Inorganic nanoparticles as carriers for efficient cellular delivery

Cellular delivery involving the transfer of various drugs and bio-active molecules (peptides, proteins and DNAs, etc.) through the cell membrane into cells has attracted increasing attention because of its importance in medicine and drug delivery. This topic has been extensively reviewed. The direct delivery of drugs and biomolecules, however, is generally inefficient and suffering from problems such as enzymic degradation of DNAs. Therefore, searching for efficient and safe transport vehicles (carriers) to delivery genes or drugs into cells has been challenging yet exciting area of research. In past decades, many carriers have been developed and investigated extensively which can be generally classified into four major groups: viral carriers, organic cationic compounds, recombinant protiens and inorganic nanoparticles. Many inorganic materials, such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide and layered double hydroxide (LDH), have been studied. Inorganic nanoparticles show low toxicity and promise for controlled delivery properties, thus presenting a new alternative to viral carriers and cationic carriers. Inorganic nanoparticles generally possess versatile properties suitable for cellular delivery, including wide availability, rich functionality, good biocompatibility, potential capability of targeted delivery (e.g. selectively destroying cancer cells but sparing normal tissues) and controlled release of carried drugs. This paper reviews the latest advances in inorganic nanoparticle applications as cellular delivery carriers and highlights some key issues in efficient cellular delivery using inorganic nanoparticles. Critical properties of inorganic nanoparticles, surface functionalisation (modification), uptake of biomolecules, the driving forces for delivery, and release of biomolecules will be reviewed systematically. Selected examples of promising inorganic nanoparticle delivery systems, including gold, fullerences and carbon nanotubes, LDH and various oxide nanoparticles in particular their applications for gene delivery will be discussed. The fundamental understanding of properties of inorganic nanoparticles in relation to cellular delivery efficiency as the most paramount issue will be highlighted.     

Rapid microwave-assisted synthesis of gold loaded hydroxyapatite collagen nano-bio materials for drug delivery and tissue engineering application

A rapid microwave assisted facile synthetic technique was adopted to load gold nanoparticles (Au) on hydroxyapatite (HAp) surface. HAp nanoparticles were primarily synthesized by wet precipitation technique and further used for gold loading and successive collagen coating for biomedical applications. The microwave-assisted controlled synthesis technique with three heating cycles allows the very fast growing of Au seeds over HAp facets. Different sophisticated analytical techniques and spectroscopic characterization were employed to confirm the structural, chemical, and morphological features. The synthesized different concentration “Au” loaded hetero nanostructures coated with collagen (Au–HAp–Col) optimized for drug (Doxorubicin: DOX) loading and releasing purposes for biomedical applications. The maximum drug-loading efficiency of ~58.22% and a pH responsive releasing of ~53% (at pH 4.5) was obtained for 0.1?wt% Au–HAp–Col nanoparticles. To study the cytotoxic effects from the hetero nanostructures, MG-63 osteoblast-like cells were exposed to different concentration ranges on Au–HAp, Au–HAp–Col, and DOX loaded Au–HAp–Col nanoparticles. The non-toxic and bioactive properties of the synthesized nanoparticle-fabricated scaffold promotes cellular attachment, growth, and proliferation. These results indicated that optimized Au–HAp–Col nanoparticles may be promising drug delivery and scaffold materials for multifunctional biomedical applications.     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Functionalization of magnetic nanoparticles for biomedical applications

Interest in utilizing magnetic nanoparticles for biomedical treatments originates from their external controllability of transportation and movement inside biological objects and magnetic heat generation. Advances in nanoparticle and nanotechnology enable us to produce magnetic nanoparticles of specific morphology and to engineer particle surfaces to manipulate their characteristics for specific applications. Intensive investigations and developments have been carried out in improving the quality of magnetic particles, regarding their size, shape, size distribution, their magnetism and their surface. The magnetic nanoparticles with appropriate surface chemistry can conjugate various biomaterials such as drugs, proteins, enzymes, antibodies, or nucleotides to be used for numerous in vivo applications including MRI contrast enhancement, immunoassay, hyperthermia, drug delivery, and cell separation. Here we review both the key technical principles of magnetic nanoparticle synthesis and the ongoing advancement of biomedical treatments using magnetic nanoparticles, specifically, the advancement in controlled drug delivery and hyperthermia.     

Shape control synthesis of polymeric hybrid nanoparticles via surface‐initiated atom‐transfer radical polymerization

Polymeric hybrid nanoparticles were synthesized via surface‐initiated atom‐transfer radical polymerization (SI‐ATRP) method on the surface of gold nanoparticles in cyclohexanone. Tetraoctyl ammonium bromide (TOAB) as a phase transfer agent was used to transfer the gold nanoparticles into cyclohexanone, which will be replaced by disulfide initiator on the surface of gold nanoparticles. Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and UV–vis spectroscopy were utilized to characterize the product to make sure the experiment had been conducted. The results showed that the polymeric gold hybrid nanoparticles with different structures could be controlled by adjusting the ratio of initiator and gold nanoparticles in ATRP. If the ratio is very little, asymmetric polystyrene–gold hybrid nanoparticles were synthesized, and a single gold nanoparticle was attached with a polystyrene sphere. If the ratio becomes larger, core–shell polystyrene–gold nanocomposite particles were obtained resulting in gold nanoparticle encapsulated by a uniform polymer shell. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43584.     

Acetylation of dendrimer‐entrapped gold nanoparticles: Synthesis,stability, and X‐ray attenuation properties

Functionalized dendrimer‐entrapped gold nanoparticles (Au DENPs) are of scientific and technological interest in biomedical applications. In this study, Au DENPs prepared with amine‐terminated generation 5 (G5) poly(amido amine) dendrimers as templates were subjected to acetylation to neutralize the positive surface charge of the particles. By varying the molar ratio of Au salt to G5 dendrimer, we prepared acetylated Au DENPs with a size range of 2–4 nm. Meanwhile, we attempted to add glucose to the dialysis liquid of the acetylated Au DENPs to prevent possible particle aggregation after lyophilization. The acetylated Au DENPs with different compositions (Au salt/dendrimer molar ratios) were characterized with ¹H‐NMR, transmission electron microscopy, ultraviolet–visible (UV–vis) spectrometry, and ζ‐potential measurements. We show that when the molar ratio of Au salt to dendrimer was equal to or larger than 75:1, the acetylated Au DENPs showed a significant aggregation after lyophilization, and the addition of glucose was able to preserve the colloidal stability of the particles. X‐ray absorption measurements showed that the attenuation of the acetylated Au DENPs was much higher than that of the iodine‐based contrast agent at the same molar concentration of the active element (Au vs iodine). In addition, the acetylated Au DENPs enabled X‐ray computed tomography (CT) imaging of mice after intravenous injection of the particles. These findings suggest a great potential for acetylated Au DENPs as a promising contrast agent for CT imaging applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

In situ incorporation of monodisperse drug nanoparticles into hydrogel scaffolds for hydrophobic drug release

The effective and locally sustained delivery of hydrophobic drug with hydrogels as carriers is still a challenge owing to the inherent incompatibility of hydrophilic hydrogel network and hydrophobic drug. One promising approach is to use porous hydrogels to encapsulate and deliver hydrophobic drug in the form of nanoparticles to the disease sites. However, this approach is currently limited by the inability to load concentrated hydrophobic drug nanoparticles into the hydrogels because of the severe nanoparticle aggregation during the loading process. In this article, we firstly designed and fabricated efficient drug nanoparticles embedded hydrogels for hydrophobic drug delivery by incorporating monodisperse silybin (hydrophobic drug for liver protection) nanoparticles into acrylated hyaluronic acid (HA‐AC) based hydrogels through in situ cross‐linking. The silybin nanoparticles embedded hydrogel scaffolds proved to be a good sustained release system with a long period of 36 h. The drug release from this hybrid hydrogels could be modulated by tuning HA‐AC concentration, cross‐linking ratio, chain length of cross‐linker and drug loading amount. The different kinetic models were applied, and it was observed that the release profile of silybin best followed the Hixson‐Crowell model for the release of drug from the hydrogels embedding silybin nanoparticles. It could be envisioned that this process would significantly advance the potential applications of hydrogel scaffolds mediated hydrophobic drug delivery in clinical therapies. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43111.     

Development of Core-Shell Nanoparticle Drug Delivery Systems Based on Biomimetic Mineralization

Among various drug-delivery systems, core-shell nanoparticles have many advantages. Inspired by nature, biomimetic synthesis has emerged as a new strategy for making core-shell nanoparticles in recent years. Biomimetic mineralization is the process by which living organisms produce minerals based on biomolecule templating that leads to the formation of hierarchically structured organic–inorganic materials. In this minireview, we mainly focus on the synthesis of core-shell nanoparticle drug-delivery systems by biomimetic mineralization. We review various biomimetic mineralization methods for fabricating core-shell nanoparticles including silica-based, calcium-based and other nanoparticles, and their applications in drug delivery. We also summarize strategies for drug loading in the biomolecule-mineralized core-shell NPs. Current challenges and future directions are also discussed.     

PAMAM Dendrimers Mediate siRNA Delivery to Target Hsp27 and Produce Potent Antiproliferative Effects on Prostate Cancer Cells

RNA interference (RNAi) holds great promise for the treatment of inherited and acquired diseases, provided that safe and efficient delivery systems are available. Herein we report that structurally flexible triethanolamine (TEA) core PAMAM dendrimers are able to deliver an Hsp27 siRNA effectively into prostate cancer (PC‐3) cells by forming stable nanoparticles with siRNA, protecting the siRNA nanoparticles from enzymatic degradation, and enhancing cellular uptake of siRNA. The Hsp27 siRNA resulted in potent and specific gene silencing of heat‐shock protein 27, an attractive therapeutic target in castrate‐resistant prostate cancer. Silencing of the hsp27 gene led to induction of caspase‐3/7‐dependent apoptosis and inhibition of PC‐3 cell growth in vitro. In addition, the siRNA–dendrimer complexes are non‐cytotoxic under the conditions used for siRNA delivery. Altogether, TEA core PAMAM dendrimer‐mediated siRNA delivery, in combination with RNAi that specifically targets Hsp27, may constitute a promising approach for combating castrate‐resistant prostate cancer, for which there is no efficacious treatment.     

Preparation of new dendrimer‐like star‐shaped amphiphilic poly(ethylene glycol)–poly(ϵ‐caprolactone) copolymers for biocompatible and high‐efficiency curcumin delivery

Novel amphiphilic star‐shaped terpolymers comprised of hydrophobic poly(?‐caprolactone), pH‐sensitive polyaminoester block and hydrophilic poly(ethylene glycol) (M_n = 1100, 2000 g mol^?1) were synthesized using symmetric pentaerythritol as the core initiator for ring‐opening polymerization (ROP) reaction of ?‐caprolactone functionalized with amino ester dendrimer structure at all chain ends. Subsequently, a second ROP reaction was performed by means of four‐arm star‐shaped poly(?‐caprolactone) macromer with eight ‐OH end groups as the macro‐initiator followed by the attachment of a poly(ethylene glycol) block at the end of each chain via a macromolecular coupling reaction. The molecular structures were verified using Fourier transform infrared and ¹H NMR spectroscopies and gel permeation chromatography. The terpolymers easily formed core–shell structural nanoparticles as micelles in aqueous solution which enhanced drug solubility. The hydrodynamic diameter of these agglomerates was found to be 91–104 nm, as measured using dynamic light scattering. The hydrophobic anticancer drug curcumin was loaded effectively into the polymeric micelles. The drug‐loaded nanoparticles were characterized for drug loading content, encapsulation efficiency, drug–polymer interaction and in vitro drug release profiles. Drug release studies showed an initial burst followed by a sustained release of the entrapped drug over a period of 7days at pH = 7.4 and 5.5. The release behaviours from the obtained drug‐loaded nanoparticles indicated that the rate of drug release could be effectively controlled by pH value. Altogether, these results demonstrate that the designed nanoparticles have great potential as hydrophobic drug delivery carriers for cancer therapy. © 2015 Society of Chemical Industry     

Valproate‐Loaded hydrogel nanoparticles: Preparation and characterization

Developing a simple and efficient approach to formulate biodegradable nanoparticles for intravenous delivery of sodium valproate (a hydrophilic small molecule drug chronically used in epileptic patients), is the principal objective of the current study. To fabricate particles via ionotropic gelation approach, a polycation polymer (chitosan) along with a polyanion (tripolyphosphate) was utilized in the presence of sodium valproate, and the Taguchi experimental design method was drawn upon so as to determine the optimum conditions of nanoparticle generation. In the following step, the researchers investigated sodium valproate‐loaded nanoparticles to explore various features of the nanoparticles including drug loading parameters, particle size distribution, zeta‐potential, morphology, stability, yield, and in vitro drug release profile. Nanoparticles with sizes of 63 ± 1 nm (number‐based) and 79 ± 3.21 (volume‐based) were obtained with slightly negative zeta–potential, which was more positive in drug‐loaded nanoparticles than the unloaded ones. The TEM imaging of the hydrogel nanoparticles manifested spherical shapes and corroborated the size achieved via particle size analyzer. The loading efficiency, loading amount, and loading ratio were determined to be 21.81 ± 3.90%, 10.31 ± 1.82 (mg sodium valproate/g nanoparticle) and 23.70 ± 4.54%, respectively, in optimum conditions. Moreover, there was observed a gradual drug release for nearly a week consisting, in average, about 94.64 ± 2.71% of the nanoparticles' drug content. In a nutshell, the present study introduces a practical, simple, and effective ionotropic gelation approach to generate sodium valproate‐loaded nanoparticles, leaving open a window of promising prospects in the field of intravenous long‐term delivery of this chronically used drug. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Recent advances in nanocellulose for biomedical applications

Nanocellulose materials have undergone rapid development in recent years as promising biomedical materials because of their excellent physical and biological properties, in particular their biocompatibility, biodegradability, and low cytotoxicity. Recently, a significant amount of research has been directed toward the fabrication of advanced cellulose nanofibers with different morphologies and functional properties. These nanocellulose fibers are widely applied in medical implants, tissue engineering, drug delivery, wound‐healing, cardiovascular applications, and other medical applications. In this review, we reflect on recent advancements in the design and fabrication of advanced nanocellulose‐based biomaterials (cellulose nanocrystals, bacterial nanocellulose, and cellulose nanofibrils) that are promising for biomedical applications and discuss material requirements for each application, along with the challenges that the materials might face. Finally, we give an overview on future directions of nanocellulose‐based materials in the biomedical field. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41719.     

Monodisperse magnetic nanoparticles for biomedical applications

Magnetic nanoparticles that are superparamagnetic with high saturation moment have great potential for biomedical applications. Solution‐phase syntheses have recently been applied to make various kinds of monodisperse magnetic nanoparticles with standard deviation in diameter of less than 10%. However, the surface of these nanoparticles is coated with a layer of hydrocarbon molecules due to the use of lipid‐like carboxylic acid and amine in the syntheses. Surface functionalization leads to the formation of water‐soluble nanoparticles that can be further modified with various biomolecules. Such functionalization has brought about several series of monodisperse magnetic nanoparticle systems that have shown promising applications in protein or DNA separation, detection and magnetic resonance imaging contrast enhancement. The goal of this mini review is to summarize the recent progress in the synthesis and surface modification of monodisperse magnetic nanoparticles and their applications in biomedicine. Copyright © 2007 Society of Chemical Industry     

State of arts on the bio-synthesis of noble metal nanoparticles and their biological application

Nanomaterials are materials in which at least one of the dimensions of the particles is 100 nm and below. There are many types of nanomaterials, but noble metal nanoparticles are of interest due to their uniquely large surface-to-volume ratio, high surface area, optical and electronic properties, high stability, easy synthesis, and tunable surface functionalization. More importantly, noble metal nanoparticles are known to have excellent compatibility with bio-materials, which is why they are widely used in biological applications. The synthesis method of noble metal nanoparticles conventionally involves the reduction of the noble metal salt precursor by toxic reaction agents such as NaBH₄, hydrazine, and formaldehyde. This is a major drawback for researchers involved in biological application researches. Hence, the bio-synthesis of noble metal nanoparticles (NPs) by bio-materials via bio-reduction provides an alternative method to synthesize noble metal nanoparticles which are potentially non-toxic and safer for biological application. In this review, the bio-synthesis of noble metal nanoparticle including gold nanoparticle (AuNPs), silver nanoparticle (AgNPs), platinum nanoparticle (PtNPs), and palladium nanoparticle (PdNPs) are first discussed. This is followed by a discussion of these biosynthesized noble metal in biological applications including antimicrobial, wound healing, anticancer drug, and bioimaging. Based on these, it can be concluded that the study on bio-synthesized noble metal nanoparticles will expand further involving bio-reduction by unexplored bio-materials. However, many questions remain on the feasibility of bio-synthesized noble metal nanoparticles to replace existing methods on various biological applications. Nevertheless, the current development of the biological application by bio-synthesized noble metal NPs is still intensively ongoing, and will eventually reach the goal of full commercialization.     

Designing Molecular Building Blocks for Functional Polymersomes

In recent years various polymeric vesicles have been reported that show promising results for drug delivery applications, nanomotors and/or nanoreactors. These polymeric vesicles can be assembled from many different materials and various coupling reactions have been applied for functionalization of the vesicles. However, the designs reported are still rather simple, as it is challenging to mimic biological complex systems. In this review we focus on the properties of widely used hydrophobic polymers to better understand polymersome properties for various applications. Examples are shown of how researchers have used and modulated block‐copolymers and their properties to their advantage. Furthermore, an overview of possible end group functionalizations of nanoparticles is reported, giving insight in recent developments of smart nanoparticles for biomedical applications.     

Fabrication of galactosylated chitosan–5‐fluorouracil acetic acid based nanoparticles for controlled drug delivery

In this study, a novel type of macromolecular prodrug, N‐galactosylated chitosan (GC)?5‐fluorouracil acetic acid (FUA) conjugate based nanoparticles, was designed and synthesized as a carrier for hepatocellular carcinoma drug delivery. The GC–FUA nanoparticles were produced by an ionic crosslinking method based on the modified ionic gelation of tripolyphosphate with GC–FUA. The structure of the as‐prepared GC–FUA was characterized by Fourier transform infrared and ¹H‐NMR analyses. The average particle size of the GC–FUA nanoparticles was 160.1 nm, and their drug‐loading content was 21.22 ± 2.7% (n = 3). In comparison with that of the freshly prepared nanoparticles, this value became larger after 7 days because of the aggregation of the GC–FUA nanoparticles. An in vitro drug‐release study showed that the GC–FUA nanoparticles displayed a sustained‐release profile compared to 5‐fluorouracil‐loaded GC nanoparticles. All of the results suggest that the GC–FUA nanoparticles may have great potential for anti‐liver‐cancer applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42625.     

Preparation and characterization of poly(ϵ‐caprolactone‐co‐p‐dioxanone)–poly(ethylene glycol)–poly(ϵ‐caprolactone‐co‐p‐dioxanone)/bioactive inorganic particle nanocomposites

With an aim to develop injectable hydrogel with improved solution stability and enhanced bone repair function, thermogelling poly(ε‐caprolactone‐co‐p‐dioxanone)‐poly(ethylene glycol)‐poly(ε‐caprolactone–co‐p‐dioxanone) (PECP)/bioactive inorganic particle nanocomposites were successfully prepared by blending the triblock copolymer (PECP) with nano‐hydroxyapatite (n‐HA) or nano‐calcium carbonate (n‐CaCO₃). The hydrogel nanocomposites underwent clear sol–gel transitions with increasing temperature from 0 to 50°C. The obtained hydrogel nanocomposites were investigated by ¹H NMR, FT‐IR, TEM, and DSC. It was found that the incorporation of inorganic nanoparticles into PECP matrix would lead to the critical gelation temperature (CGT) shifting to lower values compared with the pure PECP hydrogel. The CGT of the hydrogel nanocomposites could be effectively controlled by adjusting PECP concentration or the content of inorganic nanoparticles. The SEM results showed that the interconnected porous structures of hydrogel nanocomposites were potentially useful as injectable scaffolds. In addition, due to the relatively low crystallinity of PECP triblock copolymer, the aqueous solutions of the nanocomposites could be stored at low temperature (5°C) without crystallization for several days, which would facilitate the practical applications. The PECP/bioactive inorganic particle hydrogel nanocomposites are expected to be promising injectable tissue engineering materials for bone repair applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Alkylamine capped metal nanoparticle "inks" for printable SERS substrates, electronics and broadband photodetectors

We report a facile and general method for the preparation of alkylamine capped metal (Au and Ag) nanoparticle "ink" with high solubility. Using these metal nanoparticle "inks", we have demonstrated their applications for large scale fabrication of highly efficient surface enhanced Raman scattering (SERS) substrates by a facile solution processing method. These SERS substrates can detect analytes down to a few nM. The flexible plastic SERS substrates have also been demonstrated. The annealing temperature dependent conductivity of the nanoparticle films indicated a transition temperature above which high conductivity was achieved. The transition temperature could be tailored to the plastic compatible temperatures by using proper alkylamine as the capping agent. The ultrafast electron relaxation studies of the nanoparticle films demonstrated that faster electron relaxation was observed at higher annealing temperatures due to stronger electronic coupling between the nanoparticles. The applications of these highly concentrated alkylamine capped metal nanoparticle inks for the printable electronics were demonstrated by printing the oleylamine capped gold nanoparticles ink as source and drain for the graphene field effect transistor. Furthermore, the broadband photoresponse properties of the Au and Ag nanoparticle films have been demonstrated by using visible and near-infrared lasers. These investigations demonstrate that these nanoparticle "inks" are promising for applications in printable SERS substrates, electronics, and broadband photoresponse devices.     

Plant‐mediated synthesis of silver and gold nanoparticles and their applications

Nanobiotechnology deals with the synthesis of nanostructures using living organisms. Among the use of living organisms for nanoparticle synthesis, plants have found application particularly in metal nanoparticle synthesis. Use of plants for synthesis of nanoparticles could be advantageous over other environmentally benign biological processes as this eliminates the elaborate process of maintaining cell cultures. Biosynthetic processes for nanoparticles would be more useful if nanoparticles were produced extracellularly using plants or their extracts and in a controlled manner according to their size, dispersity and shape. Plant use can also be suitably scaled up for large‐scale synthesis of nanoparticles. In view of this, we have reviewed here the use of plants or their extracts in the synthesis of silver and gold nanoparticles for various human applications. Copyright © 2008 Society of Chemical Industry