NANOPARTICLES IN CANCER DIAGNOSIS AND TREATMENT

Introduction • Nanotechnology promises changes in many

significant areas of medicine, material science, construction, etc. In medicine advanced nanostructures, such as functional nanoparticles, dendrimers, fullerenes, carbon nanotubes and semiconductor nanocrystals have been exploited for drug delivery, diagnostics and treatment of diseases at the molecular level.

NANOMEDICINE• Specific application of nanobiotechnology to nano and

molecular scale design of devices for the prevention, treatment, and cure of illness and disease is called nanomedicine.

• In cells, proteins are nanomachines that act as transporters, actuators, and motors. They are responsible for specific monitoring and repair processes. In this role nanoparticle is usually a nano-sized polymeric colloidal particle with the drug either encapsulated within the polymer or conjugated onto its surface.

• Nanoparticle-based therapeutics – nanopharmaceuticals – are colloidal particles of 10 to 1000 nm (1 micron) that are diverse in size, shape and composition. Therapeutic delivery systems are designed to deliver a range of therapeutic agents, including drugs, proteins, vaccine and plasmid DNA for gene therapy, by exposing target cells to their payload. This requires the carrier to enter cells where, once internalized, the therapeutic agent is released through vehicle degradation and diffusion mechanisms.

• Current nanoscale delivery systems are divisible into two major categories: surface modification systems designed to prevent immune response or promote cell growth, and particle-based systems designed to deliver therapeutics to cell and tissues.

Nanomaterials used for cancer diagnosis and treatment

• Nanoshells• Dendrimers • Quantum dots• Superparamagnetic Nanoparticles• Nanowires • Nanodiamonds • Nanosponges

One of new findings for nanoscale drug delivery in diagnosing and treating cancer are nanoshells – gold-coated silica. These nanoshells, set in a drug-containing tumor-targeted hydrogel polymer, injected into the body, accumulate near tumor cells. When heated with an infrared light, the nanoshells selectively absorb a specific infrared frequency, melting the polymer and releasing the drug payload at a specific site. They are designed for specific targeting micrometastases, tiny aggregates of cancer cells too small to remove with a scalpel.

• Another nanoscale drug delivery system can be created with the use of dendrimers. Dendrimer is precisely constructed molecule built on the nanoscale in a multistep process through up to ten generations and from 5 to 50 nm in scale .

• A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. Drugs and recognition molecules can be attached to their ends or placed inside cavities within them.

• The dendritic multifunctional platform is ideal to combine various functions like imaging, targeting, and drug transfer into the cell.

• Quantum Dots• Quantum dots are semiconductors, the most commonly used

cadmium selenide capped by zinc sulphide (CdSe/ ZnS). The size of quantum dots range from 2 to 10 nm in diameter and these are composed of 10–50 atoms, containing electron–hole, pairs to a discrete quantized energy.

How Quantum Dots Work?• When energy is applied to an atom, electrons are energised and

move to a higher level. When the electron returns to its lower and stable state, this additional energy is emitted as light corresponding to a particular frequency. QDs work in much the same way but a QD crystal acts as one very large atom. The energy source used to stimulate a QD is commonly ultraviolet light. The frequency or colour of light given off is not related to the material used in the quantum dot, but by the size of the QD.

• Superparamagnetic Nanoparticles• Iron oxide particles (Fe3O4) are referred as magnetic nanoparticles

and developed as superparamagnetic nanoparticles.• The sizes of the nanoparticles are less than 10 nm in diameter. These

nanoparticles are having potential application in magnetic resonance imaging. Many reports revealed that superparamagnetic nanoparticles can be functionalized with other type of nanoparticle, so as to permit specific tumor targeting.

• These are also having importance in the use of magnetic fields to localize magnetic nanoparticles to targeted sites, a system known as magnetic drug targeting.

• Superparamagnetic nanoparticles can be modified by improving the solubility and specificity of iron oxide particles. Iron oxide nanoparticles can also be used in imaging techniques that can selectively image proliferating cells in vivo can provide critically important insights of tumor growth rate, degree of tumor angiogenesis, effectiveness of treatment and vigor normal cells.

• Nanowires• Nanowires are nanoparticles with diameters of only a

few nanometres and extended lengths. Predictably, the length and width ration is extremely large making them effectively one-dimensional structures. These are revolutionized innovative compounds these would be used to link together tiny components into extremely small circuits. These nanowires are purported to have functions in monitoring brain electrical activity without having to use a brain probe and violating the brain parenchyma.

• Nanodiamonds• Nanodiamonds are synthesized in 1962 by detonation and also

can be prepared by covalent and noncovalent modification to absorb or graft a variety of functional groups and complex moieties, including proteins and DNA. These are attractive agents for use in biological and medical applications largely due to their greater biocompatibility than other carbon nanomaterials, stable photoluminescence, commercial availability and minimal cytotoxicity.

• Nanodiamonds can be used for cell labeling and tracing because they do not interrupt cell division or differentiation, have minimal cytotoxicity, and are easily functionalized with proteins and other markers for targeting purposes. Nanodiamonds have successfully have been used as biomarkers or tracers to label or trace HeLa cells, lung cancer cells, and murine fibroblasts.

• Nanosponge• Nanosponge is like a three-dimensional network or scaffold. Its

backbone is a long length of polyester and the size is of about virus. Nanosponge is mixed in solution with small molecules called cross-linkers that act like tiny seizing hooks to tie up different parts of the polymer together. The net effect of this arrangement is to form spherically shaped particles filled with cavities where drug molecules can be stored and then injected into the body. This tiny sponge circulates around the tumor cell until they encounter the surface to sustain releasing their drug cargo. Nanosponge is three to five times more effective at reducing tumor growth than direct injection. The targeted delivery systems of nanosponge have several basic advantages like, the drug is released at the tumor instead of circulating widely through the body, it is more effective for a given dosage . The nanosponge should have basic features such as fewer harmful side effects because smaller amounts of the drug will come into contact with healthy tissue.

MRI Contrast enhancement and diagnosis kits

Basic Principles of Magnetic Resonance ImagingContrast Agents in MRITypes of gadolinium contrast agentsSuperparamagnetic contrast agents

Basic Principles of Magnetic Resonance Imaging

• Magnetic resonance imaging is an imaging modality which is primarily used to construct Images of the NMR signal from the hydrogen atoms in an object.

• In medical MRI, radiologists are most interested in looking at the NMR signal from water and fat, the major hydrogen containing components of the human body .

• MRI utilizes the strong static homogenous magnetic field generated by the magnet. When the high frequency magnetic field is applied to the subject placed in the homogeneous static magnetic field, it excites proton nuclear spins within the patient's tissues.

• The excited proton spins rotate at a rate dependent upon the static magnetic field. As they flip, they emit radio frequency signals, referred as magnetic resonance signals.

Contrast Agents in MRI

MRI signal strength depends on the longitudinal (T1) and transverse (T2) relaxation time of water protons, the difference in the relaxation times causes different contrasts in MRI images . To maximize image quality, MR contrast agents are often needed to decrease T1 and T2 relaxation times. Several materials have been recently developed to enhance the image contrast and diagnostic accuracy of MRI. MRI contrast agents can be divided into two main categories of paramagnetic and super paramagnetic compounds. Paramagnetic contrast gents, also called T1 or positive contrast agents, are usually composed of Gadolinium3+ or Mn2+, which generates positive signals on T1-weighted images. Superparamagnetic contrast agents, also called T2 or negative contrast agents, are usually constructed with iron oxide, which generates negative signal on T2 weighted images.

• Paramagnetic Agents• Currently paramagnetic metal ions are used as contrast agents

in MRI. These materials are metals with unpaired electrons in their outer shell (transition and lanthanide metals). The two main and widely used compounds of this class are Gadolinium and manganese

Gd-based magnetic resonance contrast agents (GBCAs) for molecular imaging

• Gadolinium Gd(III) chelates• Macromolecular Gd(III) complexes• Dendrimer• Gadolinium-Based Hybrid Nanoparticles• Biodegradable macromolecular• Liposomal particles• Targeted contrast agents

Types of gadolinium contrast agents:• Extracellular fluid agents: Dotarem, Magnevist, Omniscan,

OptiMARK, and Prohance• Blood pool agents (intravascular agents): Polydisulfide Gd(III)

complexes have relatively long blood circulation time are gradually into small compounds that are rapidly excreted through the kidney filtration converted. The use of biodegradable macromolecular contrast agents in MRI imaging cardiovascular disease and cancer, and to evaluate the response to treatment

• Organ-specific agents: Tetra-P-aminophenylporphyrin (TPP) was conjugated with gadolinium diethylenetriaminepen-taacetic acid (DTPA) (Gd2(DTPA)4TPP) could be a useful in MR imaging contrast agent with an specific tumors contrast agent. A new class of metal-loaded nanoparticles has developed that have potential as contrast agents for medical imaging.

Superparamagnetic contrast agents• Several classes of magnetic iron oxide nanoparticles, also

known as superparamagnetic IONPs (SPIO) and ultrasmall SPIO (USPIO) developed in 1980s, has been approved by FDA (e.g., Feridex) for clinical applications with capabilities of traditional “blood pool” agents.[20, 21] The important properties of cell phagocytosis of magnetic nanoparticles has expanded the applications of contrast enhanced MRI beyond the vascular and tissue morphology imaging, enabling many novel applications of magnetic IONPs for MRI diagnosis of liver diseases, cancer metastasis to lymph nodes, and in vivo tracking of implanted cell and grafts with MRI.

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