Recent prospective of surface engineered Nanoparticles in the management of Neurodegenerative disorders

Figures & data

Figure 1. Different pathways leading to oxidative stress in PD.

Table I. Advantages of surface-modified nanoparticles over unmodi-fied nanoparticles (Huang et al. 2013, Gaoet al. 2006).

Surface-modified nanoparticles	Unmodified nanoparticles
Modified nanoparticles exhibit higher cellular uptake and gene expression in brain cells	Low uptake, which results to low gene expression
By surface-functionalization of nanoparticles to improve the absorption by increasing the retention (with adsorption on capillary walls leading to high concentration gradient) time at tight endothelial junctions on nasal administration	Absorption of unmodified nanoparticles were found to be 2.5-fold less than surface-functionalized nanoparticles
Surface-functionalized nanoparticles are able to deliver the drug site-specifically at the concentration required, are able to open the tight junctions and minimize the side-effects associated with the drug	Unmodified nanoparticles lack site-specificity
Surface-modified nanoparticles offer significant improvement over traditional nanoparticles in terms of efficiency and effectiveness	Are of less importance because of lack of control of over release, uncontrolled bio-distribution
These nanoparticles are able to bypass the RES uptake	Traditional carriers as such are taken up easily by the RES

Table II. Various pharmaceutical approaches to overcome the BBB.

Approach	Description	References
Colloidal carrier	Colloidal carriers offer an attractive and promising approach that could deliver drugs site-specifically, enhance the bioavailability, mask the physicochemical properties of the drug, and protect from enzymatic and gastric degradation. Examples include the nanoparticles, liposomes, and emulsions	Karanth and Murthy (2008)
Lipidization	It is a method of converting small hydrophilic molecules into lipid form in order to gain allowance by the BBB	Pardridge (2007), Rautioa and Chikhale (2004)
Modification of carrier	Surface modification is mainly carried out to eliminate the problem associated with conventional carriers and to enable advanced therapy. In this method, the surface of the carrier is modified either by adsorption or conjugation with polymer, amino acids, antibodies, ligand, monoclonal antibodies, PEG, or copolymer	Patel et al. (2009), Immordino et al. (2006), Cosco et al. (2009), Paolino et al. (2010), Licciardi et al. (2010)
BBB disruption	This method involves the reversible breaking down of tight endothelial junctions, which allows the passage of drug across the barrier (for example, mannitol or arabinose alkyl glycerol, or a bradykinin analog), and surgical implantation of polymeric carrier to improve drug concentration in the brain. Hynynen and coworkers reported that low frequency ultrasound bursts can reversibly disrupt the BBB. However, just after disruption, other xenobiotics may also inter into the CNS along with the drug (Hynynen et al. 2006)	Blanchette and Fortin (2011), Neuwelt et al. (2008), Borlongan and Emerich (2003), Erdlenbruch et al. (2003)
Modulation of efflux transporter	The Pgp transport function can be modulated by down- regulating the Pgp expression at the transcriptional and translational level or chemical inhibition of the transporter function, for example, laniquidar, zosuquidar, tariquidar, quinidine, quinine, cyclosporin, verapamil	Czeisler and Janigro (2006), Su and Sinko (2006)
Use of block polymer	The Pluronics block polymers are used for nanoparticle preparation. They are inert, possess intermediate hydrophilic and lipophilic properties, which enables them to bypass the RES uptake and enhances the drug transport across the BBB by acting on various transporters	Batrakova et al. (2001), Begley (2004)
Endogenous transporter	The conjugation of transporter to the carrier system that creates a mimic of the endogenous nutrient are easily able to cross the BBB, for example mannose liposomes, thiamine-coated nanoparticles	Juillerat-Jeanneret (2008), Vauthier et al. (2003)
Polymer coating	On coating, different types of functions can be Achieved, for example, PEG coating to bypass the RES uptake, poloxamer coating to stabilize the nanoparticles, and coating of polysorbate 80 to enhance the permeability	Gref et al. (1994)
Intra nasal delivery	Recently, it was shown through various studies that the drug is directly transported from the olfactory portion to the CNS. It offers rapid absorption and bypasses first-pass metabolism in the liver	Chou and Donovan (1998), van Laar et al. (1999)
Direct drug delivery	The delivery of drug directly to the intraventricular and intracerebral routes or reservoirs and catheter implantation. In case of injection, the response may be for a shorter duration of time because of total renewal of fluid within 5–6 hours	Chauhan (2002)
Prodrug approach	This technique is targeted to enhance the permeability and lipid solubility by esterification or amidation of amino, carboxylic acid, hydroxyl group-containing molecules. Increment in lipophilicity may enhance the diffusion across the BBB	Temsamani et al. (2000)

Figure 2. Different mechanisms of nanoparticle transport across the BBB (A) Receptor-mediated transcytosis (B) Adsorption-mediated transcytosis (C) Transcellular pathway (D) Paracellular transport (E) Passive diffusion.

Figure 3. Surface-modified nanoparticles (A) Antibody-coated (B) Ligand-appended (C) Cyclodextrin-modified (D) PEGylated nanoparticle.

Figure 4. Different surface modification techniques.

Table III. Various studies on surface-modified nanoparticles and their potential to overcome.

Polymer	Modification	Drug	Used animal	Objective of modification	Comment	References
PEG-substitute d lysine	Plasmid DNA compacted with PEG-substituted lysine	DNA	Rat	To measure the transfection potential in CNS disorder	Results shows that nanoparticle s are able to bypass the BBB, and transfect and express the encoded gene	Harmon et al. (2014)
PLA	PEG coating along with ligand	Peptide (QSH)	Mice	BBB targeting	Promising tool for diagnosis and therapy	Zhang et al. (2014)
PCL	PEG conjugation with cell-penetrating peptide	siRNA	Rat	Good cell-penetrating property in nose to brain delivery	Intranasal delivery of final formulation was found to be effective in comparison with the i.v route	Kanazawa et al. (2013)
PLGA	Nanoparticles modified by conjugation with Aβ antibody.	Anti-Aβ antibody	Cellular cerebral amyloid angiopathy model	Enhance uptake at BBB and Aβ targeting	Capable to delivering the drug to the cerebrovascular amyloid	Jaruszewski et al. (2012)
1,1-dicyano-2-[6-(dimethyl amino)naphthalene-2-yl]propene (DDNP)	DDNP conjugate with carboxyl derivative to oleic acid-treated SPIONs	Contrast agent		MRI imaging	Promising contrast agent of Alzheimer's disease in MRI	Zhou et al. (2014)
l-glutamic and l-aspartic as surface capping agents	Bio conjugated with the surface active neurotransmitter			Biomarker, cell signaling	potential biomarkers in cell targeting and signaling applications	Mansur et al. (2013)
PLGA	TGPS coating			Drug delivery along with Vitamin E	In Vitamin E and the associated neurological disorder	Jalali et al. (2011)
PEG-CO-PCL	Lactoferrin coating	Neuro protective peptide	Mice	To enhance the uptake drug nanoparticles in the brain along with the bio distribution	In neurological disorder	Liu et al. (2013)
PLGA	Tween 80 coating	Estradiol	Rats	To improve the oral bioavailability. Successful in preventing the expression of amyloid beta-42	In AD therapy	Mittal et al. (2011)
PEG-PLGA	Pep TGN	Coumarin 6 (fluorescent probe)	Mice	Site specific delivery to brain. To increase cellular uptake	These modified nanoparticle s are of good potential to overcome the BBB	Li et al. (2011)
Chitosan	A polyamine-modified F (ab’) portion of IgG4.1, an anti-amyloid antibody.	Antibody	Mice	SNV capable of permeating the BBB. To target cerebrovascular amyloid in AD and cerebrovascular amyloid angiopathy (CAA)	Nanoparticles are a good option for protein and peptide to cross the BBB	Agyare et al. (2008)
poly(ethy l glycol)-co-poly (E-caprolact one)	Angiopep conjugate	Rhoda mine B (fluorescent probe	Mice	To enhance of selective uptake of nanoparticles. Receptor-mediated transcytosis	Promising approach for the therapy and diagnosis of neurological disorders	Xin et al. (2012)
PEG-PLA	Lactorferrin conjugation	Urocortin (peptide)	Mice	To identify the application of ligand-conjugated nanoparticles in PD	Better uptake (by clathrin-mediated endocytosis) of surface modified nanoparticles as compared to unmodified nanoparticles, and lesions in striatum were attenuated	Hu et al. (2011)
PEG-PEI Polyethylene glycol-polyethylene imine	PEG-PEI siSNCA complex	siSNCA	PC12 cells	To develop and characterize PEG-PEI siSNCA as a vector to target PC12 cells for Parkinson's	Nanoparticles had low toxicity and high transfection efficiency, and successfully suppressed the SNC mRNA expression	Liu et al. (2014)
PEG-PLA	Odorranalectin conjugation	Urocortin (peptide)	Rats	To increase brain delivery, and to enhance the therapeutic effects	Such type of modification enhances the brain delivery. Could be a potential carrier for CNS drug delivery	Wen et al. (2011)
DGL dendrigraft poly-L-lysine	Angiopep-conjugated nanoparticles	Gene	Rats	To evaluate the neuroprotective effects	Modified nanoparticles exhibit the higher cellular uptake, and gene expression in brain cells of rats	Huang et al. (2013)
Silica	Conjugation	Gene	Mice	Cationic charge will enhance the binding with negatively charged plasmid	To introduce the gene into the dopaminergic cell of substantianigra and parscompecta	Bharali et al. (2005)
PEG-PLGA	Odorranalectin conjugated to PEG-PLGA	Urocortin peptide	Mice	To enhance the nose-to-brain delivery and reduce immunogenicity of traditional lectins associated carrier	Such a modification enhance brain delivery, along with therapeutic effects	Wen et al. (2011)
Poly(amidoamine) derivative	Lactoferrin conjugation	Gene therapy	Rats	To develop the polymer ligand conjugate to overcome the BBB	High gene expression for longer period of time, improvement in locomotor activity, and reduced neuronal loss	Huang et al. (2010)
β-cyclodextrin	Amphiphilic β-cyclodextrin (oligosaccharide based molecules)	siRNA	Mouse	To develop an efficient, nontoxic delivery vehicle to the CNS	Developed carrier was shown to be able to reduce the expression of Huntingtin protein in striatum, with limited toxicity	Godinho et al. (2013)

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