Folate targeted PEGylated titanium dioxide nanoparticles as a nanocarrier for targeted paclitaxel drug delivery

A novel titanium dioxide nanocarrier was synthesized for targeted delivery of the anticancer drug, paclitaxel, by grafting folic acid (FA) onto the PEGylated titanium dioxide nanoparticles. Titanium dioxide is used in biomedical field for its stability and no toxicity characteristics. Titanium dioxide is one of the most promising nanoparticles (NPs) capable of a wide variety of applications in medicine and life science. Polyethylene glycol (PEG), when attached to the surface of the nanoparticles, increases the biocompatibility of the nanoparticles. PEGylated nanocarriers evade the reticuloendothelial system (RES). Folic acid (FA) is used as the ligand to target folate receptors, which are found abundant in cancer cells. FA–PEG–TiO₂ nanoparticles when used as drug carriers have the ability to target cancer cells and also capable of evading the reticuloendothelial system. Titanium dioxide nanoparticles were synthesized by wet chemical method. It was annealed at 450° for 3 h. XRD analysis confirms the formation of anatase titanium dioxide. Analyses by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the nanoparticles had an average size of 12 nm and uniform size distribution. The PEGylation and folic acid grafting was confirmed by UV spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA). The study on the loading of anticancer drug paclitaxel revealed that the titanium dioxide nanocarrier possessed a considerably higher adsorption capability. In addition, the in vitro release profile of paclitaxel from FA–PEG–TiO₂ nanoparticles was characterized by an initial fast release followed by a sustained release phase.     

Core/shell nanoparticles for pH-sensitive delivery of doxorubicin

Core/shell nanoparticles with lipid core were prepared and characterized as pH-sensitive delivery system of anticancer drug. The lipid core is composed of drug-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of drug-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a pH-sensitive drug delivery system for anticancer drug, doxorubicin was loaded into the core/shell nanoparticles and the drug loading amount and drug release behavior in response to pH change were observed.     

Receptor-mediated gene delivery into antigen presenting cells using mannosylated chitosan/DNA nanoparticles

Dendritic cells (DCs) are professional antigen presenting cells that induce, sustain, and regulate immune responses. Gene modification of DCs is of particular interest for immunotherapy of diseases where the immunes system has failed or is abnormally regulated, such as in cancer or autoimmune disease. Gene transfer using non-viral vectors is a promising approach for the safe delivery of therapeutic DNA. Among various non-viral vectors, chitosan is considered to be a good candidate for gene delivery system, however, lack of cell specificity and low transfection of chitosan need to be overcome prior to clinical use. In this study, mannosylated chitosan (MC) was prepared to induce the receptor-mediated endocytosis and targeting into antigen presenting cells (APCs), especially DCs having mannose receptors. MC showed great ability to form complexes with DNA and showed suitable physicochemical properties for gene delivery system. It had low cytotoxicity and exhibited much enhanced gene transfer efficiency on the macrophage cell line than chitosan itself. Also, MC/DNA complex was more efficient for transferring IL-12 gene into DCs rather than water-soluble chitosan (WSC)/DNA one, which resulted in better induction of INF-gamma from DCs. Therefore, MC is a promising gene delivery system for repeated administration to maintain sustained gene expression, thereby opening the possibility for immunotherapy.     

Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C

Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG-CS-DA). mPEG-CS-DA was synthesized and characterized by ¹H nuclear magnetic resonance (¹H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57?µg/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231?nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection.     

O-Carboxymethyl-chitosan/organosilica hybrid nanoparticles as non-viral vectors for gene delivery

Polymeric non-viral vectors, such as chitosan nanoparticles show good biocompatibility, but low transfection efficiency. The objective of this study was to improve the transfection efficiency of chitosan based non-viral vectors by using o-carboxymethyl-chitosan which is a kind of water-soluble chitosan derivative and also has good biocompatibility. O-Carboxymethyl-chitosan-organosilica hybrid nanoparticles (CMG NPs) were synthesized through a rapid one-step aqueous synthetic approach for gene delivery. The size of nanoparticles was 276 ± 25 nm and zeta potential was 31.6 ± 0.4 mV in deionized water. Zeta potential increased with the decrease of pH, and it had been discovered that pH = 5.5 is the best point for CMG NPs to bond with plasmid DNA. DNA inclusion and integrity was evaluated by gel electrophoresis, and it is indicated that CMG NPs could protect DNA against DNase I and serum degradation. The results of MTT for cell viability and in vitro transfection also support the idea that CMG NPs could be used as efficient and safe vectors for gene delivery.     

Self assembly of DNA nanoparticles with polycations for the delivery of genetic materials into cells

Increasing attention has been paid to technology used for the delivery of genetic materials into cells for gene therapy and the generation of genetically engineered cells. So far, viral vectors have been mainly used because of their inherently high transfection efficiency of gene. However, there are some problems to be resolved for the clinical applications, such as the pathogenicity and immunogenicity of viral vectors themselves. Therefore, many research trials with non-viral vectors have been performed to enhance their efficiency to a level comparable to the viral vector. Two directions of these trials exist: Material improvement of non-viral vectors and their combination with various external physical stimuli. In this study gelatin was selected as a non-viral carrier for DNA. To give a positive charge to gelatin, different extents introduction of ethylenediamine (Ed), spermidine (Sd), and spermine (Sm) were reacted with gelatin in the presence of a water-soluble carbodiimide. When positively charged gelatin derivatives (Ed, Sd, and Sm) were mixed with negatively charged DNA, a self assembly of DNA nanoparticle (complex) was formed within few minutes through electrostatic interaction. Irrespective of the type of gelatin derivatives, the apparent molecular size of DNA was reduced by increasing the gelatin/DNA mixing ratio to attain a saturated value of about 150 nm. The condensed gelatin/DNA complexes showed the zeta potential of 10-15 mV. The amount of DNA internalized into the cells was significantly increased by the complexation with every gelatin derivative. The cells incubated with the gelatin/DNA complexes exhibited significantly stronger luciferase activities than naked plasmid DNA. This study clearly demonstrates and self-assembled DNA complexes has potential as a gene delivery vechile and are stable to transfer genetic materials to cells.     

PEGylated bioreducible poly(amido amine)s for non-viral gene delivery

A facile method for PEGylated bioreducible poly(amido amine)s is described by a one-pot Michael-type addition polymerization of N, N′-cystaminebisacrylamide (CBA) with a mixture of 4-amino-1-butanol (ABOL) and mono-tert-butoxycarbonyl (Boc) PEG diamine. By this approach, two Boc-amino-PEGylated p(CBA-ABOL) copolymers were obtained with the PEG/ABOL composition ratio of 1/10 (1a) and 1/6 (2a), respectively. These copolymers were characterized by ¹H NMR and gel permeation chromatography. The PEGylated copolymers 1a, and its deprotected analog 1b with a terminal amino group at the PEG chain, were further evaluated as gene delivery vectors. The copolymers 1a and 1b condense DNA into nano-scaled PEGylated polyplexes (< 250 nm) with near neutral (2–5 mV, 1a) or slightly positive (9–13 mV, 1b) surface charge which remain stable in 150 mM buffer solution over 24 h. UnPEGylated polyplexes from p(CBA-ABOL), however, are relatively less stable and increase in size to more than 1 μm. The PEGylated polyplexes showed very low cytotoxicity in MCF-7 and NIH 3T3 cells and induced appreciable transfection efficiencies in the presence of 10% serum, although that are lower than those of p(CBA-ABOL) lacking PEG. The lower transfection efficiency of the PEGylated p(CBA-ABOL) polyplexes is discussed regarding the effect of PEGylation on endosomal escape of the PEGylated polyplexes.     

Microcapsules of PEGylated gold nanoparticles prepared by fluid-fluid interfacial assembly

Amphiphilic, PEGylated gold nanoparticles, of approximately 2 nm average core diameter, were synthesized by reduction of hydrogen tetrachloroaurate in the presence of the ligand (1-mercaptoundec-11-yl)tetra(ethylene glycol). These PEGylated gold nanoparticles were found to assemble cleanly at the oil-water interface. This self-assembly process gave a microencapsulated oil phase, water as the continuous phase, and a monolayer of gold nanoparticles at the oil-water interface. The capsules could be cross-linked from the organic phase by reaction of the chain-end hydroxyl groups of the PEG ligands with suitable electrophiles such as terephthaloyl chloride.     

Bioadhesive mannosylated nanoparticles for oral drug delivery

The aim of this work was to design mannosylated Gantrez AN nanoparticles (M-NP) and to describe their gut bioadhesive properties in order to develop a promising carrier for future applications in oral drug delivery. For that purpose, the process of the nanoparticles coating with mannosamine was optimized by the incubation of Gantrez AN nanoparticles with different volumes of mannosamine aqueous solutions at different times. Then, the nanoparticles were characterized by measuring the size, zeta potential, mannosamine content, and concanavalin A (Con A) binding. Furthermore, in vivo quantitative bioadhesion study and kinetic analysis of the bioadhesion curves were performed after oral administration to rats of fluorescently labelled nanoparticles. The selected mannosylated nanoparticles (M-NP1 and M-NP10) were of homogenous sizes (about 300 and 200 nm), negatively charged and successfully coated with 36 and 18 microg mannosamine/mg NP, respectively. In vitro agglutination assay using Con A confirmed the successful coating of nanoparticles with mannosamine. The gut distribution profile of M-NP1 indicated a stronger bioadhesive capacity than M-NP10 and non-mannosylated ones, 1 h post-administration. Interestingly, M-NP1 showed an important ileum tropism where around 20% of the given dose remained adhered. Besides, the kinetic parameters of the bioadhesion profile of M-NP1 indicated their higher bioadhesive capacity with Q(max) and AUC(adh) about 2-times higher than control ones. Moreover, fluorescence microscopy corroborated the stronger interactions of M-NP1 with the normal mucosa and demonstrated a strong uptake of these carriers by Peyer's patches. In conclusion, we propose that mannosylated nanoparticles could be a promising non-live vector for oral delivery strategies.     

Functionalized solid lipid nanoparticles for transendothelial delivery

The objectives of this study were to synthesize and characterize functionalized solid lipid nanoparticles (fSLN) to investigate their interaction with endothelial cell monolayers and to evaluate their transendothelial transport capabilities. fSLN bearing tetramethylrhodamine-isothiocyanate-labeled bovine serum albumin (TRITC-BSA) and Coumarin 6 were prepared using a single-step phase-inversion process that afforded concurrent surface modification with a variety of macromolecules such as polystyrene sulfonate (PSS), poly-L-lysine (PLL), heparin (Hep), polyacrylic acid (PAA), polyvinyl alcohol, and polyethylene glycol (PEG). TRITC-BSA/Coumarin 6 encapsulated in fSLN with composite surface functionality (PSS-PLL and PSS-PLL-Hep) were also investigated. Size and surface charge of fSLN were analyzed using dynamic light scattering and transmission electron microscopy. Transport across bovine aortic endothelial cell (BAEC) monolayers was assessed spectrophotometrically using a transwell assay, and fSLN localization at the level of the cell and permeable support was analyzed using fluorescence microscopy. fSLN with tunable size and surface functionality were successfully produced, and had significant effects on cell localization and transport. Specifically, fSLN with PSS-PLL-Hep composite surface functionalization was capable of translocating 53.2 +/- 8.7 mug of TRITC-BSA within 4 h, with fSLN-PEG, fSLN-PAA, and fSLN-PSS exhibiting near-complete apical, paracellular, and cytosolic localization, respectively. Coumarin 6 was released by fSLN as indicated by dye labeling of BAEC membranes. We have developed a rapid process for the production of fSLN bearing low- and high-molecular-weight payloads of varying physicochemical properties. These findings have impications for drug delivery and bioimaging applications, since due to tunable surface chemistry, fSLN internalization and/or translocation across intact endothelial cell monolayers is possible.     

Biodegradable nanoparticles for drug delivery and targeting

Throughout the world today, numerous researchers are exploring the potential use of polymeric nanoparticles as carriers for a wide range of drugs for therapeutic applications. Because of their versatility and wide range of properties, biodegradable polymeric nanoparticles are being used as novel drug delivery systems. In particular, this class of carrier holds tremendous promise in the areas of cancer therapy and controlled delivery of vaccines.     

Engineered redox-responsive PEG detachment mechanism in PEGylated nano-graphene oxide for intracellular drug delivery

In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS-mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release.     

Polymer-based nanoparticles for the delivery of nucleoside analogues

Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in the treatment of cancer and viral infections. In both cases, they act as antimetabolite agents and interfere with the synthesis of cellular or viral nucleic acids. However, the need of high doses due to the rapid elimination of these compounds, to their poor activation, and/or to their non-specific distribution, often leads to side effects and resistances. The present paper aims to review the different types of polymer nanoparticles which have been designed as drug delivery devices to address these issues. Thus, poly(alkylcyanoacrylate) nanoparticles have been demonstrated as potential carriers for antiviral nucleoside analogues, especially for anti-HIV agents, regarding both intravenous and oral routes. Nanoparticles based on polyesters such as poly(lactic acid) and poly(lactide-co-glycolide) have been used as nanocarriers for nucleosides analogues too, and especially for their ocular delivery. Albumin has shown interesting properties in the design of nanoparticles for the same application, but also for the oral administration of anticancer analogues. Finally, new hydrophilic nanoparticles consisting of cross-linked polymer network ('Nanogels') open the perspective to deliver nucleoside analogues within their active triphosphate form.     

Functionalization of silica nanoparticles for nucleic acid delivery

Silica nanoparticles (SiNPs) have been widely engineered for biomedical applications, such as bioimaging and drug delivery, because of their high tunability, which allows them to perform specific functions. In this review, we discuss the functionalization and performance of SiNPs for nucleic acid delivery. Nucleic acids, including plasmid DNA (pDNA) and small interfering RNA (siRNA), constitute the next generation molecular drugs for the treatment of intractable diseases. However, their low bioavailability requires delivery systems that can circumvent nuclease attack and kidney filtration to ensure efficient access to the target cell cytoplasm or nucleus. First, we discussed the biological significance of nucleic acids and the parameters required for their successful delivery. Next, we reviewed SiNP designing for nucleic acid delivery with respect to nucleic acid loading and release, cellular uptake, endosomal escape, and biocompatibility. In addition, we discussed the co-delivery potential of SiNPs. Finally, we analyzed the current challenges and future directions of SiNPs for advanced nucleic acid delivery.     

Chitosan nanoparticles for prolonged delivery of timolol maleate

Timolol maleate-loaded chitosan (CS) nanoparticles were prepared by desolvation method. Experimental variables such as molecular weight of CS and amount of crosslinking agent were varied to study their effect on drug entrapment efficiency, size and release rates of nanoparticles. Chemical stability of timolol maleate (TM) and crosslinking of CS were confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetric studies were performed on drug-loaded nanoparticles to investigate crystalline nature of the drug after entrapment. Results indicated amorphous dispersion of drug in the polymer matrix. Scanning electron microscopy revealed irregularly shaped particles. Mean particle size of nanoparticles ranged between 118 and 203 nm, while zeta potential ranged between +17 and +22 mV. Entrapment efficiency of nanoparticles ranged between 47.6 and 63.0%. In-vitro release studies were performed in phosphate buffer saline of pH 7.4. A slow release of TM up to 24 h was observed. A 3² full factorial design was employed and second-order regression models were used to study the response (% drug release at 4 h). Release data as analyzed by an empirical relationship suggested that drug release deviated from the Fickian trend.     

Purification of PEGylated nanoparticles using tangential flow filtration (TFF)

A tangential flow filtration system was evaluated to purify PEGylated nanoparticles. Two widely used surfactants, PVA and sodium cholate were efficiently removed from an empty nanoparticles suspension using the proposed system. During drug loading, surfactant (PVA) was observed to be entrapped within the core of the nanoparticle to a higher extent, hence was purified at a comparatively slower rate. The presence of dextran sulfate enhanced the drug loading but also resulted in reduced purification rate; this was described by the hypothesis of PVA inclusion within the core of the nanoparticles. Practically, it was possible to correlate the slow purification rate of PVA to its reduced filtration flow during the purification of the empty and loaded nanoparticles containing dextran sulfate. Indirectly, this system was capable of revealing the influence of an excipient and drug on the nanoparticle surface.     

In vitro and in vivo evaluation of puerarin-loaded PEGylated mesoporous silica nanoparticles

Puerarin, which is extracted from Chinese medicine, is widely used in China and mainly used as a therapeutic agent for the treatment of cardiovascular diseases. Owing to its short elimination half-life in human beings, frequently intravenous administration of high doses of puerarin may be needed, which possibly leads to severe and acute side effects. The development of an effective sustained-release drug delivery system is urgently needed. In this study, PEGylated mesoporous silica nanoparticles (PEG-MSNs) had become a preferred way to prolong the half-life and improve the bioavailability of drugs. The release of puerarin from PEG-MSNs was pH dependent, and the release rate was much faster at lower pH than that at higher pH. Moreover, the PEG-MSNs exhibited improved blood compatibility over the MSNs in terms of low hemolysis, and it could also reduce the side effect of hemolysis induced by PUE. Compared with puerarin, PUE-loaded PEG-MSNs showed a 2.3-fold increase in half-life of puerarin and a 1.47-fold increase in bioavailability. Thus, the PEG-MSNs hold the substantial potential to be further developed as an effective sustained-release drug delivery system.     

Preparation of N-trimethyl chitosan-protein nanoparticles intended for vaccine delivery

In this paper, various N-trimethyl chitosan (TMC) of different molecular-weights (approximately 100 KD, approximately 200 KD, and approximately 400 KD, respectively) with the approximately degree of quartenization (DQ) of 40% were successfully synthesized. In vitro cytotoxicity of TMC solution showed the dependence of TMC concentration from 20 microg/ml to 500 microg/ml on the relative cell activity. Molecular weight of TMC did not greatly affect the cytotoxicity of TMC against HEK293 and L929 cells. TMC nanoparticles and alginate modified TMC nanoparticles were prepared by the ionic gelation method. Subsequently, we investigated the properties of TMC nanoparticles and alginate modified TMC nanoparticles intending for oral delivery of antigens. Molecular weight of TMC did not affect the loading capacity (LC) and in vitro release behavior of TMC nanoparticles. However, BSA concentration and alginate modification have strongly effect on properties of TMC nanoparticles (particle size; surface charge; loading efficiency and loading capacity). In vitro release behavior indicated that alginate modification could efficiently decrease initial burst release and extend release time in phosphate buffer (PBS, pH 7.4) and acidic solution (0.1 M HCl, pH = 1) at 37 degrees C. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) assay showed that alginate modification could effectively improve the stability of TMC nanoparticles and protect BSA from degradation or hydrolysis in acidic condition for at least 2 h.     

Folate-conjugated albumin nanoparticles for rheumatoid arthritis-targeted delivery of etoricoxib

Objective: The present study discusses folic acid-etoricoxib-bovine serum albumin nanoparticles (F-ETX-NPs) using folic acid as an over expressed folate receptor ligand for activated macrophages in targeting of rheumatoid arthritis.

Materials and methods: For this purpose etoricoxib-loaded BSA nanoparticles (ETX-NPs) were prepared by desolvation method and activated folic acid conjugation with free amine group of BSA was confirmed by FTIR study and zeta potential measurements.

Results: The F-ETX-NPs showed spherical in shape with 215.8?±?3.2?nm average size?+?7.8?mV zeta potential, 72?±?1.3% etoricoxib entrapment efficiency and showed 93.1?±?2.2% cumulative etoricoxib release upto 72?h. The etoricoxib concentration from F-ETX-NPs was found to be 9.67?±?0.34?µg/g in inflamed joint after 24?h administration revealed remarkably targeting potential to the activated macrophages cells and keep at a high level during the experiment.

Discussion and conclusion: These results suggest that F-ETX-NPs are potentially vector for activated macrophages cells targeting of rheumatoid arthritis.