1. NANOTECHNOLOGY IN DERMATOLOGY Sneha. M 26/01/2016

2. INTRODUCTION Nanoscience-study of particles on an atomic or molecular scale, whose size is measured in nanometres. Nanotechnology- a collection of methods & techniques for processing material at an atomic & molecular scale to create products with special physiochemical properties in relation to conventional products. Nanobiotechnology.

3. 1950, physicist, Richard Feynman – father of nanotechnology, nobel prize. Skin - first point of contact – topical applications, articles of clothing, domestic utensils, sports items, & industrial products. Gene therapy, medication therapy.

4. Promising areas in nanodermatolgy research-- Area of developmentPotential areas of application Consumer productsSunscreen, antimicrobials, dressings, slow liberation of volatile compounds (perfumes & insect repellants) Diagnostic equipmentReal time visualization of tumours & sentinel lymphnodes, real time diagnosis of infections & malignant disease, minimally invasive biopsies Therapeutic agentsAntimicrobials, skin fillers, cutaneous paralysing agents, corticosteroids located in the epidermis, gene silencers, cutaneous vaccines, induced skin treatments (optical, magnetic, thermal,& radiofrequency)

5. Nanoparticles- Small substances– behave & react as a total unit, 1nm – 100nm. Classification –  Organic & inorganic substances.  Shape, size, surface, physiochemical properties.  Particles interact with biological surfaces – malleable & rigid ones.

6. Malleable nanoparticles – organic lipids (lipids, proteins, polymers), size changed by stress or contact with surface.  Liposomes - hydrophilic & lipophilic, high penetration into hair follicle.  Matrixes – lipids, cholesterol, saponifiers, antigens used in vaccines.  Virosomes – viral hybrid liposomes & proteins applied in vaccines (HBV & HPV).

7. Polymerised particles – cytotoxicity & non-biodegradable accumulation. Fullerences – supermolecular structures – absorb UV radiation & eliminate free radicals. Dendrimers are used to transport medications. Increase skin penetration. Solid Lipid Nanoparticles (SLN) & Nanostructured Lipid Carriers – loose liposome micelle structure - stable in both lipophilic & hydrophilic environment, safe – carriers & liberators.

8. Rigid nanoparticles – made of inorganic material. Colloidal structures made of – encapsulating medication in their interior, transferring, & liberating molecules at the desired site of action (else degraded on their way)  Metal (gold or silver)  Metal oxide (iron)  Ceramic material (silica)

9. ACTION MECHANISMS- 1.Transfollicle permeation- hair follicle & ducts 2.Transcellular permeation – solutes pass directly through the horny cells & the intercellular lipid matrix. 3.Intercellular permeation – solutes tortuously diffuse around horny cells, constantly remaining in the lipid matrix. Maximum size of 400Daltons – permeation through intact skin. Small, non-electrolytic water soluble molecules diffuse to systemic circulation 1000 times faster when horny layer is absent – follicle route – important.

10. Skin- mechanical nano-porous barrier, penetrated by large number of nearly semi-circular channels or pathways – 0.4-36nm. Active substance liberation systems for topical administration- specific site & liberation rate. Liposomes & niosomes Cyclodextrines Microparticles (microcapsules & microspheres) Nanoparticles (nanocapsules & nanospheres) – no technology limitation, high physiochemical stability, & -- incorporated in different formulations.

11. Aims- 1.Facilitate labile substance transport, increasing compound efficacy, & improving final product appearance. 2.Maximize the length of time compounds remain in the skin, minimising transdermal absorption. 3.Liberate products in specific areas.

12. SizePenetration > 10µmNo penetration via follicle orifices or horny layer 9 -10µmConcentrate around follicle without penetrating 7µmDeeper regions of hair follicle but rarely penetrate the horny layer 5µmHigh concentration in the hair duct, does not penetrate the horny layer. < 3µmReach interior of hair follicle.

13. Polymeric micro & nanoparticles- Sustained release properties & their capacity to reach specific site for drug action. Diameter < 1µm- nanoparticles. Diameter 1µm or more – microparticles. Two different types of structures –  Micro/nanocapsules.  Micro/nanospheres.

14. Spheres – systems – active substance is distributed homogenously within the polymeric matrix --- gelatine, alginate, albumin, acrylates, lactic acid, glycolic acid. Solid matrix systems-- one polymerised material forms a 3D net. Active substance is – absorbed, incorporated, or covalently bond on the particle surface. Generate dissolving, dispersion, or porous systems.

15. Ex – Microsponge Delivery System (MDS) – porous liberator microspheres. Emollients, fragrances, essential oils, sun filters, antibacterials, antifungals, & anti-inflammatories. Rigid or soft form – depending on– polymeric composition, level of crosslinking, & parameters required to achieve active liberation rate through pores.

16. Capsules – reservoir systems –  differentiated nucleus,  with a cover material surrounding the central region – organic polymers, fats, proteins, polysaccharides,  containing in a solid or liquid active substance. 200 methods- processes & materials—produce microparticle systems. Content liberation– mechanism rupture of the wall, bioerosion, or active substance diffusion.

17. Advantages of nanoparticles— Greater bioavailability. Prolonged gradual release of the active drug component, with transport of smaller drug quantities. Improved tolerance. Maximised action. Final objective--- to carry the active ingredient to the deepest layer of the epidermis.

18. Applications in dermatology- CONSUMER PRODUCTS: PHOTOPROTECTORS Titanium oxide & zinc oxide promote less skin whitening. Generate more effective products in relation to the capacity to disperse, absorb, and reflect UV radiation. Aesthetically elegant. Free radicals & ROS –potential to damage cellular DNA – generate mutations– irreversible cell damage.

19. INNOVATIONS IN COSMETICS- Advantages of Solid Lipid Nanoparticles (SLNs) & Nanostructured Lipid Carriers(NLCs) – higher stability, create a lipid film on skin –avoid water evaporation– increase skin hydration. More contact with horny layer—active ingredient reaches the action site. Cutaneous penetration –optimized– low surface tension.

20. Microcapsules-insoluble nanoparticles used in cosmetics. Resolve – incompatibility -- protect substances susceptible to oxidation or affected by atmospheric humidity. Chitin nanofibrils—natural polysaccharide – crustacean shell—carbonate & protein removal. Metabolised by endogenous body enzymes, bio- & eco degradable.

21. Nanofibrils –  Activate keratinocyte & fibroblast proliferation.  Regulate collagen synthesis.  Cytokine & macrophage secretion.  Improve photoaged skin.  Promote wound healing- reduce hypertrophic scars.

22. TREATMENT OF INFLAMMATORY DISORDERS Barrier function of skin against irritants is altered—atopic dermatitis– emulsions with active ingredients –used to transform or imprison allergens. Nanoparticles are used to evenly distribute substances. Ex- antioxidant carriers.

23. Nanoparticles barrier creams are more effective than lipid content moisturizers-  Protect skin against water loss.  Minimize the threat of contact dermatitis on hands.  Better occlusive results.  Better action against antioxidants.

24. Corticosteroids - liposomal formulations minimize cutaneous atrophy– which otherwise limits its chronic use. Podophylotoxin encapsulated in SLN – genital warts. Liposomal T- cell inhibitor, cyclosporine, tacrolimus, methotrexate, psoralens, clotrimazole.

25. ANTISEPSIS & ASEPSIS Chlorhexidine gluconate -- immediate antibacterial effect - due to fast absorption from the capsule wall - prolonged effect due to sustained liberation from the particle nucleus. 60% isopranolol—alternative to alcohol based hands products—exhibit some skin damage after skin exposure.

26. PHOTOTHERAPY Short Pulse Lasers - target melanosomes. Principle of specific directioning for cells which do not have endogenous pigments - immune conjugates of iron oxide microparticles & gold nanoparticles– light absorbers. Absorb light & liberate absorbed energy in the form of heat - high temperatures attained microscopic cell rupture & damage.

27. Photothermal therapy - agitated gold nanoparticle inhibit tumour growth in rat SCC. Less damage to surrounding tissue, remedial treatment viable. Conjugating nanoparticles with monoclonal antibodies or other ligands such as hormones– active segmantation of malignant cell population.

28. Ex - anti-EGFR antibodies. Low weight gold nanospheres conjugated with MSH - murine melanoma. Principle of optical activation of a photosensitive agent & subsequent conversion of local tissue oxygen into various radicals harmful to the tissue.

29. TREATMENT OF SEBACEOUS GLAND DISEASES Sebaceous gland key component of pilosebaceous unit. Sebaceous gland opens into hair follicle canal- strategy for treating follicle associated disease. Schaefer et al. – adapelene particles carried by polymerised particles– intrafollicular drug delivery – acne & pilosebaceous disorders.

30. After particle penetration of follicles, encapsulated fluorescent stains released from polymerised particles -- selective stains sebaceous glands. Various physiochemical properties of liposomes, polymerised nanoparticles, Solid Lipid Nanoparticles -- increased follicle penetration, reaching much higher drug concentrations, & optimising the therapeutic effect.

31. Advantage improved tolerability to irritation caused by retinoids -- improves compliance. Encapsulation design technique -- improve therapeutic index of retinoid formulations. Benzoyl peroxide microsphere 5.5 %. Benzoyl peroxide wash 7%. High skin tolerance levels, aesthetic attributes, patient satisfaction.

32. TREATMENT OF SCALP DISORDERS- Liposomal delivery. Encapsulation of minoxidil in 40-130nm polyethylene glycol nanoparticles. Finasteride. Alopecia areata – cyclosporine.

33. NANOBIOTECHNOLOGY IN COMBATING CANCER- Chemotherapy—resistant to drugs, tissue barriers, need for high doses, toxicity, & side- effects. Rituximab- anti-CD20- B cell lymphoma. Liposomes – chemotherapies, DNA, radioactive particles.

34. NANODIAGNOSIS—EARLY DIAGNOSIS Gold, silver, gadolinium, iron oxide. Visualization of tumours & topographical location. Two methods-  Optical fabric.  Quantum dots.

35. Optic fabric- Clothing made of fibre optic fabric– Nevus mapping Tracking psoriasis Atopic dermatitis Mycosis fungoides.

36. Quantum dots- High fluroscent– emission turned to infrared to UV light– fluorescence. Topical application on lesion (tumour)– sentinel lymph node mapping.

37. Risks of nanotechnology Risk to cell & tissue damage. Oncogenic potential. Life cycle of nanoparticles. Different exposure routes. Behaviour of residual particles. Nanotechnology toxicity screening-immediate & long term– initial triage.

38. CONCLUSION Advantages. Risks. Advances & experimental stage.

39. REFERENCES Antonio JR, Antonio RC, Cardeal ILS, Ballavenuto JMA, Oliveria JR. Nanotechnology in Dermatology. An Bras Dermatol 2014;89:126- 136. DeLousise LA. Applications of Nanotechnology in Dermatology. Journal of Investigative Dermatology 2012;132:964-975.

40. Arif T, Nisa N, Amin SS, Shoib S, Mushtaq, Shawl MR. Therapeutic and diagnostic applications of nanotechnology in dermatology and cosmetics. J Nanomedicine Biotherapeutic Discov 2015;134:1- 10. Saraceno R, Chiricozzi A, Gabellini M, Chimenti S. emerging applications of naomdicine in dermatology. Skin Res Technol 2013;19:13-19. Kristi J, Teskac K, Grabnar PA. Current view on naosized lipid carriers for drug delivery to the skin. J Biomed Nanotechnol 2010;6:529-542.