NANOMEDICINE : NANOPARTICLES,

NANODEVICES, NANOROBOTICS (MICROBOTICS), NANOMEDICINE NANOSURGERY FOR CANCERS , NEUROLOGICAL DISORDERS

- Greek word nano means dwarf

- Defined by the National Nanotechnology Initiative - is the understanding & control of matter at dimensions of roughly 1100 nm, where unique phenomena enable novel applications
- Involves imaging, measuring, modeling, and manipulating matter at this length scale - Application of nanotechnology to medicine NANOMEDICINE - It is the preservation & improvement of human health, using molecular tools & molecular knowledge of the human body - Nanobiotechnology (originated from nanotechnology) is related to Nanomedicine

Fig: Relationship of nanobiotechnology to Nanomedicine

NORMAL SCALE

NANOSCALE

Landmarks in the Evolution of Nanomedicine

Cont.

Nanomedicine is based on three mutually overlapping and progressively more powerful molecular technologies
1. Nanoscale - structured materials and devices, which hold great promise for Advanced diagnostics biosensors, targeted drug delivery, and smart drugs 2. Benefits of molecular medicine via genomics, proteomics, and artificially engineered Microorganisms 3. Molecular machine systems such as nanorobots that will allow instant diagnosis With destruction of cause of pathology, chromosome replacement and individual Cell surgery in vivo, and the efficient augmentation and improvement in natural Physiological function

Major Areas of Development of Nanomedicine

Prevention and control
Early detection Imaging diagnostics

Multifunctional Therapeutics
Artery Cleaner
Virus Seeking Probes

- Simplest form of structures with sizes in the nm range - Any collection of atoms bonded together with a structural radius of < 100 nm can be considered - nanoparticle - EG: metal clusters (agglomerates of metal atoms), large molecules, such as proteins, and even hydrogen-bonded assemblies of water molecules, which exist in water at ambient temperatures

TYPES
QUANTUM DOTS NANOCRYSTALS LIPOPARTICLES MAGNETIC NANOPARTICLES POLYMER NANOPARTICLES

Cu clusters

 NANOCRYSTALS - Crystalline nanoparticles

- Nanocrystals embedded in solids exhibit much more complex melting behaviour than conventional solids - Crystalline nanoparticles made with zeolite are used as filter to turn crude oil onto diesel fuel - Layer of crystalline nanoparticles is used in a new type of solar panel cheaper, more flexible, & more efficiency
NANOCRYSTALLINE SILVER

- Silver - medicinal properties - Thin layer of silver to large wounds to prevent infection & promote healing - In vitro tests demonstrated - active silver clusters of ions Provide antimicrobial activity immediately & kill many organisms in 30 min, faster than other forms of silver

- Silver nanocrystalline technology technology that decreases the particle size, thus changing the physical &chemical properties
: Sustained release of active silver to the dressings over a longer period of time : Cover the wound providing sustained release of silver to the dressing, acting as a barrier to infection for up to 7 days - Silver Sulfadiazine & Silver Nitrate treatment - characterized by rapid depletion of active silver, forcing the regular scraping of creams or applications of solutions to open wounds multiple times per day : Labor intensive & extremely traumatic for patients

 Quantum Dots
- Nanoscale crystals of semiconductor material that glow, or fluoresce when Excited by a light source such as a laser
- Size of the QD determined - frequency of light emitted when irradiated with low energy light - Costly and inconvenient for biomedical laboratories - as synthesis requires high-temperature techniques - Advantages of QD technology are as follows: * Simple excitation, * Simple instrumentation, * Availability of red/infrared colors enables whole-blood assays, * High sensitivity

- Potential applications of QDs in molecular diagnostics are as follows : * Cancer, * Genotyping,

* Whole-blood assays,
* Multiplexed diagnostics, * DNA mapping,

* Immunoassays and antibody tagging,

* Detection of pathogenic microorganisms, * Imaging of Living Tissue

- Other Applications of QDs include the following :

Life sciences research tracking proteins in living cells,

Fluorescence detection microscopy, biosensors, multicolor flow cytometry, Molecular diagnostics, Ex vivo live cell imaging,

In vivo targeting of cells, tissues, and tumors with monitoring by PET and MRI,
High-throughput screening

 Lipoparticles
- Nanometer - Spheres surrounded by a lipid bilayer and embedded with conformationally intact Integral membrane proteins

- Characteristic features :
Nanometer particles - surrounded by a lipid bilayer They are embedded with integral membrane proteins

They retain native structural conformations

Proteins spanning the membrane up to 14 times have been incorporated, including G protein-coupled receptors (GPCRs)

They are soluble & stable target storage system

They enable existing detection platforms to work with complex integral membrane proteins

-The ability to solubilize integral membrane proteins has applications for microfluidics, biosensors, high-throughput screening, antibody development, structural studies of complex receptors & drug discovery

 Polymer Nanoparticles
- Are Poly (ethylene glycol) (PEG)-coated poly (lactic acid) (PLA) Nanoparticles, Chitosan (CS)-coated poly (lactic acidglycolic acid (PLGA) Nanoparticles & CS Nanoparticles - Biodegradable - Can carry and deliver proteins in an active form - Transport them across the nasal and intestinal mucosae

Accurins - polymeric nanoparticles

- PEG coating improves the stability of PLGA Nanoparticles in the gastrointestinal fluids and helps the transport of the encapsulated protein, tetanus toxoid, across the intestinal and nasal mucous membranes, also intranasal administration of these Nanoparticles provide high and long-lasting immune responses

- Coating of PLGA Nanoparticles with the mucoadhesive CS improves the stability of the particles in the presence of lysozyme
& enhance the nasal transport of the encapsulated tetanus

toxoid

- Nanoparticles made solely of CS are stable upon incubation with lysozyme - Improve local & systemic immune responses to tetanus toxoid - Polymeric Micelles - biocompatible Nanoparticles varying in size from 50 to 200nm * Poorly soluble drugs can be encapsulated - represent a possible solution to the delivery problems associated with such compounds * Can potentially alleviate toxicity problems * Amphiphilic pH-responsive poly (N-isopropylacrylamide) (PNIPAM) or poly (alkyl(meth)acrylate) derivatives - example

 Superparamagnetic nanoparticles
- Are molecules that get attracted to magnetic field but do not retain residual magnetism after the field is removed

- Nanoparticles of iron oxide with diameters in the 5-100 nm range, have been used for selective magnetic bioseparations

- Typical techniques involve coating the particles with antibodies to cell-specific antigens, for separation from the surrounding matrix

- Used in * Membrane transport studies * Superparamagnetic iron oxide Nanoparticles (SPION) are applied for drug delivery & gene transfection * Targeted delivery of drugs, bioactive molecules or DNA vectors is dependent on the application of an external magnetic force that accelerates and directs their progress towards the target tissue * Are also useful as MRI contrast agents

NANODEVICES
- Devices based on nanobiotechnology - Powerful tools for the treatment of human diseases & the augmentation of human biological systems - 100 to 10,000 times smaller than human cells

- Can readily interact with biomolecules on both the surface of cells and inside of cells
- Nanoscale devices (less than 100 nanometers) can enter cells & the organelles inside them to interact with DNA and proteins - Used to diagnose illness and to repair damages and infections - Examples:- Nanorobots, Nanosensor, Nanoendoscopy etc.,

- Applications:- Diagnosis, Cancer treatment, Imaging etc.,

 DESIGNING NANODEVICES FOR USE IN THE BODY "

- Nanostructures - so small - the body may clear them too rapidly - Larger Nanoparticles - accumulate in vital organs - toxicity problem - Creation of Nanodevices body will accept

 NANODEVICE MANUFACTURE
- Two basic approaches - top-down & bottom-up

- Top-down - molding or etching materials into smaller components traditional method for making parts of Computer & Electronics
- Bottom-up - assembling structures atom-by-atom or molecule-bymolecule method for manufacturing devices used in medicine

- Nanodevices Can Improve Cancer Detection and Diagnosis

- Can Improve Sensitivity

- Can Make Cancer Tests Faster and More Efficient - Can Preserve Patients' Samples

Dendrimers - Nanoparticle mediated nanodevice created to facilitate drug delivery

- Potential to link treatment with detection and diagnosis - Man-made molecules about the size of an average protein - Have a branching shape - vast amounts of surface area to which scientists can attach therapeutic agents or other biologically active molecules

Cancer cell

Dendrimer

Water dendrimer

Nanodevice molecule

White blood cell

Dendrimers as Cancer Therapy

Therapeutic agent

Cancer detector

Reporter

Cell death monitor

Water molecule

Nanodevices

Dendrimer

White blood cell

Nanopores
- Improved methods of reading the genetic code
- Detect errors in genes that may contribute to cancer - Nanopores - tiny holes that allow DNA to pass through one strand at a time, will make DNA sequencing more efficient - As Dna passes through this pore - scientists can monitor the shape & electrical properties of each base, or letter, on the strand - These properties - unique for each of the four bases that make up the genetic code - Can use the passage of DNA through a nanopore to decipher the encoded information, including errors in the code known to be associated with cancer

- Single dendrimer can carry molecules that recognizes cancer cells, a therapeutic agent to kill those cells,

& a molecule that recognizes the signals of cell death

- Modification manipulate dendrimer to release their contents only in the presence of certain trigger molecules associated with cancer - Following drug release, the Dendrimers may also report back whether they successfully killed their targets

Nanopores
Single-stranded DNA molecule

Nanopore

A T C G

A
Nanopore

Singlestranded DNA molecule

T
Nanopore

Single-stranded DNA molecule

Water molecule

Nanodevices
Nanopores

White blood cell

Nanotubes
- Help identify DNA changes associated with cancer
- Are carbon rods about half the diameter of a molecule of DNA that not only can detect the presence of altered genes

- But may help pinpoint the exact location of those changes

- To prepare DNA for analysis - bulky molecule is attached to the regions of DNA that are associated with cancer - Can design tags that seek out specific mutations in the DNA & bind to them - So Nanotubes used for Marking Mutations

Nanotubes Marking Mutations

Cancer cell

DNA

Mutation

Bulky molecule tag

Cancerassociated changes are tagged with bulky molecules.

Water molecule

Nanodevices Bulky molecule tag

White blood cell

- Once mutation been tagged Nanotube tip resembling the needle on a record player is used to trace the physical shape of DNA & pinpoint the mutated regions - Nanotubes creates a map showing - shape of DNA molecule, including the tags - identifying important mutations

- Since the location of mutations can influence the effects they have on a cell, these techniques will be important in predicting disease

Nanotubes Mapping Mutations

Nanotube A Nanotube traces the shape of the DNA and makes a map.

Water molecule

Nanodevices
Nanotube

White blood cell

 Nanorobotics
- Robotics is the use of technology to design & manufacture (intelligent) machines, built for specific purposes, programmed to perform specific tasks
- Robots are programmable machines, They range from small, miniature machines, to large crane size constructions - Nanobiotechnology Nanorobotics (Nanobots)

- It is concerned with atomic and molecular-sized objects and is also called Molecular Robotics (Microbotics)

- Nanorobot is a specialized nanomachine - Has dimensions on the order of nanometers - Possibility of nanorobots was first proposed by Richard Feyman in his talk Theres Plenty of Room at the Bottom in 1959

- Have the capability to perform precise and refined intracellular surgery - beyond the capability of manipulations by human hand
- Nanorobots can be categorized into two groups - Autonomous robots & Insect robots - Nanorobots - require very little energy to operate

 Remain operational for years, decades or centuries

High speed . Can operate much faster than their larger counterparts For introduction into the body through the vascular system or at the end of catheters into various vessels & other cavities in the human body

An example of how nanotechnology robots might interact with our bodies in the future, repairing and maintaining red blood cells

Nanorobotics is mainly concerned with :

(1) Manipulation of Nanoscale objects by using micro or macro devices,

(2) Construction & programming of robots with overall dimensions at the Nanoscale (or with microscopic dimensions but nanoscopic components)
Nanorobots have dimensions comparable to those of biological cells, & are expected to have remarkable applications in health care & environmental monitoring For example, they might serve as programmable artificial cells for early detection & destruction of pathogens

Applications using Nanorobots

To cure skin disease and as cosmetic cream Can be used a a mouthwash to do all brushing and flossing Would augment immune system by finding and killing bacteria & viruses It would prevent heart attack , kill cancer cells etc To monitor potentially dangerous microorganisms in the ocean Future nanorobots equipped with operating instruments & mobility - able to perform precise and refined intracellular surgeries

Fig : Nanorobotic artificial phagocytes called microbivores

- Could patrol bloodstream, seeking out & digesting unwanted pathogens including bacteria, viruses, or fungi
- Would achieve complete clearance of even the most severe septicemic infections in hours or less - Far better than antibiotic - assisted natural phagocytic dfenses - Do not increase the risk of sepsis or septic shock because the pathogens are completely digested into harmless sugars, amino acids & which are the only effluents from the nanorobot

Surgical Nanorobotics
- A surgical nanobot, programmed by human surgeon, could act as an autonomous on-site surgeon inside the human body
- Could be introduced into the body through the vascular system or at the ends of catheters into various vessels & other cavities in the human body - Various functions - searching for pathology, diagnosis, & removal or correction of the lesion by nanomanipulation can be performed & coordinated by an onboard computer - Its structure - two spaces consisting of interior & exterior - They will communicate with doctor by encoding messages to acoustic signals

Nanorobots can be used in blood cell to detect pathogens

NANOSURGERY FOR CANCER & NEUROLOGICAL DISORDERS

- Historically, surgery was macrosurgery - General surgery involves gross manipulation of organs & tissues by human hands & handheld instruments - Branches of surgery such as ophthalmology & otorhinolaryngology started to miniaturize & started using microsurgery - Basic feature was minimization of trauma to the body tissues during surgery - Small incisions, laparoscopic surgery by fiber-optic visualization through tubular devices, vascular surgery by catheters, & microsurgery under operating microscopes to refine the procedures & reduce trauma - Devices such as robotics & implants will be a part of this miniaturization process

nanooncology
- Application of nanotechnology in cancer
- Includes both diagnostics & therapeutics - Doxil (a liposome preparation of doxorubicin [DOX]) & Abraxane (paclitaxel in nanoparticle formulation) ) nanotechnology based Products for treatment of cancer - Nanotechnology for detection of Cancer : QDs for Cancer Diagnosis Dendrimers for Sensing Cancer Cell Apoptosis Gold Nanoparticles for Cancer Diagnosis Nanotubes for Detection of Cancer Proteins Nanoparticles for the Optical Imaging of Tumors Nanolaser Spectroscopy for Detection of Cancer in Single Cells

- Nanotechnology-Based Imaging for Management of Cancer

Nanoparticle-MRI for Tracking Dendritic Cells in Cancer Therapy

Nanoparticle-CT scan

QDs Aid Lymph Node Mapping in Cancer

Nanoparticles Designed for Dual-Mode Imaging of Cancer - Nanotechnology for Cancer Therapy

Nanoparticles for Targeting Tumors

Nanoshell-Based Cancer Therapy Nanobody-Based Cancer Therapy

Nanobomb for Cancer

- Nanobiotechnology-Based Drug Delivery in Cancer Nanoparticle Formulations for Drug Delivery in Cancer

- Devices for Nanotechnology-Based Cancer Therapy Convection-Enhanced Delivery with Nanoliposomal CPT-11 Nanocomposite Devices Nanoengineered Silicon for Brachytherapy

Carbon Nanotubes for Laser-Induced Cancer Destruction

Nanosensor Device as an Aid to Cancer Surgery

- Scientists at the University of NebraskaLincoln developed a highresolution touch sensor - That uses a self-assembling nanoparticle device & acts much like a human finger - Self-assembly process developed by the research team involves no complex lithography - Has the ability to sense texture by touch, which is vital for surgeons who need the touch sensation in order to operate with precision & accuracy, such as when it comes to detecting & removing cancer cells from the body

- Application The Potential it holds for cancer surgeons, who are faced with the difficult task of knowing where to stop cutting when removing cancer cells in the body
- The nanodevice structure can attain resolution of ~20 m - Dimension comparable to single-cell dimension one can see a single cancer cell in a tissue

- To be cost-effective and would be relatively easy to reproduce

Nanoneurology
- Nanobiotechnology for Study of the Nervous System
Nanowires for Monitoring Brain Activity Nanoparticles & MRI for Macrophage Tracking in the CNS - Nanotechnology-Based Drug Delivery to the CNS Nanoencapsulation for Delivery of Vitamin E for CNS

Disorders
Nanoparticle Technology for Drug Delivery Across BBB Delivery Across BBB Using NanoDelTM Technology NanoMed Technology to Mask BBB-Limiting Characteristics of Drugs

-Nanoparticles and MRI for Tracking Stem Cell Therapy of CNS - Application of Nanotechnology for Neuroprotection Fullerene-Based Neuroprotective Antioxidants Ceria Nanoparticles as Neuroprotective Antioxidants

- Application of Nanotechnology for Neuroregeneration

- Nanotube Neuron Electronic Interface Photochemical Activation of Nanoparticle-Film Neuronal Interface

 Nanoneurosurgery
- An extension of neurology involving surgery, nanodiagnostics, & application of new technologies for treatment of neurological disorders - Nanobiotechnology - refined many surgical approaches - diseases of the nervous system - Nanoneurosurgery

- Applications in brain cancer, Neuroregeneration, & CNS implants

Femtolaser Neurosurgery
- Understanding nerves regeneration - important step towards
developing treatments for human neurological disease - Investigation limited to complex organisms (mouse & zebra fish) in the absence of precision techniques for severing axons (axotomy) - Used for Axotomy in the roundworm Caenorhabditis elegans -

these axons are functionally regenerated after the operation

- Acts like a pair of tiny nanoscissors, which is able to cut nanosized structures like nerve axons - Application - enable nerve regeneration to be studied in vivo

 Pulse has a very short length making the photons in the laser concentrate in one area
Once cut, the axons vaporize and no other tissue is harmed

Would impair the worms backward motion. The worms could not move backwards after surgery
within 24 h, most of the severed axons regenerated and the worms recovered backward movement

Nanofibers as an Aid to CNS Regeneration by Neural Progenitor Cells

- New nanotechnology method for growing nerve cells in tissue cultures - Neural progenitor cells encapsulated in vitro within a 3-D network of nanofibers formed by self-assembly of peptide amphiphile molecules - Self-assembly of nanofiber scaffold initiated - by mixing cell suspensions in media with dilute aqueous solutions of the molecules, & cells survive growth of the nanofibers around them - Nanofibers were designed to present to cells the neurite-promoting laminin epitope - Artificial nanofiber scaffold induce very rapid differentiation of neural progenitor cells into neurons - while discouraging the development of astrocytes

- Silicon neural electrodes engineered with a nanostructured form of silicon, called porous silicon, which acts as a scaffold that reduces glial scarring from electrode implantation and enhances neural growth at the brain recording sites to create a superior interface with neurons

- Useful in the procedure of electrode implantation in neurological disorders such as PD and epilepsy

Nanofiber Brain Implants

- Brain probes & implants are used in neurosurgery - management of
epilepsy, movement disorders, and pain - Silicon probes are commonly used for recording of electrical impulses & for brain stimulation - Body generally regards these materials as foreign & the probes gets encapsulated with glial scar tissue, which prevents them from making good contact with the brain tissue

Nanoparticles as an Aid to Neurosurgery

- Oregon Health & Science University - research team- shown that an iron oxide nanoparticle can outline not only brain tumors under MRI but also other lesions in the brain that may otherwise have gone unnoticed - Ferumoxtran-10 - dextran-coated iron oxide nanoparticle, provides enhancement of intracranial tumors by MRI for more than 24 h and can be imaged histologically by iron staining - Iron oxide nanoparticle - size of a small virus and is much smaller than a bacterium but much larger than an atom or standard gadolinium contrast molecule
- An iron oxide crystal surrounded with a carbohydrate or sugar coating called dextran - gives the particle a longer plasma half-life, allowing it to slowly slip through the BBBa natural defense system that blocks the entry of foreign substances, including therapeutic agents

Nanoscaffold for CNS Repair

- Several barriers - overcome to achieve axonal regeneration after injury in the CNS : (i) scar tissue formation (ii) gaps in nervous tissue formed during phagocytosis of dying cells after injury (iii) factors that inhibit axon growth in the mature mammalian CNS (iv) failure of many adult neurons to initiate axonal extension - Using mammalian visual system as model - self-assembling peptide nanofiber scaffold designed - creates a permissive environment for axons not only to regenerate through the site of an acute injury but also to knit the brain tissue together

- Peptide nanofiber scaffold not only represents an undiscovered nanobiomedical technology for tissue repair & restoration but also raises possibility of effective treatment of CNS & other tissue or organ trauma - Peptide nanofiber scaffold has several advantages over currently available polymer biomaterials : (i) Forms a network of nanofibers - similar to native extracellular matrix - therefore provides an in vivo environment for cell growth, migration, & differentiation

(ii) Can be broken down into natural L-amino acids & metabolized by surrounding tissue
(iii) Synthetic & free of chemical & biological contaminants

that may be present in animal-derived biomaterials like collagens

(iv) Appears to be immunologically inert - avoiding the problem of neural tissue rejection

Nanoparticles for Repair of Spinal Cord Injury - Spinal cord injury lead to serious neurological disability - serious
form - paraplegia or quadriplegia - Local spinal cord lesions :

Greatly enlarged by secondary damage

Accompanied by additional massive cell death Involves neurons, microglia, & macroglia

Virtually complete at 12 h
- Immediate care involves stabilization - patients general Condition - Surgery is carried out in some cases for removal of compressing

lesions & stabilization of spinal fractures

- Stem cell therapies for Neuroregeneration & Nanoparticles can be used to track the course of stem cells