Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

Rapid growth in nanotechnology is increasing the likelihood of engineered nanomaterials coming into contact with humans and the environment. Nanoparticles interacting with proteins, membranes, cells, DNA and organelles establish a series of nanoparticle/biological interfaces that depend on colloidal forces as well as dynamic biophysicochemical interactions. These interactions lead to the formation of protein coronas, particle wrapping, intracellular uptake and biocatalytic processes that could have biocompatible or bioadverse outcomes. For their part, the biomolecules may induce phase transformations, free energy releases, restructuring and dissolution at the nanomaterial surface. Probing these various interfaces allows the development of predictive relationships between structure and activity that are determined by nanomaterial properties such as size, shape, surface chemistry, roughness and surface coatings. This knowledge is important from the perspective of safe use of nanomaterials.

Understanding biophysicochemical interactions at the nano–bio interface

1. Introduction 20642. Synthesis of Magnetic Nanoparticles 20662.1. Classical Synthesis by Coprecipitation 20662.2. Reactions in Constrained Environments 20682.3. Hydrothermal and High-TemperatureReactions20692.4. Sol-Gel Reactions 20702.5. Polyol Methods 20712.6. Flow Injection Syntheses 20712.7. Electrochemical Methods 20712.8. Aerosol/Vapor Methods 20712.9. Sonolysis 20723. Stabilization of Magnetic Particles 20723.1. Monomeric Stabilizers 20723.1.1. Carboxylates 20733.1.2. Phosphates 20733.2. Inorganic Materials 20733.2.1. Silica 20733.2.2. Gold 20743.3. Polymer Stabilizers 20743.3.1. Dextran 20743.3.2. Polyethylene Glycol (PEG) 20753.3.3. Polyvinyl Alcohol (PVA) 20753.3.4. Alginate 20753.3.5. Chitosan 20753.3.6. Other Polymers 20753.4. Other Strategies for Stabilization 20764. Methods of Vectorization of the Particles 20765. Structural and Physicochemical Characterization 20785.1. Size, Polydispersity, Shape, and SurfaceCharacterization20795.2. Structure of Ferro- or FerrimagneticNanoparticles20805.2.1. Ferro- and Ferrimagnetic Nanoparticles 20805.3. Use of Nanoparticles as Contrast Agents forMRI20825.3.1. High Anisotropy Model 20845.3.2. Small Crystal and Low Anisotropy EnergyLimit20855.3.3. Practical Interests of Magnetic NuclearRelaxation for the Characterization ofSuperparamagnetic Colloid20855.3.4. Relaxation of Agglomerated Systems 20856. Applications 20866.1. MRI: Cellular Labeling, Molecular Imaging(Inﬂammation, Apoptose, etc.)20866.2.

Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications

We investigated the intracellular uptake of different sized and shaped colloidal gold nanoparticles. We showed that kinetics and saturation concentrations are highly dependent upon the physical dimensions of the nanoparticles (e.g., uptake half-life of 14, 50, and 74 nm nanoparticles is 2.10, 1.90, and 2.24 h, respectively). The findings from this study will have implications in the chemical design of nanostructures for biomedical applications (e.g., tuning intracellular delivery rates and amounts by nanoscale dimensions and engineering complex, multifunctional nanostructures for imaging and therapeutics).

Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells.

Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can
show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we
highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for
therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Nanoparticle therapeutics: an emerging treatment modality for cancer

Many therapeutic agents have intracellular compartments as their site of action. Targeted delivery of these agents to their specific intracellular targets could result in enhanced therapeutic efficacy and reduced toxicity. Various carriers have been shown useful in targeted delivery of different classes of therapeutic agents. Among these carriers, biodegradable nanoparticles formulated from biocompatible polymers poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) have shown the potential for sustained intracellular delivery of different therapeutic agents. In this review, we discuss different intracellular targets, barriers to intracellular delivery, mechanism and pathways of intracellular delivery, and various carriers and approaches that have been investigated for intracellular drug delivery.

Targeting intracellular targets.

Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for more effective treatments. Intravenous administration of tissue plasminogen activator (t-PA) is the only FDA-approved therapy to re-establish cerebral blood flow. However, because of increased risk of hemorrhage beyond 3 h post stroke, few stroke patients (1–2%) benefit from t-PA; t-PA, which has neurotoxic effects, can also aggravate the extent of reperfusion injury by increasing blood-brain barrier permeability. An alternative strategy is needed to extend the window of intervention, minimize damage from reperfusion injury, and promote brain repair leading to neurological recovery. Reactive oxygen species (ROS), generated soon after ischemia and during reperfusion and thereafter, are considered the main mediators of ischemic injury. Antioxidant enzymes such as catalase, superoxide dismutase, etc. can neutralize ROS-mediated injury but their effective delivery to the brain remains a challenge. In this article, we review various therapeutic approaches including surgical interventions, and discuss the potential of nanoparticle-mediated delivery of antioxidants for stroke therapy.

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Advances in stroke therapy

We have prepared and studied iron-oxide nanoparticles coated with oleic acid (OA) and Pluronic® polymer. The mean diameter of the iron-oxide nanoparticles was 9.3(±)0.8nm. Saturation magnetization values measured at 10K varied from 66.1(±0.7)emu∕gto98.7(±0.5)emu∕g. At 300K the loops showed negligible coercive field. The peaks in zero-field-cooled susceptibility decreased from 280to168K with increasing OA concentration up to 10.6wt%, and remained nearly constant for higher concentrations. This suggests that incomplete coverage of the OA allows small, interacting agglomerates to form.

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Magnetic studies of iron oxide nanoparticles coated with oleic acid and Pluronic® block copolymer

Epigenetic alterations such as aberrant DNA methylation and histone modifications contribute substantially to both the cause and maintenance of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Our hypothesis is that treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes. To test our hypothesis, we used drug-resistant breast cancer cells (MCF-7/ADR) and two epigenetic drugs that act via different mechanisms--5-aza-2'-deoxycytidine (decitabine, DAC), a demethylating agent, and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor--in combination with doxorubicin. We show that the sequential treatment of resistant cells, first with an epigenetic drug (DAC), and then with doxorubicin, induces a highly synergistic effect, thus reducing the IC(50) of doxorubicin by several thousand fold. The sequential treatment caused over 90% resistant cells to undergo G2/M cell cycle arrest, determined to be due to upregulation of p21(WAF1/CIP1) expression, which is responsible for cell-cycle regulation. The induction of p21(WAF1/CIP1) correlated well with the depletion of DNA methyltransferase1 (DNMT1), an enzyme that promotes methylation of DNA, suggesting that the p21(WAF1/CIP1) gene may have been methylated and hence is inactive in MCF-7/ADR cells. Microarray analysis shows expression of several tumor suppressor genes and downregulation of tumor promoter genes, particularly in sequentially treated resistant cells. Sequential treatment was found to be significantly more effective than simultaneous treatment, and DAC was more effective than SAHA in overcoming doxorubicin resistance. Synergistic effect with sequential treatment was also seen in drug-sensitive breast cancer cells, but the effect was significantly more pronounced in resistant cells. In conclusion, the sequential treatment of an epigenetic drug in combination with doxorubicin induces a highly synergistic effect that overcomes doxorubicin resistance in breast cancer cells.

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Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest.

Since the evolution of the concept of gene therapy, delivering therapeutic genes to the diseased cells has been a major challenge. Although viral vectors have been shown to be efficient in delivering genes, the issue of their safety is still to be solved. Meanwhile, the field of developing nonviral expression vectors has seen considerable progress. As compared with viruses, these are relatively safe but are confronted with the problem of poor transfection efficiency. With the growing understanding of the biology of gene transfection, and the continued efforts at enhancing the efficiency of nonviral expression vectors, it could soon become a preferred option for human gene therapy. In this review, the potential of polymeric nanoparticles as a gene expression vector is discussed. Furthermore, the importance of understanding the pathophysiology of disease conditions in developing gene expression vectors is discussed in Section 6.

Vinod Labhasetwar

Papers

Targeting intracellular targets.

Advances in stroke therapy

Magnetic studies of iron oxide nanoparticles coated with oleic acid and Pluronic® block copolymer

Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest.

Polymeric nanoparticles for gene delivery.