NANOTECHNOLOGY IN ANTIDIABETIC THERAPY

CONTENTS
INTRODUCTION: NANOTECHNOLOGY AND DIABETES MELLITUS NANOMEDICINE APPLICATION IN GLUCOSE MONITERING DRUGS USED IN THE TREATMENT OF DM NANOCARRIERS FOR INSULIN DELIVERY CONCLUSION

 Nanotechnology is a field of applied science and technology which controls matter on molecular level in scales within the 1-100 nm. Nanometrology and nanotherapy Deliver pharmaceuticals that cannot be effectively delivered by conventional means.

DIABETES MELLITUS
Metabolic disorder in which a person has high blood

sugar (200 mg/dl) - body does not produce enough

insulin or cells do not respond to the insulin. Three types Type I diabetes mellitus Type II diabetes mellitus Gestational diabetes

Difference between Type I and Type II diabetes mellitus

 150 million people

2025 : 300 million Cardiovascular disease- hypertension Renal failure Retinal damage Nerve damage Microvascular damage Poor healing

The clinical need and the vision for nanotechnolgy in diabetes

NANO MEDICINE APPLICATION IN GLUCOSE MONITORING 1. Glucose nonosensors 2. Layer by layer (LBL) technique 3. Carbon nano tubes 4. Quantum dots

1. GLUCOSE NANOSENSORS
Smart tattoo composed of glucose responsive,

fluorescence-based nanosensors implanted into the skin but interrogated from outside the body, thus gives noninvasive measurements. The biological or artificial receptor for glucose - transduce glucose concentrations into changes in fluorescence.

 Lectins

: Plant lectin, Concanavalin

Enzymes : Hexokinase/ Glucokinase Bacterial binding proteins :

Glucose Binding Protein (GBP)

Polarity sensing dyes : Nile red Benzothiazolium squarine

FRET - FLUORESCENCE RESONANCE ENERGY TRANFER

(Salins et al., 2001)

2. THE LAYER BY- LAYER (LBL) TECHNIQUE

Encapsulation of a glucose-sensing protein in nanoengineered microcapsules The protein is adsorbed onto a template of calcium carbonate, alternating layers of poly-L-lysine and then poly-L-glutamic acid are applied, followed by dissolution of the template using EDTA

3. CARBON NANOTUBES
Single-walled carbon nanotubes (SWCNTs) fluoresce in the NIR spectral region. Fluorophore probes Dextran is bound to the carbon nanotubes

Binding of concanavalin A or apo-glucose oxidase to the

dextranSWCNT attenuates the fluorescence.

Carbon nanotubes

4. QUANTUM DOTS
Nanosized semiconductor crystals (210 nm) Cadmium selenide coated with a shell - zinc sulfide. Fluorescence - display high-intensity fluorescence that is excitable over a broad range of wavelengths.

Emission wavelength dependent on the particle size.

Glucose displaces the concanavalin a labelled QDs from gold labelled cyclodextrin, reducing the FRET and increasing the fluorescence.

DRUGS USED IN THE TREATMENT OF DIABETES MELLITUS

1. Insulin Regular, Short, Long and ultra long acting

2. Oral hypoglycemic agents

Biguanides- Metformin Sulfonylureas Glibenclamide, glipizide and glyburide Thiazolidinediones Rosiglitazone

Alpha-Glucosidase Inhibitors Acarbose

3. Islet cell transplantation 4.Pancreas transplantation

INSULIN THERAPY
Inconvenience of subcutaneous (SC) daily High financial burden on health care cost

Insulin administered orally enters the portal circulation and

passes through the liver before reaching the systemic circulation. Oral Insulin - unstable in the gastrointestinal (GI) tract and low permeability to cross the intestinal epithelium.

Hyperinsulinism

Oral delivery of Insulin drug

(Ahmad et al., 2012))

THE CLINICAL NEED AND THE VISION FOR NANOTECHNOLGY IN DIABETES

Nanosize carriers have a large specific surface area Protein encapsulation Polymerization - Affects biocompatibility. Polysaccharide - Chitosan

Mucoadhesion

NANOCARRIES FOR INSULIN DELIVERY

1.Polymeric biodegradable nanoparticles
2. Polysaccharides and polymeric nanoparticles 3. Ceramic nanoparticles 4. Gold nanoparticle 5. Chitosan 6. Liposomes 7. Dendrimer

8. Polymeric micelle
9. Artificial pancreas 10. Antisense nucleotides (Subramani et al., 2012)

POLYMERIC NANOPARTICLES
Solid, colloidal biodegradable polymers -10 to 100 nm. Nanosphere and Nanocapsule Nanosphere - matrix system in which the drug is physically and uniformly dispersed

Nanocapsule - vesicular systems in which the drug is confined

to a cavity surrounded by a unique polymer membrane These particles degrade into biologically acceptable

compounds by hydrolysis thus delivering the encapsulated medication to the target tissue.

 Polyanhydrides Polyacrylic acids Polyurethanes Poly (lactide - co - glycolide) Polyesters and poly (methyl ethacrylates) Methoxy poly(ethylene glycol) N,N- dimethylaminoethyl methacrylate Polyacrylamide

 Carriers of insulin Polymer-insulin matrix surrounded by nano porous membrane containing grafted glucose oxidase.

A rise in blood glucose level triggers a change in the

surrounding nano porous membrane causes a

lowering of the pH in the delivery system's

microenvironment. Increase in the swelling of the polymer system, resulting in biodegradation and subsequent insulin delivery.

(Dorski et al., 2011)

POLYSACCHARIDES AND POLYMERIC NANOPARTICLES

Encapsulating nanoparticles. Calcium

the

insulin

molecules

in

polymeric

phosphatepoly(ethylene

glycol)

insulin

combination was combined with casein (milk protein).

Polysaccharides

Chitosan,

dextran

sulfate,

and

cyclodextrin, - deliver the insulin molecules with polymeric nanoparticles as carrier systems.

Calcium phosphatePEGinsulincasein oral insulin delivery system

CAP - Calcium phosphate, PEG Poly ethylene glycol

BIOMEMS FOR INSULIN DELIVERY

Biological micro electro mechanical systems Drug reservoir compartment filled with insulin molecules

Biosensors and nano porous membranes with pores of 6 nm

diameter are located in the exterior to detect the changes in blood glucose level and for insulin release. Biocapsule consisting of two micromachined membranes bonded together to form a cell-containing cavity bound by

membranes with nanopores.

Biocapsule consisting of two micromachined membranes bonded together to form a cell-containing cavity bounded by membranes

Scanning electron micrographs of the microfabricated membrane of 6 nm pore size

Monograph of biocapsule membrane with 24.5 nm pores

Types of nanoparticles
Polymeric nanoparticles

Advantages
- Lesser cytotoxicity - Higher target specificity - High level of insulin entrapment

Limitations
- Mucoadhesive polymeric nanoparticles

Ability to preserve insulin structure and biological activity

- Bypassing of the enzymatic degradation in stomach

3. CERAMIC NANOPARTICLES
Calcium phosphate, silica, alumina or titanium. Easier preparative processes, high biocompatibility ultralow size (less than 50 nm) and good dimensional stability Protect the doped drug molecules against denaturation

caused by changes in external pH and temperature.

Do not undergo swelling or porosity changes caused by changes in surrounding environment.

Types of nanoparticles

Advantages

Limitations
Poor permeability across the mucosal membrane

Ceramic nanoparticles - Easy preparative processes - High biocompatibility ultra-low size (less than 50 nm) - Good dimensional stability - Protection - Manufactured with desired size shape porosity

4.GOLD NANOPARTICLE
Chitosan reducing agent in the synthesis of gold nanoparticles and promoted the penetration and uptake of insulin across the oral and nasal mucosa Long term stability

Improved pharmacodynamic activity of insulin.

Types of nanoparticles
Gold nanoparticles -

Advantages
Long term stability in terms of aggregation and good insulin loading - Higher uptake of insulin across oral & nasal mucosa - Improved pharmacodynamic activity of insulin

Limitations
Widespread distribution in organs like liver, lung, spleen, kidney, brain, heart, stomach and joints

5. CHITOSAN
Cationic polysaccharide synthesized by partial deacetylation of chitin (polymer found in crustacean shells and insects)

Glucosamine and N-acetyl-glucosamine

Carrier system - Protect insulin in the stomach and small intestine Enhanced the intestinal absorption of insulin Mucoadhesive - prolong their residence in the small intestine,

infiltrate into the mucus layer and subsequently mediate

transiently opening the tight junctions between epithelial cells.

MICROSPHERE

Protease inhibitors by protecting the encapsulated insulin from enzymatic degradation within its matrix Permeation enhancers effectively crossing the

epithelial layer after oral administration

LIPOSOMES
Spherical, self-closed structures formed by one or several concentric lipid bilayers with an aqueous phase

inside and between the lipid bilayers.

Vehicle for delivery of insulin Lecithin 100mg, cholesterol 20mg, insulin 150units, Tween 1%. The effect of insulin lioposome was prolonged in diabetic induced rats than the normal rats.

Types of nanoparticles
Liposomes

Advantages

Limitations

- Biodegradable - Non-toxic - Non-immunogenic

- Captured by the human bodys defense system (RES) - Post-treatment accumulation in skin and eyes

DENDRIMER
1978 - Fritz
Hydrophobic, branched molecules, spherical polymers with coreshell nanoarchitecture. 1 to 10 nm.

Dendrimer encapulated nanoparticles.

Encapsulation of hydrophobic delivery of drugs. compounds and for the

POLYMERIC MICELLE
Lipid-core micelles - conjugates of soluble copolymers with lipids (polyethylene glycophosphatidyl ethanolamine conjugate). Colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs. Spherical in shape. High stability both in vitro and in vivo Good biocompatibility Enhanced permeability and retention

ARTIFICIAL PANCREAS
Tiny silicon box - pancreatic beta cells taken from animals.
Box is surrounded by a material with a very specific nanopore size (20 nm in diameter) Boxes can be implanted under the skin of diabetes patients A sensor electrode repeatedly measures the level of blood glucose; this information feeds into a small computer that

energizes an infusion pump and the needed units of insulin

enter the bloodstream from a small reservoir.

ANTISENSE OLIGONUCLEOTIDES
Short strands of deoxyribonucleotides that are

complementary to specific encoding mRNA sequences and can block gene expression Helps drugs to avoid the bodys defences that the drug encounters following its systemic administration.

CONCLUSION
Diabetes is a rapidly growing global problem, which requires management at the patient level, via blood glucose control to prevent worsening effects of the disease. Applications of nanomedicine in diabetes are in their infancy and none have reached routine clinical use.

To date, there have been no approved oral insulin nanoformulations. This is probably due to the difficult requirements that need to be met by the drug preparations.
In order to be successful, orally administered insulin nanocarriers must have efficient delivery system to increase insulin bioavailability to reach therapeutic levels

 These drug delivery technologies are in various stages of research and development. It is expected that these limitations can be overcome and the discoveries to come into practical use within the next 5-10 years. Scientific community hasnt yet understood completely how the human body would react to these nanoparticles and nanosystems, which are acting as drug carriers.

Nanomedicine is at a very early stage, but progress is rapid, translational, expansive and multi-purpose. In future nanomedicine is likely to be a key technology for solving diabetes problem.