and hydrophobic moiety, was loaded with a high loading capacity into micelles by a combination of ionic bonding and hydrophobic effect. The combined interactions imparted a pH-sensitive delivery property to the system. The release rate of loaded DOX was slow at pH 7.4 (i.e., mimicking the plasma environment) but increased significantly at acidic pH (i.e., mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the carboxylate protonation of poly(methacrylic acid), which dissociated the ionic bonding between the micelles and DOX. Cellular uptake by folate receptor-overexpressing HeLa cells of the DOX-loaded folate-conjugated micelles was higher than that of micelles without folate conjugation. Thus, the DOX-loaded folate-conjugated micelles displayed higher cytotoxicity to HeLa cells.

Multifunctional magnetic calcium phosphate nanoparticles for targeted platin delivery

Magnetic mesoporous amorphous calcium phosphate nanoparticles with a size of 62 nm and abundant -COOH groups on the surface have been prepared by a simple method. The particles show excellent aqueous dispersion stability in physiological pH without any deterioration in hydrodynamic size and zetapotential. By virtue of the carboxylate groups on the surface, the platinum pharmacophore cis-diaquadiamine platinum(II), folic acid and rhodamine isothiocyanate were conjugated on these magnetic calcium phosphate nanoparticles. The cytotoxicity and internalization efficiency of these nanocarriers have been evaluated on folate receptor overexpressed HeLa cells. These drug loaded nanoagents exhibit elevated cytotoxicity and induce apoptosis in HeLa cells.

Monodisperse mesoporous cobalt ferrite nanoparticles: synthesis and application in targeted delivery of antitumor drugs

A multifunctional folic acid decorated superparamagnetic mesoporous CoFe2O4 based nanocarrier with the particle size of 35–40 nm was synthesized by a simple method. The particles show excellent aqueous dispersion stability in physiological pH without any deterioration in hydrodynamic size and zetapotential. The cytotoxicity and internalization efficiency of these nanocarriers have been evaluated on folate receptor overexpressed HeLa cells. Fluorescent molecule RITC and antitumor agents such as methotrexate and doxorubicin were successfully attached to the surface amine groups following simple organic coupling reactions thus endowing the nanoparticle with therapeutic and optical properties. These drug loaded nanoagents exhibit elevated cytotoxicity and induce apoptosis in HeLa cells.

Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe 3O 4 nanoparticle cores with a mixture of the triblock copolymer methoxy poly(ethylene glycol)- b-poly(methacrylic acid- co- n-butyl methacrylate)- b-poly(glycerol monomethacrylate) and the folate-conjugated block copolymer folate-poly(ethylene glycol)- b-poly(glycerol monomethacrylate). The model anticancer agent adriamycin (ADR), containing an amine group and a hydrophobic moiety, was loaded into the nanocarrier at pH 7.4 by ionic bonding and hydrophobic interactions. The release rate of the loaded drug molecules was slow at pH 7.4 (i.e. mimicking the blood environment) but increased significantly at acidic pH (i.e. mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the polycarboxylate protonation of poly(methacrylic acid), which broke the ionic bond between the carrier and ADR. Cellular uptake by folate receptor-overexpressing HeLa cells of the folate-conjugated ADR-loaded nanoparticles was higher than that of non-folated-conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. These findings show the potential viability of a folate-targeting, pH-responsive nanocarrier for amine-containing anticancer drugs.

Folate receptor targeting silica nanoparticle probe for two-photon fluorescence bioimaging

Narrow dispersity organically modified silica nanoparticles (SiNPs), diameter ~30 nm, entrapping a hydrophobic two-photon absorbing fluorenyl dye, were synthesized by hydrolysis of triethoxyvinylsilane and (3-aminopropyl)triethoxysilane in the nonpolar core of Aerosol-OT micelles. The surface of the SiNPs were functionalized with folic acid, to specifically deliver the probe to folate receptor (FR) over-expressing Hela cells, making these folate two-photon dye-doped SiNPs potential candidates as probes for two-photon fluorescence microscopy (2PFM) bioimaging. In vitro studies using FR over-expressing Hela cells and low FR expressing MG63 cells demonstrated specific cellular uptake of the functionalized nanoparticles. One-photon fluorescence microscopy (1PFM) imaging, 2PFM imaging, and two-photon fluorescence lifetime microscopy (2P-FLIM) imaging of Hela cells incubated with folate-modified two-photon dye-doped SiNPs were demonstrated.

Folate-PEG modified poly(2-(2-aminoethoxy)ethoxy)phosphazene/DNA nanoparticles for gene delivery: Synthesis, preparation and in vitro transfection efficiency

Target-specific technique can significantly enhance the efficacy of gene delivery system which was limited by many cellular barriers. In this work, a new folate-PEG modified poly(2-(2-aminoethoxy)ethoxy)phosphazene (PAEP), namely, folate-PEG-PAEP was synthesized as a folate receptor (FR) targeted carrier, and the cytotoxicity, transfection efficiency, cellular uptake and intracellular trafficking of folate-PEG-PAEP/DNA nanoparticles (FPPN) were investigated. Compared with the PAEP/DNA nanoparticles (PN), the cytotoxicity of FPPN decreased significantly at high dose. FPPN showed much higher transfection efficiency (15.85 ± 1.23%) compared with PN (6.71 ± 0.42%) in FR overexpressing Hela cells, but no significant difference was observed in CHO-k1 cells lacking FR. The transfection activity of FPPN could be reversed in the presence of 1.0 mM free folic acid in Hela cells. The cellular uptake of FPPN was 37.38% higher than that of PN in Hela cells. These results indicated that FPPN could be a potential targeted gene delivery system.