Mannosylation For Active Targeting & Its Applications in Drug Delivery

Javia Deep P.M.S. (Pharm.) PharmaceuticsSemester IIID- 247/13NIPER - RAEBARELI

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Outline

IntroductionActive TargetingMannose Receptors & Their Active

TargetingStrategies for Mannosylation of

MultiparticulatesApplications of Mannosylated

MultiparticulatesConclusionReferences

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Introduction

Mannosylation- a technique for Surface Modification of multiparticulates by conjugating them with a monosaccharide Mannose.

Mannosylated multiparticulates- promising carriers of various drugs to be actively targeted to the desired site in body.

In some diseases like cancer (tumor), leishmaniasis, tuberculosis and other lung infections, AIDS mannose receptors present on various body cells are overexpressed.

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Contd…

Due to this, permeability of drugs across the cell membrane is generally reduced.

Hence mannosylated multiparticulates can successively deliver the drugs to these cells. This is achieved by active targeting of drugs followed by intracellular uptake through Mannose receptors.

Therefore mannosylation of multiparticulates is one of the promising drug delivery strategy.

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Active Targeting

Also called Ligand Mediated Targeting.

Two important aspects to evaluate the efficiency of an active targeting system-1. Targeting specificity2. Delivering capacity

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Contd…

• Proteins and peptides• Sugars• Antibodies• Nucleic acids• Small molecules like

vitamins

Representative ligands

• Proteins• Sugars• Lipids

Target molecules present in diseased

organ or on to surface of cells

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Contd…

Receptors which can be

targeted actively

Transferrin

Receptor

Folate receptor

EGF Receptor

Mannose Receptor

VEGF Receptor

Endothelial cell

receptor

Vascular cell

adhesion molecule-

1

Glycoproteins

expressed on cell surface

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Mannose Receptors & Their Active Targeting

Mannose receptor is transmembrane glycoprotein belonging to C-type lectin family. Structure of

Mannose ReceptorN- Terminal

cysteine rich domain

Fibronectin-II Domain8

Carbohydrate

Recognition Domains (CRDs)

Figure-1: Structure of Mannose Receptor5/15/2014NIPER-RBL

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Strategies for Mannosylation of Multiparticulates

Mannosylation of colloidal multiparticulates can be performed by various techniques.

(A) First mannose is conjugated with the polymer and then coating of drug nanoparticles with mannose conjugated polymer is done.

(B) In another method, polymeric drug nanoparticles are prepared & then surface conjugation with Mannose is done.

Sometimes linker molecule is used to conjugate mannose to the surface of nanoparticles.

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Contd…

Figure-2: Fabrication of polyanhydride nanoparticles by the reaction of mannose derivative with copolymer before the nanoparticles formation (A) or direct coating of just formed nanoparticles (B).5/15/2014NIPER-RBL

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Contd…

Figure-3: Schematic representation of method of mannosylation of SLNs.

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Applications of Mannosylated Multiparticulates

Applications in Tumor TargetingAgrawal G. et al. prepared mannosylated

solid lipid nanoparticles of Doxorubicin hydrochloride as vectors for site-specific delivery.

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Potential Advantages

Improved BA

Increased half life

Increased MRT of Doxorubicin

Delivery of higher amount of DOX to tumor mass

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Contd…Applications in Treatment of

LeishmaniasisBanerjee et al. formulated liposomes

containing anti-leishmanial drug pentamidine isothionate or its methoxy derivative coupled with various sugars like mannose, glucose or galactose.

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Potential AdvantagesIncreased activity of drug as compared to unmodified

liposomes

Reduced toxicity of drug

Mannosylated liposomes- more effective than those modified with other sugars

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Contd…Applications in Macrophage TargetingTripathi Y. et al. formulated mannosylated

gelatin microspheres to achieve targeted delivery of isoniazid (INH) to alveolar macrophages.

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Potential AdvantagesIncreased selective uptake of drug

Association with phago-lysosomal vesicles of AMs

Maintenance of therap. conc. of INH for prolonged time

Reduced clinical doseStability of Mannosylated

microspheres in broncheo-alveolar lavage fluid

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Contd…Wijagkanalan W. et al. formulated

mannosylated liposomes containing dexamethasone palmitate.

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Potential AdvantagesInhibition of TNF-α, IL-1β

Suppression of neutrophil infiltration & myeloperoxidase

activity Inhibition of protein kinase

activation in the lung.

Improved efficacy of drug against lung inflammation

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Contd…Applications in Treatment of AIDSGajbhiye V. et al. formulated anti-HIV

zidovudine loaded sialic acid conjugated mannosylated PPI dendrimers.

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Potential Advantagessignificant increase in cellular uptake of zidovudine by

macrophage cells Increased drug concentration in lymph nodes to about 28

times in case of SMPPIReduced cytotoxicity &

hemolytic activity of drugHigher potential of SMPPI to target drug to HIV reservoir

sites

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Contd…Applications in VaccinationJain N. K. et al. formulated mannosylated

solid lipid nanoparticles as carriers for delivery of Hepatitis B surface antigen for vaccination.

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Potential Advantagesbetter cellular uptake of HBSA

Reduced cytotoxicity of HBSA

Lesser induction of TH1 type of immune responsebetter immunological potential by producing

sustained antibody titer

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ConclusionSurface modification of colloidal

multiparticulates by mannosylation has shown enhanced efficiency for active targeting of various drugs to specific cells or tumors.

Mannosylation improves the biocompatibility, selectivity and specificity of drugs to the desired target site.

Also mannosylated nanoparticles found to increase the therapeutic activity of drugs as well as cellular uptake of drugs by macrophages representing mannose receptor.

Thus mannosylation of nanoparticulates has proved enhanced BA and therapeutic efficiency of many drugs for various diseases.

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References Jubeli E., Moine L., Nicolas V., Barratt G.; Preparation of E-

selectin-targeting nanoparticles and preliminary in vitro evaluation; Int J Pharm 426 (2012) 291-301.

Bertrand N., Wu J., Xu X., Kamaly N., Farokhzad O.; Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology; ADDR, 65 (2013), 1222-1234.

Salem A. et al.; Synthesis and characterization of mannosylated pegylated polyethylenimine as a carrier for siRNA, Int J Pharm, 427 (2012), 123-133.

Agrawal G. et al.; Mannosylated solid lipid nanoparticles as vectors for site-specific delivery of an anti-cancer drug, J Cont Rel, 148 (2010), 359-367.

Banerjee K. et al.; Preparation and Evaluation of Mannose Receptor mediated Macrophage targeting Delivery System; Int J Pharm, 454 (2013), 539-552.

Wijagkanalan W. et al.; Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes; Molecular Pharmacology, 74 (2008), 1183-1192.5/15/2014NIPER-RBL

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