Medical Use of Nanoparticles

Abstract

Researchers today are able to encapsulate medicine in nanoparticles, the size of viruses. The nanoparticles are effective for drug delivery—the delivery of the medicine to the body—because they can very precisely find diseased cells and carry the medicine to them. This means that one can suffice with less dosage and thereby fewer side effects. In addition, nanoscience and nanotechnological methods are spurring the development of more sophisticated tools for detecting diseases, such as cancer and atherosclerosis, at early stages and performing neurosurgery. Applications of nanotechnology in disease diagnoses are developing rapidly. Their unique size-dependent properties make these materials superior and indispensable in many areas of human activity.

Introduction

Nanotechnology, although not a new concept, has gained significant momentum in recent years. The prefix “nano” means one-billionth. In the metric scale of linear measurements, a nanometer is one-billionth of a meter. Primarily in the material science standard, the term “nanotechnology” is now commonly used to refer to the fabrication of new materials with nanoscale of dimensions between 1 and 100 nm. ¹ However, with its development, the scope of this definition also expanded. Nanoparticles of different sizes have different biomedical purposes. In physics and electrical engineering, nanotechnology is associated with quantum behavior and the behavior of electrons and photons in nanoscale structures. Recently, Whitesides reviewed and interpreted the relationship among nanotechnology, chemistry, and biology. ²

Nanotechnology is currently employed as a tool to explore the darkest avenues of medical sciences in several ways like imaging, ³ sensing, ⁴ targeted drug delivery ⁵ gene delivery systems, ⁶ and artificial implants. ⁷ The new age drugs are nanoparticles of polymers, metals, or ceramics, which can combat conditions like cancer ⁸ and fight human pathogens like bacteria.^9–13

Applying nanotechnology in treatment, diagnosis, monitoring, and control of diseases has been referred to as “nanomedicine.” Although the application of nanotechnology in medicine appears to be a relatively recent trend, the basic nanotechnology approaches for medical application date back to several decades.

The first example of lipid vesicles that later became known as liposomes was described in 1965 ¹⁴ ; the first controlled release polymer system of macromolecules was described in 1976 ¹⁵ ; the first long circulating stealth polymeric nanoparticle was described in 1994 ¹⁶ ; the first quantum dot bioconjugate was described in 1998^17,18; and the first nanowire nanosenser dates back to 2001. ¹⁹ Recent studies on new targeted nanoparticles contrast agents for early characterization of atherosclerosis and cardiovascular pathology at the cellular and molecular levels that might represent the next frontier for combining imaging and rational drug delivery to facilitate personalized medicine. ²⁰ Nanotechnology-based highly efficient markers and precise, quantitative detection devices for early diagnosis and for therapy monitoring will have a wide influence in patient management, in improving patient’s quality of life, and in lowering mortality rates in diseases like cancer and Alzheimer’s disease.

The unique properties and utility of nanoparticles arise from a variety of attributes, including the similar size of nanoparticles and biomolecules such as proteins and polynucleic acids. Additionally, nanoparticles can be fashioned with a wide range of metal and semiconductor core materials that impart useful properties such as fluorescence and magnetic behavior. ²¹ The applicable properties of some well-known core materials and the corresponding possible ligands used for surface functionalization with their possible applications are summarized in Table 1. ²²

Table 1.

Characteristics, Ligands, and Representative Applications for Various Metal and Semiconductor Materials.

Core Material	Characteristics	Ligands	Applications
Au	Optical absorption, fluorescence, and fluorescence quenching, stability	Thiol, disulfide, phosphine, amine	Biomolecular recognition, delivery, sensing
Ag	Surface-enhanced fluorescence	Thiol	Sensing
Pt	Catalytic property	Thiol, phosphine, amine, isocyanide	Biocatalyst, sensing
CdSe	Luminescence, photostability	Thiol, phosphine, pyridine	Imaging, sensing
Fe2O3	Magnetic property	Diol, dopamine derivative, amine	MR imaging and biomolecule purification

Note: Au, gold; Ag, silver; Pt, platinum; Fe₂O_3, ferric oxide; MR, magnetic resonance

Physiologic and Biologic Characteristics of Nanoparticles

In chemotherapy, pharmacologically active cancer drugs reach the tumor tissue with poor specificity and dose-limiting toxicity. Conventional drug delivery methods include oral and intravenous (iv) routes. There are several disadvantages to these methods; for example, oral administration of tablets or capsules could result in disorderly pharmocokinetics due to the exposure of these agents to the metabolic pathways of the body. ²³ This can result in larger than necessary doses being administered, which can further cause increased toxicity. ²⁴ The traditional iv routes are often even more problematic. The specificity of some conventional iv drugs is low, resulting in harmful effects to healthy tissues. Nanoparticle drug delivery, using biodegradable polymers, provides a more efficient, less harmful solution to overcome some of these problems. It was in 1975 that Ringdorf proposed a polymer–drug conjugate model that could enhance the delivery of an anticancer model. ²⁵ He proposed that the pharmacologic properties of a polymer–drug conjugate model could be manipulated by changing the physical and chemical properties of the polymer. For example, an insoluble drug can be made water soluble by introducing solubilizing moieties into the polymer, thereby improving its bioavailability and biodegradability. The delivery of the drug to the target tissue can be achieved primarily in two ways—passive and active. ²⁶

Medical Use of Nanopartiches

Nanoparticles for Bioimaging

A number of molecular imaging techniques, such as optical imaging (OI), magnetic resonance imaging (MRI), ultrasound imaging (USI), positron-emission tomography (PET), and others, have been reported for imaging of in vitro and in vivo biological specimens.^27,28

The current development of luminescent and magnetic nanoparticles advances bioimaging technologies.^29,30 Two different type of nanoparticles have been widely used for imaging: luminescent nanoprobes for OI and magnetic nanoparticles for MRI. There are also dual-mode nanoparticles for simultaneous imaging by OI and MRI.^31,32

In Vitro Diagnostics

Novel sensor concepts based on nanotubes, nanowires, cantilevers, or atomic force microscopy are applied to diagnostic devices/sensors. The aim of these sensors is to improve the sensitivity, reduce production costs, or measure novel analytes (e.g., Alzheimer plaques) that were not detected until recently. For example, Nanomix (Emeryville, California) developed carbon nanotube–based sensors for monitoring the respiratory functions, and Bioforce’s Virichip (Ames, Iowa) uses atomic force microscopy for the detection of whole viruses for early diagnosis of viral infections. ³³ Known core materials and corresponding possible ligands used for surface functionalization with their possible applications are summarized in Table 1. ²²

Multifunctional Nanoparticles for Cancer Therapy

Biodegradable chitosan nanoparticles encapsulating quantum dots were prepared by D. K. Chatterjee and Y. Zhang, with suitable surface modification to immobilize both tumor targeting agent and chemokine on their surfaces. The interactions between immune cells and tumor cells were visualized using optical microscope. Use of quantum dots in the treatment of cancer is a great advancement in this area. Quantum dots glow when exposed to UV light. When injected they seep into cancer tumor and the surgeon can see the glowing tumor. Nanotechnology could be very helpful in regenerating the injured nerves. During the last decade, however, developments in the areas of surface microscopy, silicon fabrication, biochemistry, physical chemistry, and computational engineering have converged to provide remarkable capabilities for understanding, fabricating, and manipulating structures at the atomic level. The rapid evolution of this new science and the opportunities for its application demonstrates that nanotechnology will become one of the dominant technologies of the 21st century. ³⁴

In a recent study, antibody-conjugated magnetic poly-(d, l-lactide-co-glycolide) (PLGA) nanoparticles with doxorubicin (DOX) were synthesized for the simultaneous targeted detection and treatment of breast cancer. DOX and magnetic nanoparticles were incorporated into PLGA nanoparticles, with DOX serving as an anticancer drug and Fe₂O₃ nanoparticles used as an imaging agent (Figure 1). They also used antibody herceptin 1 for targeting the breast cancer. ²²

Figure 1.

The use of magnetic nanoparticles embedded into PLGA nanoparticles for diagnosis and treatment of diseases. PLGA = poly-(d,l-lactide-co-glycolide).

Nanoparticles as Drug Delivery Systems (DDSs)

DDSscan improve several crucial properties of “free” drugs, such as solubility, in vivo stability, pharmacokinetics, and biodistribution, enhancing their efficacy. ³⁵ In this aspect, nanoparticles can be used as a potential DDS owing to their advantageous characteristics, as mentioned previously. As an example of cellular delivery, mixed monolayer protected gold clusters were exploited for in vitro delivery of a hydrophobic fluorophore (BODIPY) (BODIPY are a class of organic fluorescent dyes which have recently become interesting for organic photovoltaics because of their strong tuneable infrared absorption and their high stability); an analog of hydrophobic drugs. ³⁶ The cationic surface of the nanoparticles facilitated the penetration through cell membrane, and the payload release was triggered by intracellular glutathione (GSH), relying on the ca. 1,000-fold higher intracellular concentration of GSH relative to the extracellular environment. Release of the dye was established by fluorogenesis upon release of the dye from the quenching nanoparticle. The controlled release of the fluorophore was observed in mouse embryonic fibroblast (MEF) cells, containing ca. 50% lower GSH levels than Hep G2; through incubation GSH monoethyl ester (GSH-OEt) is processed to GSH by esterases, transiently increasing intracellular GSH concentrations. Lin et al. have demonstrated that thiols, such as dihydrolipoic acid (DHLA) and dithiothreitol (DTT), can likewise act as stimuli to remove caps of the pores in mesoporous silica nanoparticles and hence release trapped molecules inside the pores.^37,38 The pores were capped with removable cadmium sulfide (CdS) or ferric oxide (Fe₃O₄) nanoparticles through disulfide linkers that cleave in a reducing environment. Release of encapsulated fluorescein isothiocyanate (FITC) from magnetic nanoparticle-capped MCM-41 was observed in cancer cells owing to the presence of significant amounts of intracellular DHLA.

pH-responsive nanomateials provide an alternate mechanism for release, relying on the acidic condition inside the tumor and inflamed tissues (pH 6.8) and cellular compartments including endosomes (pH 5.5–6) and lysosomes (pH 4.5–5.0). ³⁹ Toward this end, magnetic nanoparticles (Fe₃O₄) were covalently functionalized with DOX, an anticancer drug, through an acid-labile hydrazone linker. ⁴⁰ The carrier was then encapsulated with thermosensitive polymer for temperature-controlled release of the drug. The hybrid system released DOX efficiently in mild acidic buffer solution of pH 5.3. Schoenfisch et al. have likewise shown that nitric oxide (NO) can be efficiently released at acidic pH from gold nanoparticles. ⁴¹ Besides the surface chemistry of nanoparticles, the unique physical properties of nanoparticles have been utilized in the design of DDSs. Ford et al. have designed a water-soluble nanocontainer for NO storage based on electrostatic assembly of DHLA-coated quantum dots and cationic dinitro complexes that uses energy transfer from the core to release NO. ⁴² In another approach, doping of Ag/Au nanoparticles serves as an antenna to absorb the energy from a laser beam of “biologically friendly” near-infrared (NIR) region, causing local heating and disruption of microcapsules. More recently, Bhatia et al. designed multifunctional super paramagnetic nanoparticles for remote release of bound drugs. ⁴³ The particles transduce external electromagnetic force (EMF) at 350–400 kHz to local heating for breaking hydrogen bonds between DNA chains.

Surgery

At Rice University, a flesh welder is used to fuse two pieces of chicken meat into a single piece. The two pieces of chicken are placed together touching. A greenish liquid containing gold-coated nanoshells is dribbled along the seam. An infrared laser is traced along the seam, causing the two sides to weld together. This could solve the difficulties and blood leaks caused when a surgeon tries to restitch the arteries that have been cut during a kidney or heart transplant. The flesh welder could weld the arteries perfectly. ⁴⁴

Conclusions

Nanoparticles present a highly attractive platform for a diverse array of biological applications. The surface and core properties of these systems can be engineered for individual and multimodal applications, including biomolecular recognition, therapeutic delivery, biosensing, and bioimaging. Nanoparticles have already been used for a wide range of applications both in vitro and in vivo. Full realization of their potential, however, requires addressing a number of open issues, including acute and long-term health effects of nanomaterials as well as scalable, reproducible manufacturing methods and reliable metrics for characterization of these materials.