Brain Targeted Drug Delivery

APPROACH TO TARGET BRAIN DRUG DELIVERY SYSTEM

SCHOLAR: MANISH KUMAR

M.Pharm(Pharmaceutics)

GUIDED BY:Mr. SHASHANK SONI

Assistant Professor

SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH,BALAWALA, DEHRADUN, (UTTARAKHAND)

ORGANISATION INTRODUCTION

BARRIERS

DRUG TRANSPORT FACTORS AFFECTING

APPROACHES

FUTURE ASPECTS

MARKETED FORMULATION

INTRODUCTION1880

Paul Ehrlich

use vascular dyes

The existence of a blood brain barrier (BBB)

1960s

Drs. Reese, Karnovsky, and Brightman

using electron microscopy

localized tight junctions

Ramakrishnan, P. (2003). The role of P-glycoprotein in the blood-brain barrier. Einstein Quart. J. Biol. Med, 19,160-165.

BARRIERS TO CNS DRUG DELIVERY

• BBB and BCF control the entry of compounds into the brain and regulate brain homeostasis. restricts access to brain cells of blood–borne compounds and facilitates nutrients essential for normal metabolism to reach brain

cells.

• It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB.

BARRIERS

The blood brain barrier (BBB) The blood cerebrospinal fluid barrier (BCSFB)

Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44.

Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414

BLOOD BRAIN BARRIER

FUNCTIONS:

STABILIZER – stabilize CNS neurons

PROTECTION – from toxins, microbes (bacteria)

HOLDER – hold neurotransmitter within CNS

Prajapati, J., Patel H, & Agrawal, Y. K. (2012). Targeted drug delivery for central nervous system: a review. Int J Pharm Pharm Sci, 3,32-38.


ENDOTHELIAL CELLS

TIGHT JUNCTION

VERY LITTLE VESICULAR TRANSPORT

SPECIAL PROTEINSe.g. OCCLUDINS, CLOUDINS

P-GLYCOPROTEIN

OVERVIEW REPRESENTATION OF BBB

Schematic representation of BBB

Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.

BLOOD CEREBROSPINAL FLUID BARRIER (BCSFB)

.•Fenestrated Endothelial cells

.•Modified Ependymal cells (Choroidal cells)


ENDOTHELIAL CELLS

CHOROIDAL CELLS

TIGHT JUNCTIONS

BASAL MEMBRANE

Schematic representation of BCSF

Bhaskar, S., Tian, F., Stoeger, T., Kreyling, W., de la Fuente, J. M., Grazú, V., ... & Razansky, D. (2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging. Particle and fibre toxicology, 7(1),3.

DRUG TRANSPORT ACROSS THE BBB

BIG MOLECULES

HIGHLY CHARGED MOLECULES

TOXIC SUBSTANCES

SMALL MOLECULES

GLUCOSE

S.NO TRANSPORT MECHANISM

DESCRIPTION

1 PASSIVE TRANSPORT

1. Molecular weight (>600 Dalton is limiting factor)

Inversely related to passive transport

2. Lipophilicity is directly related to passive transport

log P values (- 0.2 to 1.3) is responsible for optimal cerebral transport

3. Protein binding : Protein-drug complex size is responsible for transport

(Free fraction of drug is transported.)

2 ADSORPTIVE MEDIATED TRANSCYTOSIS/ ENDOCYTOSIS

1. Adsorptive-mediated transcytosis

macromoleculs like cationic macromoleculs e.g. histone, avidineand cationized albumin

2.Brain targeting using adsorptive mediated endocytosis

cationized human serum albumin (cHSA) as a transport vector coupled to 3H-biotin is able to cross the BBB in significant amounts

2 ACTIVE TRANSPORT

requires energy

Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.

VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4),15-27.

Begley, D. J., Bradbury, M. W., & Kreuter, J. “Specific Mechanisms for Transporting Drugs Into Brain” The Blood–Brain Barrier and Drug Delivery to the CNS, Akira Tsuji (e.d.) , 2000 by Marcel Dekker,Inc., 8.

TRANSPORTERS

Receptor-mediated transport

Active efflux-mediated transport Transporter(Carrier) -mediated transport

Transferrin receptor (TfR) Adenosine triphosphate-binding cassette (ABC) transporter subfamily B, member 1 (P-glycoprotein)

Glucose transporter(Glut1)

Insulin receptor(IR) MRPs(1&5) Large neutral amino acid transporter (LAT1)

Nicotinic acetylcholine receptor

Organic anion transporting peptide Cationic amino acid transporter (CAT1)

Low-density lipoprotein receptor

Glutamic acid amino acid transporter

Monocarboxylic acid transporter (MCT1)

Insulin-like growth factor receptor(IGF-R)

Taurine transporter Choline transporter

Diphtheria toxin receptor Organic anion transporter(oatp2)

Nucleobase transporter

Leptin receptor(OB-R) BBB-specific anion transporter type 1 (BSAT1)

CNT2 adenosine transporter

Neonatal Fc receptor (FcRn)

Gao H. (2016). Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharmaceutica Sinica B, 6(4),268-286.

Amino Acid Transporters large neutral amino acid transporters, LA

transporters, cationic-, anionic- and neutral-amino acid transporters

E.g. L-Dopa is transported by LA transporters in the BBB

.

Glucose Transporterstype 1, glucose transporter, GLUT 1E.g. Glycosylated analogs of various

opioid compounds

Monocarboxylic Acid Transporter (MCT)

E.g. salicylic acid HMG-CoA reductase inhibitors

Nucleoside Transporter1. facilitative nucleoside transporters that carry selective nucleosides either into or

out of the cell 2. active and the sodium-dependent transporters that can move selective nueleosides into the cell against a

concentration gradientE.g. anticancer agent, the antiviral agents

Carrier-mediated (Active) Transport

Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92

Molecular Antibody (Mab) - Molecular Trojan Horse

Act as ligands for RMT e.g. CRM197 (Carrier Protein) uses HB-EGF(heparin binding epidermal growth factor) as its transport receptor (Diptheria Toxin Receptor)used for Multiple Sclerosis, Parkinsonism, Alzhemier, Poliovirus

Trojan Horse LiposomeAttachment of a MTH to tips of PEG strands of liposome triggers RMTEncapsulation of plasmid DNA inside pegylated liposome eliminates nuclease sensitivity

Low Density Lipoprotein Receptor (LRP1&2)Multiligand lipoprotein receptor interacting with proteinsapoE(apolipoprotein E)Alpha2 M(macroglobulin)APP(Amyloid precursor protein)PAI-1 & tPA

Transferin And Insulin Receptor BDNF-HIR Mab

EGF-TR mabFGFT-HIR Mab

Beta galactosidase –TR Mab Neurotrophin-HIR fusion

Receptor Mediated Transport

Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiology of disease, 37(1),48-57.

FACTORS AFFECTING DRUG TRANSPORT ACROSS

THE BBB

PARAMETERS CONSIDERED OPTIMUM FOR A COMPOUND TO TRANSPORT ACROSS THE BBB ARE:


Compound should be unionized.

Approximately log p value must be 2.

Its molecular weight must be less than 400 Da

Cumulative number of hydrogen bonds between 8 to 10

BBB BROKEN

TRAUMA INFLAMMATION INFECTION IRRADIATION NEUOPLASM HYPERTENSION HIGH ALTITUDE HYPOXIA ISCHEMIA

BBB BROKEN

WATER INFLOW

EDEMA

LIFE THREATENING


APPROACHES FOR BRAIN

TARGETED DRUG DELIVERY

CNS DRUG DELIVERY APPROACHES

INVASIVE TECHNIQUES

NON INVASIVE TECHNIQUES

MISCELLANEOUS TECHNIQUES

Woodworth, G. F., Dunn, G. P., Nance, E. A., Hanes, J., & Brem, H. (2014). Emerging insights into barriers to effective brain tumor therapeutics. Frontiers in oncology, 4,126.

INVASIVE APPROACH

INTRA CEREBRAL IMPLANTS

INTRA VENTRICULAR

INFUSION

BBB DISRUPTION

A

wide range of compound and formulation can be considered for ICV or

IC administration. both large and small molecules can be delivered

Drill the hole in the head

place the implant by intra-cerebral

(IC) method

give infusion by intra-cerebro-

ventricular (ICV) method

INTRA CEREBRAL IMPLANTS

delivery of drugs directly into the brain parenchymal space the drugs can be administered by:

Direct injection via intrathecal catheter Control release matrices & Microencapsulated chemicals.

The basic mechanism is diffusion. Useful in the treatment of different CNS diseases e.g. brain tumor, Parkinson’s

Disease etc. Example: Intrathecal injection of baclofen for spasticity Infusion of opioids for severe chronic pain Limitations :

1.Distribution in the brain by diffusion decreases exponentially with distance.

2.The injection site has to be very precisely mapped to get efficacy and overcome the problem associated with diffusion of drugs in the brain parenchyma.

INTRA CEREBRO VENTRICULAR INFUSION

pharmacological effect is seen if the target receptors of the drug are located near the ependymal surface of the brain.

Drug is infused using an ommaya reservoir, a plastic reservoir implanted subcutaneously in the scalp and connected to ventricles

Limitations: The diffusion of the drug in the brain parenchyma is very low . unless the target is close to the ventricles it is not an efficient method

of drug delivery. Example Glycopeptide and an aminoglycoside antibiotics used in

meningitis.

VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.

BBB DISRUPTION

Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol may disrupt BBB.

Osmotic disruption :

Example : Intracarotid administration of a hypertonic mannitol solution with subsequent administration of drugs can increase drug concentration in brain and tumour tissue to reach therapeutic concentration

MRI-guided focused ultrasound BBB disruption technique

example: distribution of Herceptin is increased in brain tissue by 50% in a mice model.

The osmotic shock

endothelial cells shrink

disrupting the tight junctions

Injection of microbubbles of ultrasound contrast agent ( eg. optison, dia. 2-6 μm ) and manganese into the blood stream

exposures to ultrasound

LIMITATIONS OF INVASIVE APPROACH

relatively costly require anaesthesia and hospitalization. It may enhance tumour dissemination after

successful disruption of the BBB. Neurons may be damaged permanently from

unwanted blood components entering the brain

NON INVASIVE APPROACH

CHEMICAL

PRODRUGS

DRUG CONJUGATES

BIOLOGICAL

MONOCLONAL / CATIONIC

ANTIBODIES CONJUGATES

RECEPTOR / VECTOR

MEDIATED

APROTONIN / CHIMERIC

PEPTIDES AS CARRIER

COLLOIDAL

NANOPARTICLES

LIPOSOMES

B

PRODRUGS

Prodrug is lipid soluble (pharmacologically inactive compounds)

cross the BBB

metabolized within the brain

converted to the parent drug

Esterification or amidation of hydroxy-, amino-, or carboxylic acid- containing drugs, may greatly enhance lipid solubility and, hence, entry into the brain

WHAT TO DO AND WHY Drug covalently linked to an inert chemical moiety. Improve physicochemical property such as solubility and membrane

permeability. Prodrug is cleaved by hydrolytic or enzymatic processes. Examples levodopa, gaba, niflumic acid, valproate. Heroin, a diacyl derivative of morphine, is a notorious example that

crosses the bbb about 100 times more easily than its parent drug just by being more lipophilic.

Limitations of the prodrug: Adverse pharmacokinetics. The increased molecular weight of the drug that follow from

lipidation.

VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.

CO-DRUG Drugs that inhibit a BBB AET could be used as a “co-drug” to

cause increased brain penetration of a therapeutic drug that isnormally excluded from brain by a BBB AET system.

Example:

Loperamide produced no respiratory depression when administered alone, but

respiratory depression occurred when loperamide (16 mg), a known inhibitor

of p-glycoprotein was given with quinidine at a dose of 600 mg (P < .001).

Increased brain penetration of the chemotherapeutic agent, paclitaxel (taxol®),

by co-administration of the pglycoprotein inhibitor, psc-833 (valspodar).

Aromatic amino acid decarboxylase (aaad) inhibitors are administered as

codrugs in conjunction with l-dopa to optimize brain penetration of the L-dopa.

Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development. Molecular interventions, 3(2),90.

DRUG CONJUGATESLipidization of molecules generally increases the volume of distibution.

Chemical approaches include lipophilic addition and modification of hydrophilic drugs ( e.g. Nmethylpyrimidium 2 carbaldoxime chloride)

Example:

Glycosylated analogs of various opioid compounds Antioxidant + pyrrolopyrimidines – increase accessFor Ganciclovir : to hydroxymethyl group + 1methyl 1,4 dihydronicotinate- increase transportFor small drugs: use of fatty acids like N docosahexaenoyl(DHA) increase uptake


Example of drug transfered via LAT1: Melphalan for brain cancer Alpha methyl dopa for high blood pressure Gabapentin for epilepsy Ldopa for parkinsonism

CARRIER MEDIATED TRANSPORT


RECEPTOR / VECTOR MEDIATED

Conjugation of drug to transport vector is facilitated with chemical linkers avidin–biotin technology, polyethylene glycol linkers,

vector such as the Monoclonal antibody (Mab) Portals of entry for large molecular drug attached to endogenous RMT ligands.

VECTORBRAIN

SPECIFICITYPHARMACOKINETI

CS

HIGH YIELD COUPLING CLEAVABILITY

RETENTION OF AFFINITY

AAFTER

INTRINSIC RECEPTOR

LINKER

DRUG

CHIMERIC PEPTIDES AS CARRIER

DRUG VECTOR MODIFIEDPRODUCT

Conjucated proteins may be endogenous peptides, monoclonal antibodies, modified protein, cationized albumin etc.

Chimeric peptides are transported to brain by various pathways like peptide specific receptor.

E.g. Insulin and transferrin by transcytosis

Conjugation of drug with antibodies e.g. OX-26, 8D3 Mab antibody to red transferrin receptor

Targeting


Begley David J., Bradbury Michael W. , Kreuter Jörg “Targeting Macromolecules to the Central Nervous System” The Blood–Brain Barrier and Drug Delivery to the CNS, Ulrich Bickel(e.d.) , 2000 by Marcel Dekker,Inc., 8.

COLLOIDAL The vesicular systems are highly ordered assemblies of one or several

concentric lipid bilayer formed, when certain amphiphillic building blocks are confronted with water

Coated with surfactants like polyoxyethylene/propylene, PEG AIM: control degradation of drug Prevent harmful side effects increase the availability of the drug at the disease site. slowly degrade, react to stimuli and be site-specific Advantages: Prolong the existence of the drug in systemic circulation Improves the bioavailability especially of poorly soluble drugs. Both hydrophilic and lipophilic drugs can be incorporated. Delays elimination of rapidly metabolizable drugs and thus function as

sustained release systems.

NANOPARTICLES

Size 1-1000 nm includes both nanocapsules, with a core-shell structure

(a reservoir system) and nanospheres (a matrix system). Materials used: polyacetates, acrylic copolymers, poly(lactide),

poly(alkylcyanoacrylates) (PACA), poly(D,L-lactide-co-glycolide) Polysorbate coated nanoparticles can mimic LDL to cross BBB. Polyoxyethylene sorbitan monooleate coated nanoparticles containing drug

easily cross BBB. Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate

nanospheres targeted and accumulated in a rat gliosarcoma. Mechanisms of transport

Adhesion

Fluidization of BBB endothelium by surfactants

Opening of tight junction

Transcytosis / Endocytosis

Blockage of glycoprotein

TARGETTING

These particles loaded with doxorubicin for the treatment of glioblastomas are presently in Clinical Phase I.

Human serum albumin nanoparticles conjucated with antibodies(OX26/R17217) against transferrin receptor e.g. For loperamide, 5-florouracil(5-FU)

Human serum albumin nanoparticles conjucated with antibodies(29B4) against insulin receptor e.g. for targeting loperamide

Cell penetrating peptide(trans activating transduction protein ) modified liposome i.e. Tat-LIP having positive charge transported via adsorptive mechanism. e,.g. for caumarin

The coating of polyalkylcyanoacrylate or poly-lactic-co-glycolic acid (PLGA) nanoparticles with polysorbate 80 or poloxamer 188.

Due to this coating the particles adsorb apolipoproteins E or A-1 from the blood

Interact with the LRP1 or with the scavenger receptor followed by transcytosis across the blood-brain barrier into the brain.

Advantages of using nanoparticles for CNS targeted drug delivery protect drugs against chemical and enzymatic degradation. small size --- penetrate into even small capillaries ---taken up within cells ----drug

accumulate at the targeted sites The use of biodegradable materials ---allows sustained drug release at the targeted

site after injection Limitations of using nanoparticles for CNS targeted drug delivery small size and large surface area ----particle-particle aggregation-- physical

handling of nanoparticles difficult in liquid and dry forms. small particles size and large surface area readily result in limited drug loading and

burst release.

Avhad, P. S., Patil, P. B., Jain, N. P., & Laware, S. G. (2015). A Review on Different Techniques for Brain Targeting. International Journal of Pharmaceutical Chemistry and Analysis, 2(3),143-147.


LIPOSOMES

lipid based vesicles are microscopic (unilamellar or multilamellar) vesicles Lipid soluble or lipophilic drugs get entrapped within the bilayered

membrane whereas water soluble or hydrophilic drugs get entrapped in the central aqueous core of the vesicles

Advantages suitable for delivery of hydrophobic, amphipathic and hydrophilic drugs and

agents. could encapsulate macromolecules like superoxide dismutase,

haemoglobin, erythropoietin, interleukin-2 and interferon-g. reduced toxicity and increased stability of entrapped drug via encapsulation

(eg.Amphotericin B, Taxol). Limitation : High production cost , Short half-life , Low solubility , Less stability Leakage and fusion of encapsulated drug / molecules Sometimes phospholipid undergoes oxidation and hydrolysis

Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular Basis of Targeted Drug Delivery, 1,508.

A non viral supercoiled plasmid DNA is encapsulated in an interior of an 85nm liposome

Liposome surface is conjucated with 1000-2000 strands of 2000 dalton peg to form pegylated liposome

Tips of 1-2 % peg strands are conjucated with a peptidomimetic Mab(HIR/TR) to form pegylated immunoliposomeS

Transfer via RMT

TARGETING

Mechanism: receptor/adsorptive mediated transport

liposome coated with mannose reaches brain tissue where mannose coat assists transport

Addition of sulphatide (a sulphate ester of galactocerebroside) to liposome increases availability


Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J PharmaSciTech, 3,1-8.

MONOCYTES

Used as a Torjan Horse Ideal endogenous carriers Express certain receptors involved in receptor mediated endocytosis upon interaction

with suitable ligands

CARRIER MONOCYTE BBB DRUG

Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular Basis of Targeted Drug Delivery, 1,508.

MISCELLANEOUS TECHNIQUE

INTRANASAL DELIVAERY

IONTOPHORETIC DELIVERY

C

INTRANASAL DELIVERY Drug delivered intranasally are transported along olfactory sensory neurons to

yield significant concentrations in the CSF and olfactory bulb and then enter into other regions of brain by diffusion(facilitated by perivascular pump)

DIFFICULTIES : enzymatic activity, low pH nasal epithelium, mucosal irritation or large variability caused by nasal pathology (common cold)

THE OLFACTORY PATHWAYS: the olfactory nerve pathway (axonal transport) and the olfactory epithelial pathway.

AXONAL TRANSPORT (slow route) :

THE EPITHELIAL PATHWAY (faster route) :direct nose-to-brain transfer

Agent enters the olfactory neuron via endocytotic or pinocytotic mechanisms

travels to the olfactory bulb

compounds pass paracellularly across the olfactory epithelium into the perineural space

continues to the subarachnoid space & in direct contact with the CSF.


IONTOPHORETIC DELIVERY

Iontophoresis is the introduction of ionised molecules into tissues

by means of an electric current

biologically active agent is transported by means of iontophoresis

and/or phonophoresis directly to the CNS using the olfactory

pathway to the brain and thereby circumventing the BBB and is

known as transnasal iontophoretic delivery



FUTURE ASPECTS

Identify new BBB transporters Develop brain drug targeting systems enabling the brain delivery of

recombinant protein neuro-therapeutics. Validate new drug targeting systems using in vivo models. Optimize pharmacokinetics of in vivo brain drug targeting systems. Improve/enhance release of nanoparticles from implantable

devices/nanochips Multifunctional nanoparticles Universal formulation schemes that can be used as I/V, I/M & oral.


S.NO BRAND NAME ACTIVE PHARMACEUTICAL INGREDIENT

ROLE

1 AMBISOME AMPHOTERICIN B LIPOSOME

2 CASELYX PEGYLATED LIPOSOME OF DOXORUBICIN HYDROCHLORIDE

BRAIN TUMOUR

3 ARICEPT DONEPEZPIL ALZHEIMER’S DISEASE

4 AUROSHELL GOLD COATED SILICA NANOPARTICLES IV

SOLID TUMOURS

5 AURIMMUNE COLLOIDAL GOLD IV NANOPARTICLES

SOLID TUMOURS

MARKETED FORMULATIONS

S.NO.

DRUG TRADE NAMES COMPANY NAME

1 LOMUSTINE LUSTIN SAMARTH PHARMA PVT LTD

VHB-NU V.H. BHAGAT PHARMACEUTICALS PVT LTD

LOMUWIN CHANDRA BHAGAT PHARMA PVT LTD

LOMUSTINE VHB LIFE SCIENCE INC

LOMUSTINE(GSK) GSK

2 ETOPOSIDE ESIDE INJ VHB LIFE SCIENCE INC

ETOSID CIPLA LIMITED

ACTITOP KHANDELWAL LAB LTD

ETOLON CELON LABS

POSID CADILA PHARMACEUTICAL LTD

3 CYCLOPHOSPHAMIDE ONCOPHOS CADILA PHARMACEUTICALS

CYPHOS INTAS PHARMACEUTICALS

ONCOMIDE KHANDELWAL LAB

CYCLOXAN BIOCHEM PHARMACEUTICAL

CYDOXAN ALKEM LAB

Brain tumor drugs, www.medindia.net , 17/2/2017

YEAR RECENT WORK

2017 Gao, W., Liu, Y., Jing, G., Li, K., Zhao, Y., Sha, B.,& Wu, D. (2017). Rapid and efficient crossing blood-brain barrier: Hydrophobic drug delivery system based on propionylated amylose helix nanoclusters. Biomaterials, 113, 133-144.

2016 Cardoso AM, Guedes JR, Cardoso AL, Morais C, Cunha P, Viegas AT, Costa R, Jurado A, Pedroso de Lima MC.“Recent Trends in Nanotechnology Toward CNS Diseases: Lipid-Based Nanoparticles and Exosomes for Targeted Therapeutic Delivery” Int Rev Neurobiol. ;130:1-40. Baghirov, H. (2016). Nanoparticle uptake by brain endothelial cells and focused ultrasound-mediated transport across the blood-brain barrier.

2015 Jain A, Jain SK.Crit (2015) ”Ligand-Appended BBB-Targeted Nanocarriers (LABTNs)” The Drug Carrier Syst. 32(2):149-80Timbie KF, Mead BP, Price RJ.(2015)“Drug and gene delivery across the blood-brain barrier with focused ultrasounda” Control Release.10;219:61-75.

2014 Aryal, M., Arvanitis, C. D., Alexander, P. M., & McDannold, N. (2014). Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system. Advanced drug delivery reviews, 72, 94-109.

2013 Zou LL, Ma JL, Wang T, Yang TB, Liu CB.(2013) “Cell-penetrating Peptide-mediated therapeutic molecule delivery into the central nervous system.”11(2):197-208Dufès C, Al Robaian M, Somani S.“Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells” Their Delivery ;4(5):629-40.

RECENT WORK

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REFERENCES


Avhad, P. S., Patil, P. B., Jain, N. P., & Laware, S. G. (2015). A Review on Different Techniques for Brain Targeting. International Journal of Pharmaceutical Chemistry and Analysis, 2(3),143-147.

Cornford, E., Kabanov, A., Del Zoppo, G., Muldoon, L., Rooney, W., & Shusta, E. (2014). Delivery and the brain barriers.


Pardridge, W. M. (1991). Peptide Drug Delivery to the Brain Raven Press. New York, pp. l-357. Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular

Basis of Targeted Drug Delivery, 1,508. Prajapati, J., Patel H, & Agrawal, Y. K. (2012). Targeted drug delivery for central nervous system: a

review. Int J Pharm Pharm Sci, 3,32-38. Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat

brain diseases. Neurobiology of disease, 37(1),48-57.

Ramakrishnan, P. (2003). The role of P-glycoprotein in the blood-brain barrier. Einstein Quart. J. Biol. Med, 19,160-165.

Pardridge, W. M. (2002). Drug and gene targeting to the brain with molecular Trojan horses. Nature Reviews Drug Discovery, 1(2),131-139.

Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J PharmaSciTech, 3,1-8.

THANK YOU

Health & Medicine

Brain Targeted Drug Delivery