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Trop J Pharm Res, June 2009; 8 (3):275

Tropical Journal of Pharmaceutical Research, June 2009; 8 (3): 275-287 Pharmacotherapy Group,

Faculty of Pharmacy, University of Benin,Benin City, 300001 Nigeria.

All rights reserved.

Available online at http://www.tjpr.org

Review Article

Nanotechnology and Drug DeliveryPart 2: Nanostructures for Drug Delivery

Nelson A Ochekpe1*, Patrick O Olorunfemi2and Ndidi CNgwuluka21Department of Pharmaceutical Chemistry and 2Department of Pharmaceutics and Pharmaceutical Technology,Faculty of Pharmaceutical Sciences, University of Jos, PMB 2084, Jos, Nigeria

Abstract

This is the second part of a review on nanotechnology in general and particularly as it pertains to drugdeliver. In the earlier paper (Part 1), nanotechnology in nature, its history as well as design and methodswere discussed. Its applications, benefits and risks were also outlined. In this paper (Part 2), variousnanostructures employed in drug delivery, their methods of fabrication and challenges of nano drugdelivery are reviewed. Nanotechnology is one approach to overcome challenges of conventional drugdelivery systems based on the development and fabrication of nanostructures. Some challengesassociated with the technology as it relates to drug effectiveness, toxicity, stability, pharmacokineticsand drug regulatory control are discussed in this review. Clearly, nanotechnology is a welcomedevelopment that is set to transform drug delivery and drug supply chain management, if optimallydeveloped.

Keywords:Nanotechnology, Nanobiotechnology, Drug delivery, Nanostructures, Nanomaterials,

Nanocarriers.

Received: 4 Nov 2008 Revised accepted: 13 Jan 2009

*Corresponding author: E-mail: [email protected]; Tel: +234-(0)8037006372


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INTRODUCTION

Nanotechnology by manipulation ofcharacteristics of materials such as polymersand fabrication of nanostructures is able toprovide superior drug delivery systems forbetter management and treatment ofdiseases. The nanostructures employed asdrug delivery systems have multipleadvantages which make them superior toconventional delivery systems. In Part I, theadvantages of nanostructures in drug deliverywere outlined.

These benefits account for the extensiveresearch that have been undertaken into thedevelopment of nanostructures such asliposomes, nanocapsules, nanoemulsions,solid lipid nanoparticles, dendrimers,polymeric nanoparticles, etc, for delivery ofdrugs. The materials employed in thefabrication of nanostructures determine thetype of nanostructures obtained and thesenanostructures, in turn, determine the

different properties obtained and the releasecharacteristics of incorporated drugs.

MATERIALS AND TYPES OFNANOSTRUCTURES

Polymeric nanoparticles

Polymeric nanoparticles are colloidal solidparticles with a size range of 10 to 1000nm

1

and they can be spherical, branched or shell

structures. The first fabrication ofnanoparticles was about 35 years ago ascarriers for vaccines and cancerchemotherapeutics

2. They are developed

from non-biodegradable and biodegradablepolymers. Their small sizes enable them topenetrate capillaries and to be taken up bycells, thereby increasing the accumulation ofdrugs at target sites. Drugs are incorporatedinto nanoparticles by dissolution, entrapment,adsorption, attachment or by encapsulation,

and the nanoparticles provide sustainedrelease of the drugs for longer periods, e.g.,days and weeks

3. Nanoparticles enhance

immunization by prevention of degradation of

the vaccine and increased uptake by immune

cells

4

. One of the determinants of the extentof uptake by immune cells is the type ofpolymer employed. In a study

4 comparing

poly-(-caprolactone) (PCL), poly (lactide-co-glycolide) (PLGA) and their blend, PCLnanoparticles were the most efficiently takenup by immune cells due to theirhydrophobicity. However, all polymericnanoparticles elicited vaccine (diphtheriatoxoid) specific serum IgG antibody responsesignificantly higher than free diphtheriatoxoid.

To target drugs to site of action, the drug canbe conjugated to a tissue or cell specificligand or coupled to macromolecules thatreach the target organs. To target ananticancer agent to the liver, polymericconjugate nanoparticles which comprisedbiotin and diamine-terminated poly (ethyleneglycol) with a galactose moiety fromlactobionic acid were prepared

5.

Some other applications of nanoparticlesinclude possible recognition of vascularendothelial dysfunction

6; oral delivery of

insulin7; brain drug targeting for

neurodegenerative disorders such asAlzheimers disease

8; topical administration

to enhance penetration and distribution inand across the skin barrier

9; and pH-sensitive

nanoparticles to improve oral bioavailability ofdrugs such as cyclosporine A

10. Some

polymers used in the fabrication of

nanoparticles include chitosan, alginate,albumin, gelatin, polyacrylates, polycaprol-actones, poly(D, L-lactide-co-glycolide) andpoly (D, L-lactide) However, there areconcerns about polymeric nanoparticlesincluding cytotoxicity of by-products (althoughsome, such as polyanhydrides, degrade intoproducts that are biocompatible) andscalability.

Liposomes

Liposomes were first developed about 40years ago

2. They are small artificial vesicles

(50 100nm) developed from phospholipids


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such as phosphatidylcholine, phosphatidyl-

glycerol, phosphatidylethanolamine andphosphatidylserine, which have been used inbiology, biochemistry, medicine, food andcosmetics

11-14. The characteristics of

liposomes are determined by the choice oflipid, their composition, method ofpreparation, size and surface charge

1.

Liposomes have been applied as drugcarriers due to their ability to preventdegradation of drugs, reduce side effects andtarget drugs to site of action

15. However,

limitations of liposomes include low

encapsulation efficiency, rapid leakage ofwater-soluble drug in the presence of bloodcomponents and poor storage stability

15,16.

However, surface modification may conferstability and structure integrity against harshbio-environment after oral or parenteraladministration

17. Surface modification can be

achieved by attaching polymers such as poly(methacrylic acid-co-stearyl methacrylate)and polyethylene glycol units to improve thecirculation time of liposomes in the blood; and

by conjugation to antibodies or ligands suchas lectins for target specific drug delivery andstability

16-18.

Applications of liposomes includetransdermal drug delivery to enhance skinpermeation of drugs with high molecularweight and poor water solubility

19; a carrier

for delivery of drugs, such as gentamicin, inorder to reduce toxicity

20; possible drug

delivery to the lungs by nebulisation21

; ocular

drug delivery

22

and in the treatment ofparasitic infections. However, solid lipidnanoparticles (SLNs) provide an effectivealternative due to their stability, ease ofscalability and commercialisability

23.

Other vesicular structures includetransferosomes, ethosomes, niosomes andmarinosomes which are used mainly fortransdermal delivery

11,24,25. Transferosomes

are developed by incorporation of surfactantmolecules (edge activators) such as sodium

chlorate into liposomes while ethosomes areliposomes that are high in ethanol (up to45%). Niosomes are vesicles developed from

non-ionic surfactants and marinosomes are

liposomes produced from a natural marinelipid extract containing a high poly(unsaturated) fatty acid (PUFA) ratio.

Dendrimers

Dendrimers are nanostructures producedfrom macromolecules such aspolyamidoamine (PAMAM), polypropylene-imine and polyaryl ether; and are highlybranched with an inner core. The particle sizerange is between 1 to 100nm although their

sizes are mostly less than 10nm. About 20years ago, dendrimer studies centred on theirsynthesis, physical and chemical propertieswhile exploration of their biologicalapplications was initiated about thirteen yearsago

26. The uniqueness of dendrimers is

based on their series of branches,multivalency, well defined molecular weightand globular structure with controlled surfacefunctionality, which enhances their potentialas carriers for drug delivery

26,27. Their

globular structures and the presence ofinternal cavities enable drugs to beencapsulated within the macromoleculeinterior. Dendrimers have been reported toprovide controlled release from the innercore

27. However, drugs are incorporated both

in the interior as well as attached on thesurface. Due to their versatility, bothhydrophilic and hydrophobic drugs can beincorporated into dendrimers.

Controlled multivalency of dendrimersenables attachment of several drugmolecules, targeting groups and solubilisinggroups onto the surfaces of the dendrimers ina well defined manner

26. Dendrimers are

employed due to their size (less than 10nm),ease of preparation, functionality and theirability to display multiple copies of surfacegroups for biological recognition process

28.

Water soluble dendrimers can bind andsolubilise small molecules and can be usedas coating agents to protect drugs and deliver

to specific sites. Other applications ofdendrimers include catalysis, gene and DNAdelivery, biomimetics and as solution phase


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supports for combinatorial chemistry29

. Some

of the drug delivery applications includetherapeutic and diagnostic utilization forcancer treatment

30; enhancement of drug

solubility and permeability (dendrimer-drugconjugates)

31; and intracellular delivery

32

Solid lipid nanocarriers

Solid lipid nanoparticles (SLN) arenanostructures made from solid lipids suchas glyceryl behenate (Compritol), stearictriglyceride (tristearin), cetyl palmitate and

glycerol tripalmitate (tripalmitin) with a sizerange of 50 and 1000 nm

33,34. Research

interest in SLN emerged about ten years agodue to their scalability potential. The lipidsemployed are well tolerated by the body;large scale production will be cost effectiveand simple by using high pressurehomogenization. Some of the features of SLNinclude good tolerability, site-specifictargeting, stability (stabilized by surfactants orpolymers), controlled drug release and

protection of liable drugs from degradation34

.However, SLN are known for insufficient drugloading, drug expulsion after polymorphictransition on storage and relative high watercontent of the dispersions

34. SLN has been

studied and developed for parenteral, dermal,ocular, oral, pulmonary and rectal routes ofadministration

34-39

To overcome the limitations of SLN,nanostructured lipid carriers (NLC) were

introduced. NLC is composed of solid lipidsand a certain amount of liquid lipids withimproved drug loading and increased stabilityon storage thereby reducing drugexpulsion

34,36. NLCs have been explored for

dermal delivery in cosmetics anddermatological preparations

34,36.

Lipid drug conjugate (LDC) nanoparticleswere introduced to overcome the limitation oftypes of drugs incorporated in the solid lipidmatrix. Lipophilic drugs are usually

incorporated in SLN but due to partitioningeffects during production, only highly potenthydrophilic drugs effective in low

concentrations are incorporated in SLN34

.

LDC enables the incorporation of bothhydrophilic (e.g., doxorubicin and tobramycin)and lipophilic (e.g., progesterone andcyclosporine A) drugs

34.

Polymeric micelles

Micelles are formed when amphiphilicsurfactant or polymeric moleculesspontaneously associate in aqueous mediumto form core-shell structures or vesicles.Polymeric micelles are formed from

amphiphilic block copolymers, such aspoly(ethylene oxide)-poly(-benzyl-L-aspartate) and poly(N-isopropylacrylamide)-polystyrene, and are more stable thansurfactant micelles in physiologicalsolutions

39. They were first proposed as drug

carriers about 24 years ago39

. The inner coreof a micelle is hydrophobic which issurrounded by a shell of hydrophilic polymerssuch as poly (ethylene glycol)

40. Their

hydrophobic core enables incorporation of

poorly water soluble and amphiphilic drugswhile their hydrophilic shell and size (

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