Magnetic nanoparticles for targeted vascular delivery

Magnetic targeting has shown promise to improve the efficacy and safety of different classes of therapeutic agents by enabling their active guidance to the site of disease and minimizing dissemination to nontarget tissues. However, its translation into clinic has proven difficult because of inherent limitations of traditional approaches inapplicable for deep tissue targeting in human subjects and a need for developing well-characterized and fully biocompatible magnetic carrier formulations. A novel magnetic targeting scheme based on the magnetizing effect of deep-penetrating uniform fields is presented as an example of a strategy providing a potentially clinically viable solution for preventing injury-triggered reobstruction of stented blood vessels (in-stent restenosis). The design of optimized magnetic carrier formulations and experimental results showing the feasibility of uniform field-controlled targeting for site-specific vascular delivery of small-molecule pharmaceuticals, biotherapeutics, and cells are discussed in the context of antirestenotic therapy. The versatility of this approach applicable to different classes of therapeutic agents exerting their antirestenotic effects through distinct mechanisms prompts exploring the utility of uniform field-mediated magnetic stent targeting for combination therapies with enhanced efficiencies and improved safety profiles. Additional improvements in terms of site specificity and protracted carrier retention at the site of injury may be expected from the development and use of magnetic carriers exhibiting affinity for arterial wall-specific antigens.     

A new method for targeted drug delivery using polymeric microcapsules

Recent research and clinical evidence suggest that thalidomide could potentially be used to treat inflammation associated with Crohn's disease. However, systemic side effects associated with large doses of this drug have limited its widespread use. Treatment, with thalidomide would prove more efficacious if the drug could be delivered directly to target areas in the gut, thereby reducing systemic circulation. Microcapsule encapsulation could enable direct delivery of the drug. To assess the latter, we designed and tested drug-targeting release characteristics of alginate-poly-l-lysine-alginate (APA) microcapsules in simulated gastrointestinal environments. The results show that APA capsules enabled delivery of thalidomide in the middle and distal portions of the small intestine. We also compared the APA membrane formulation with an earlier designed alginate chitosan (AC) membrane thalidomide formulation. The results show that both APA and AC capsules allow for successful delivery of thalidomide in the gut and could prove beneficial in the treatment of Crohn's disease. However, further research is required.     

Controlling the thickness of polymeric shell on magnetic nanoparticles loaded with doxorubicin for targeted delivery and MRI contrast agent

The polymeric functionalization of superparamagnetic iron oxides nanoparticles is developed for cancer targeting capability and magnetic resonance imaging. Here the nanoparticles (NP) are decorated through the adsorption of a polymeric layer around the particle surface for the formation of core-shell. The synthesized magnetic nanoparticles (MNPs) are conjugated with fluorescent dye, targeting ligand, and drug molecules for improvement of target specific diagnostic and possible therapeutics applications. In this investigation doxorubicin was loaded into the shell of the MNPs and release study was carried out at different pH. The core-shell structure of magnetic NP coated chitosan matrix was visualized by TEM observation. The cytotoxicity of these magnetic NPs is investigated using MTT assay and receptor mediated internalization by HeLa and NIH3T3 cells are studied by fluorescence microscopy. Moreover, compared with T₂-weighted magnetic resonance imaging (MRI) in the above cells, the synthesized nanoparticles are showed stronger contrast enhancements towards cancer cells.     

Gold nanoparticles: Emerging paradigm for targeted drug delivery system

The application of nanotechnology in medicine, known as nanomedicine, has introduced a plethora of nanoparticles of variable chemistry and design considerations for cancer diagnosis and treatment. One of the most important field is the design and development of pharmaceutical drugs, based on targeted drug delivery system (TDDS). Being inspired by physio-chemical properties of nanoparticles, TDDS are designed to safely reach their targets and specifically release their cargo at the site of disease for enhanced therapeutic effects, thereby increasing the drug tissue bioavailability. Nanoparticles have the advantage of targeting cancer by simply being accumulated and entrapped in cancer cells. However, even after rapid growth of nanotechnology in nanomedicine, designing an effective targeted drug delivery system is still a challenging task. In this review, we reveal the recent advances in drug delivery approach with a particular focus on gold nanoparticles. We seek to expound on how these nanomaterials communicate in the complex environment to reach the target site, and how to design the effective TDDS for complex environments and simultaneously monitor the toxicity on the basis of designing such delivery complexes. Hence, this review will shed light on the research, opportunities and challenges for engineering nanomaterials with cancer biology and medicine to develop effective TDDS for treatment of cancer.     

Cell-specific delivery of polymeric nanoparticles to carbohydrate-tagging cells

Carbohydrates on cell surfaces contribute a variety of communications between the cell and its environment, and they have been assumed to act as markers for cellular recognition. In this research, 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer nanoparticles, which can react with specific carbohydrates of target cells, were newly prepared to serve as novel drug carriers. A water-soluble MPC polymer bearing hydrazide groups (PMBH) was synthesized by conventional radical polymerization. The MPC polymer showed amphiphilic nature and worked as an emulsifier to form nanoparticles. The nanoparticles covered with PMBH were prepared by the solvent evaporation method and exhibited monodispersity. They were approximately 200 nm in diameter and -2.0 mV in surface potential. According to a surface analysis of the nanoparticles, phosphorylcholine and hydrazide groups were observed, and the surface was fully covered with PMBH. Unnatural carbohydrates having ketone groups on human cervical carcinoma cell (HeLa) surfaces were expressed by treatment with levulinoyl mannosamine (ManLev). When the PMBH nanoparticles were in contact with the ManLev-treated HeLa cells, they accumulated in the cells. In contrast, the nanoparticles were not observed in native HeLa cells (without unnatural carbohydrates). These results indicate that the hydrazide groups of the nanoparticles selectively reacted to the ketone groups of the carbohydrates on the cell surface. The PMBH nanoparticles immobilized with anticancer drugs such as doxorubicin or paclitaxel were in contact with either ManLev-treated or untreated HeLa cells. The viability of the ManLev-treated HeLa cells was effectively reduced, but that of the untreated cells was preserved. This indicated that the anticancer drugs were selectively delivered to the ManLev-treated cells. Nonspecific cellular uptake of the nanoparticles was effectively reduced by MPC polymer coating. Furthermore, the immobilization processes of the drugs differed because of the solubility of the drugs. In conclusion, cellular-specific drug delivery by means of the novel nanoparticles was demonstrated with the selective reaction between unnatural carbohydrates on the cell surface and the hydrazide groups bearing the phosphorylcholine polymer nanoparticles.     

Reduction/pH dual-sensitive PEGylated hyaluronan nanoparticles for targeted doxorubicin delivery

To minimize the side effect of chemotherapy, a novel reduction/pH dual-sensitive drug nanocarrier, based on PEGylated dithiodipropionate dihydrazide (TPH)-modified hyaluronic acid (PEG-SS-HA copolymer), was developed for targeted delivery of doxorubicin (DOX) to hepatocellular carcinoma. The copolymer was synthesized by reductive amination via Schiff's base formation between TPH-modified HA and galactosamine-conjugated poly(ethylene glycol) aldehyde/methoxy poly(ethylene glycol) aldehyde. Conjugation of DOX to PEG-SS-HA copolymer was accomplished through the hydrazone linkage formed between DOX and PEG-SS-HA, and confirmed by FTIR and ¹H NMR spectra. The polymer–DOX conjugate could self-assemble into spherical nanoparticles (∼150 nm), as indicated by TEM and DLS. In vitro release studies showed that the DOX-loaded nanoparticles could release DOX rapidly under the intracellular levels of pH and glutathiose. Cellular uptake experiments demonstrated that the nanoparticles could be efficiently internalized by HepG2 cells. These results indicate that the PEG-SS-HA copolymer holds great potential for targeted intracellular delivery of DOX.     

Synthesis of chemically functionalized superparamagnetic nanoparticles as delivery vectors for chemotherapeutic drugs

Superparamagnetic iron oxide nanoparticles (SPIONs) are in clinical use for disease detection by MRI. A major advancement would be to link therapeutic drugs to SPIONs in order to achieve targeted drug delivery combined with detection. In the present work, we studied the possibility of developing a versatile synthesis protocol to hierarchically construct drug-functionalized-SPIONs as potential anti-cancer agents. Our model biocompatible SPIONs consisted of an iron oxide core (9-10 nm diameter) coated with polyvinylalcohols (PVA/aminoPVA), which can be internalized by cancer cells, depending on the positive charges at their surface. To develop drug-functionalized-aminoPVA-SPIONs as vectors for drug delivery, we first designed and synthesized bifunctional linkers of varied length and chemical composition to which the anti-cancer drugs 5-fluorouridine or doxorubicin were attached as biologically labile esters or peptides, respectively. These functionalized linkers were in turn coupled to aminoPVA by amide linkages before preparing the drug-functionalized-SPIONs that were characterized and evaluated as anti-cancer agents using human melanoma cells in culture. The 5-fluorouridine-SPIONs with an optimized ester linker were taken up by cells and proved to be efficient anti-tumor agents. While the doxorubicin-SPIONs linked with a Gly-Phe-Leu-Gly tetrapeptide were cleaved by lysosomal enzymes, they exhibited poor uptake by human melanoma cells in culture.     

Iron nanoparticles from animal blood for cellular imaging and targeted delivery for cancer treatment

Background

Iron nanoparticles (INPs) are usually prepared from inorganic sources, but we have prepared it from goat blood using incineration method. These INPs are then coated with chitosan (C) and coupled with folic acid (F) to form bionanocomposite for folate receptors.

Methods

The bionanocomposite was characterized for its physicochemical properties and cancer cell targeting studies using Fourier transform infrared spectroscopy, transmission electron microscopy, Zeta potential analysis, scanning electron microscopy–energy dispersive X-ray spectroscopy and magnetic resonance imaging analyses.

Results

The results have shown that the particle size of the INP-CF was found to be 80–300 nm and confirmed the presence of chitosan and folic acid in the bionanocomposite. Cancer and normal mouse embryonic cell line study confirmed the internalization of INP-CF and this phenomenon was also supported by physicochemical studies.

Conclusion

Thus, nanobiocomposite prepared using natural sources as a raw material will be beneficial compared to commercially available synthetic sources and can be used as receptor targeting agent for cancer treatment. This nanobiocomposite when coupled with substances such as monoclonal antibodies might act as a theranostic nanoagent for cancer therapy in the years to come.

General significance

The prepared novel nanobiocomposite containing INPs isolated from natural source may be used as multifunctional agent due its paramagnetic property apart from its drug delivery effect.     

Magnetic dipole interaction of endogenous magnetic nanoparticles with magnetoliposomes for targeted drug delivery

Dynamics of magnetoliposomes binding to the tumor cells and the efficiency of their recognition for targeted drug delivery is largely determined by physical interaction. In this paper we assess the strength of magnetic dipole interaction that occurs between endogenous magnetic nanoparticles in tumor cells and exogenous magnetic nanoparticles as a component of magnetoliposomes, and compare it with the forces of specific binding of the antigen-antibody complex. To assess the strength of magnetic dipole interaction the model of chains of identical particles was used, and an order of magnitude, 10^?9 N, was obtained. Thus, the indicated force has an order of magnitude close to the forces of specific binding, and even more. The force of magnetic dipole interaction between a magnetically marked dosage form and tumor cells is virtually the additional specific binding force — “passive targeting” for targeted drug delivery in consequence of the fact that tumor cells tend to contain the number of biogenic nanoparticles of magnetite (Fe₃O₄) by an order of magnitude greater than normal.     

In-situ injectable physically and chemically gelling NIPAAm-based copolymer system for embolization

The goal of this work is to make an injectable physically and chemically cross-linking NIPAAm-based copolymer system for endovascular embolization. A copolymer with N-isopropylacrylamide (NIPAAm) and hydroxyethyl methacrylate (HEMA) was synthesized and converted to poly(NIPAAm-co-HEMA-acrylate) functionalized with olefins. When poly(NIPAAm-co-HEMA-acrylate) was mixed with pentaerythritol tetrakis 3-mercaptopropionate (QT) stoichiometrically in a 0.1 N PBS solution of pH 7.4, it formed a temperature-sensitive hydrogel with low swelling through the Michael-type addition reaction and showed improved elastic properties at low frequency compared to physical gelation. This material could be useful for applications requiring water-soluble injection but lower swelling and lower creep properties than available with other soluble in-situ-gelling materials.     

Injectable in situ physically and chemically crosslinkable gellan hydrogel

An injectable, in situ physically and chemically crosslinkable gellan hydrogel is synthesized via gellan thiolation. The thiolation does not alter the gellan's unique 3-D conformation, but leads to a lower phase transition temperature under physiological conditions and stable chemical crosslinking. The synthesis and hydrogels are characterized by (1)H NMR, FT-IR, CD, or rheology measurements. The injectability and the tissue culture cell viability is also tested. The thiolated gellan hydrogel exhibits merits, such as ease for injection, quick gelation, lower gelling temperature, stable structure, and nontoxicity, which make it promising in biomedicine and bioengineering as an injectable hydrogel.     

Generic delivery of payload of nanoparticles intracellularly via hybrid polymer capsules for bioimaging applications

Towards the goal of development of a generic nanomaterial delivery system and delivery of the 'as prepared' nanoparticles without 'further surface modification' in a generic way, we have fabricated a hybrid polymer capsule as a delivery vehicle in which nanoparticles are loaded within their cavity. To this end, a generic approach to prepare nanomaterials-loaded polyelectrolyte multilayered (PEM) capsules has been reported, where polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) polymer capsules were employed as nano/microreactors to synthesize variety of nanomaterials (metal nanoparticles; lanthanide doped inorganic nanoparticles; gadolinium based nanoparticles, cadmium based nanoparticles; different shapes of nanoparticles; co-loading of two types of nanoparticles) in their hollow cavity. These nanoparticles-loaded capsules were employed to demonstrate generic delivery of payload of nanoparticles intracellularly (HeLa cells), without the need of individual nanoparticle surface modification. Validation of intracellular internalization of nanoparticles-loaded capsules by HeLa cells was ascertained by confocal laser scanning microscopy. The green emission from Tb(3+) was observed after internalization of LaF(3):Tb(3+)(5%) nanoparticles-loaded capsules by HeLa cells, which suggests that nanoparticles in hybrid capsules retain their functionality within the cells. In vitro cytotoxicity studies of these nanoparticles-loaded capsules showed less/no cytotoxicity in comparison to blank capsules or untreated cells, thus offering a way of evading direct contact of nanoparticles with cells because of the presence of biocompatible polymeric shell of capsules. The proposed hybrid delivery system can be potentially developed to avoid a series of biological barriers and deliver multiple cargoes (both simultaneous and individual delivery) without the need of individual cargo design/modification.     

Functionalized nanosystems for targeted mitochondrial delivery

Mitochondrial dysfunction including oxidative stress and DNA mutations underlies the pathology of various diseases including Alzheimer's disease and diabetes, necessitating the development of mitochondria targeted therapeutic agents. Nanotechnology offers unique tools and materials to target therapeutic agents to mitochondria. As discussed in this paper, a variety of functionalized nanosystems including polymeric and metallic nanoparticles as well as liposomes are more effective than plain drug and non-functionalized nanosystems in delivering therapeutic agents to mitochondria. Although the field is in its infancy, studies to date suggest the superior therapeutic activity of functionalized nanosystems for treating mitochondrial defects.     

Molecular vehicles for targeted drug delivery

Targeted drug delivery by cell-specific cytokines and antibodies promises greater drug efficacy and reduced side effects. We describe a novel strategy for assembly of drug delivery vehicles that does not require chemical modification of targeting proteins. The strategy relies on a noncovalent binding of standardized "payload" modules to targeting proteins expressed with a "docking" tag. The payload modules are constructed by linking drug carriers to an adapter protein capable of binding to a docking tag. Using fragments of bovine ribonuclease A as an adapter protein and a docking tag, we have constructed vascular endothelial growth factor (VEGF) based vehicles for gene delivery and for liposome delivery. Assembled vehicles displayed remarkable selectivity in drug delivery to cells overexpressing VEGF receptors. We expect that our strategy can be employed for targeted delivery of many therapeutic or imaging agents by different recombinant targeting proteins.     

Sendai virus-based liposomes enable targeted cytosolic delivery of nanoparticles in brain tumor-derived cells

Background

Nanogold has been investigated in a wide variety of biomedical applications because of the anti-inflammatory properties. The purpose of this study was to evaluate the effects of TPU (Therapeutic Pulsed Ultrasound) with gold nanoparticles (GNP) on oxidative stress parameters and the expression of pro-inflammatory molecules after traumatic muscle injury.

Materials and methods

Animals were divided in nine groups: sham (uninjured muscle); muscle injury without treatment; muscle injury + DMSO; muscle injury + GNP; muscle injury + DMSO + GNP; muscle injury + TPU; muscle injury + TPU + DMSO; muscle injury + TPU + GNP; muscle injury + TPU + DMSO + GNP. The ROS production was determined by concentration of superoxide anion, modulation of antioxidant defenses was determined by the activity of superoxide dismutase, catalase and glutathione peroxidase enzymes, oxidative damage determined by formation of thiobarbituric acid-reactive substance and protein carbonyls. The levels of interleukin-1?? (IL-1??) and tumor necrosis factor-?? (TNF-??) were measured as inflammatory parameters.

Results

Compared to muscle injury without treatment group, the muscle injury + TPU + DMSO + GNP gel group promoted a significant decrease in superoxide anion production and lipid peroxidation levels (p < 0.050). It also showed a significant decrease in TNF-?? and IL-1?? levels (p < 0.050) when compared to muscle injury without treatment group.

Conclusions

Our results suggest that TPU + DMSO + GNP gel presents beneficial effects on the muscular healing process, inducing a reduction in the production of ROS and also the expression of pro-inflammatory molecules.     

Silk-fibroin-coated liposomes for long-term and targeted drug delivery

Many barriers to drug delivery into a tumor site require careful consideration when designing a new drug. In this study, the adhesive targeting and drug specificity of modified liposomal vesicles on human-scar-producing cells, keloid fibroblasts, were investigated. Keloids express abundant levels of mucopolysaccharides and receptor tyrosine kinase (RTK). In this report, the structural properties, drug release kinetics, and therapeutic availability of silk-fibroin-coated, emodin-loaded liposomes (SF-ELP), compared with uncoated, emodin-loaded liposomes (ELP), were investigated. SF-ELP had a highly organized lamellae structure, which contributed to 55% of the liposomal diameter. This modified liposomal structure decreased emodin release rates by changing the release kinetics from a swelling and diffusional process to a purely diffusional process, probably due to steric hindrance. SF-ELP also increased adhesion targeting to keloid fibroblasts. Increased retention of SF-ELP is most likely due to the interaction of the fibrous protein coating around the ELP with the pericellular molecules around the cell. SF-ELP also decreased survival rate of keloids that expressed high levels of RTK. These results demonstrated that SF-ELP enhanced emodin delivery by improved diffusion kinetics and specific cell targeting.     

"Clickable" nanoparticles for targeted imaging

Nanomaterials functionalized with targeting ligands are increasingly recognized as useful materials for molecular imaging and drug delivery. Here we describe the development and validation of azide-alkyne reactions ("click chemistry") for the rapid, site-specific modification of nanoparticles with small molecules. The facile preparation of stable nanoparticles bearing azido or alkyne groups capable of reaction with their corresponding counterpart functionalized small molecules is demonstrated. The Cu(I)-catalyzed cycloaddition of azides and alkynes is shown to be a highly efficient and selective method for point functionalization of magnetic nanoparticles. Derivatized nanoparticles bearing biotin, fluorochrome, or steroid moieties are stable for several months. Nanoparticle click chemistry will be useful for other nanomaterials, design of novel sensors, and drug delivery vehicles.     

Magnetic nanoparticles for multi-imaging and drug delivery

Various bio-medical applications of magnetic nanoparticles have been explored during the past few decades. As tools that hold great potential for advancing biological sciences, magnetic nanoparticles have been used as platform materials for enhanced magnetic resonance imaging (MRI) agents, biological separation and magnetic drug delivery systems, and magnetic hyperthermia treatment. Furthermore, approaches that integrate various imaging and bioactive moieties have been used in the design of multi-modality systems, which possess synergistically enhanced properties such as better imaging resolution and sensitivity, molecular recognition capabilities, stimulus responsive drug delivery with on-demand control, and spatio-temporally controlled cell signal activation. Below, recent studies that focus on the design and synthesis of multi-mode magnetic nanoparticles will be briefly reviewed and their potential applications in the imaging and therapy areas will be also discussed.