**4. Nanopharmaceuticals: brain targeting mechanisms**

Nanopharmaceuticals could able to breach blood-brain barriers through various mechanisms. On the simple edge, their smaller size leads to passive delivery of the drugs through transcellular route across brain's epithelial cells or choroid plexus. Criteria for the simple passive diffusion across the barriers are molecular size less than 400 Da, low hydrogen bonding capacity and lipophilicity [13, 14]. Therefore, lipophilic and tailored nanocarriers could deliver the drug through this mechanism.

While extremely hydrophobic molecules like nutrients (glucose and amino acids) pass through active diffusion mechanism with the aid of special transporter proteins. On the other hand, hydrophilic and larger molecules like transferrin and insulin pass through receptor-mediated transport across the membrane [15]. BBB majorly comprised of the endothelial layer which possessed tight junctions; the presence of proteins, namely occludins, claudins and adhesion molecules in the tight junction, make it a tougher barrier [16].

Nanopharmaceuticals are custom-made to surpass the brain barriers through these mechanisms:


Liposomes have been extensively studied and even FDA approved nanocarrier for brain disorders. Surface modulation of liposomes with functional proteins, peptides and polyethers aided targeted drug delivery for brain diseases [18]. PEGylated liposomes and glutathione-PEGylated liposomes evade body's reticuloendothelial system and facilitate enhanced drug uptake across BBB [19]. Moreover, transferrinmodified liposomes [20], TAT peptide-conjugated liposomes [21], glucose-modified liposomes [22], and transferrin-folate bound liposome effectively deliver the drug

**121**

delivery [30].

*Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery*

across the barrier to treat multiple sclerosis [23]. Similarly, transferrin bound SLN and thiamine coated SLN were found to be efficacious in the treatment of cerebral malaria and increased drug uptake in the brain [24]. Mechanisms of transport

*Different pathways for nanopharmaceuticals mediated transport across the blood-brain barrier (Under Creative Commons Attribution License 4.0, https://creativecommons.org/licenses/by/4.0/) [96].*

Polymeric nanoparticles accumulate in the brain tissue by both passive and active mechanisms. Chitosan-poly lactic-co-glycolic acid (PLGA) nanoparticles showed enhanced delivery of coenzyme Q to the brain of transgenic mice through absorption mediated endocytosis [25]. In another study, PLGA was coupled with Tet-1 peptide to achieve neuronal targeting of curcumin in the treatment of Alzheimer's disease. Retrograde transportation of curcumin across the barriers destroyed amyloid aggregates and scavenges oxidative radicals in the brain [26]. Similarly, ligand attached polymeric-lipidic nanoparticles like nerve growth factor (NGF) loaded poly butyl cyanoacrylate (PBCA) liposomes considerably deliver the drug across the BBB cholinergic system in the amnesic rodent model [27]. Likewise, inorganic nanocarriers show promising outcomes in terms of brain targeting. Amine functionalized multi-walled carbon nanotubes adopted transcytosis mechanism to pass BBB [28]. A natural substance wheat germ agglutinin-horseradish peroxide (WGA-hrp) was conjugated to gold nanoparticles (AuNPs) and administered in the IM injection into the mice. Results were remarkable in terms of drug

Dendrimers are the excellent drug carriers; their surface functionalization with

folic acid, peptides, aptamers, amino acids, biotin, antibodies facilitated more site-specific targeting. To penetrate CNS barriers, dendrimers were conjugated with transferrin, lactoferrin, D-glucosamine, and leptin for more effective brain drug

*DOI: http://dx.doi.org/10.5772/intechopen.83040*

across BBB are shown in **Figure 1**.

**Figure 1.**

penetration across BBB [29].

### *Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.83040*

#### **Figure 1.**

*Pharmaceutical Formulation Design - Recent Practices*

for the brain are mentioned in **Table 1**.

tight junction, make it a tougher barrier [16].

triphosphate (ATP) [17]

these mechanisms:

**4. Nanopharmaceuticals: brain targeting mechanisms**

surface to volume ratio and flexibility to alter their properties [11]. An alternate definition can be pharmaceuticals engineered on the nanoscale for the therapeutic purpose [12]. Nanopharmaceuticals comprised of different nanomaterial like polymers, lipids, amphiphilic material, metals, inorganic elements, carbon nanotubes, dendrimers, etc., to constitute nanocarriers which can be fabricated in different sizes, shapes, morphology, surface charges and surface groups for the brain-specific targeted delivery of the drug across barriers. Nanopharmaceuticals mediated drug delivery system has the power to penetrate drug moieties across CNS, either passively or actively, and improve bioavailability and therapeutic efficacy of the drug even at a lower concentration. Currently, available marketed nanopharmaceuticals

Nanopharmaceuticals could able to breach blood-brain barriers through various mechanisms. On the simple edge, their smaller size leads to passive delivery of the drugs through transcellular route across brain's epithelial cells or choroid plexus. Criteria for the simple passive diffusion across the barriers are molecular size less than 400 Da, low hydrogen bonding capacity and lipophilicity [13, 14]. Therefore, lipophilic and tailored nanocarriers could deliver the drug through this mechanism. While extremely hydrophobic molecules like nutrients (glucose and amino acids) pass through active diffusion mechanism with the aid of special transporter proteins. On the other hand, hydrophilic and larger molecules like transferrin and insulin pass through receptor-mediated transport across the membrane [15]. BBB majorly comprised of the endothelial layer which possessed tight junctions; the presence of proteins, namely occludins, claudins and adhesion molecules in the

Nanopharmaceuticals are custom-made to surpass the brain barriers through

• Lipophilic nanocarriers (liposomes, solid lipid nanoparticles SLN) fuse with the endothelial cells and transport the drug through the transcellular pathway or endocytosis. Moreover, nanoparticles provide a sustained drug release pattern in the bloodstream, enabling higher drug concentration to cross BBB [17].

• Furthermore, nanoparticles are functionalized with ligands or specific surfaces to trigger receptor-mediated transcytosis or carrier-mediated transport across BBB. Attachment of ligands like lactoferrin, transferrin, insulin facilitated receptor-mediated transport. Cationized ligands and peptides like albumin cross through receptor-mediated absorptive transport. Nanoparticles surface can be modified to utilize active transport system comprising P-glycoproteins, L-transporters, nucleoside transporter, ionic transporter, multidrug-resistant proteins that transfer the molecules into the brain by consuming adenosine

Liposomes have been extensively studied and even FDA approved nanocarrier for brain disorders. Surface modulation of liposomes with functional proteins, peptides and polyethers aided targeted drug delivery for brain diseases [18]. PEGylated liposomes and glutathione-PEGylated liposomes evade body's reticuloendothelial system and facilitate enhanced drug uptake across BBB [19]. Moreover, transferrinmodified liposomes [20], TAT peptide-conjugated liposomes [21], glucose-modified liposomes [22], and transferrin-folate bound liposome effectively deliver the drug

**120**

*Different pathways for nanopharmaceuticals mediated transport across the blood-brain barrier (Under Creative Commons Attribution License 4.0, https://creativecommons.org/licenses/by/4.0/) [96].*

across the barrier to treat multiple sclerosis [23]. Similarly, transferrin bound SLN and thiamine coated SLN were found to be efficacious in the treatment of cerebral malaria and increased drug uptake in the brain [24]. Mechanisms of transport across BBB are shown in **Figure 1**.

Polymeric nanoparticles accumulate in the brain tissue by both passive and active mechanisms. Chitosan-poly lactic-co-glycolic acid (PLGA) nanoparticles showed enhanced delivery of coenzyme Q to the brain of transgenic mice through absorption mediated endocytosis [25]. In another study, PLGA was coupled with Tet-1 peptide to achieve neuronal targeting of curcumin in the treatment of Alzheimer's disease. Retrograde transportation of curcumin across the barriers destroyed amyloid aggregates and scavenges oxidative radicals in the brain [26]. Similarly, ligand attached polymeric-lipidic nanoparticles like nerve growth factor (NGF) loaded poly butyl cyanoacrylate (PBCA) liposomes considerably deliver the drug across the BBB cholinergic system in the amnesic rodent model [27]. Likewise, inorganic nanocarriers show promising outcomes in terms of brain targeting. Amine functionalized multi-walled carbon nanotubes adopted transcytosis mechanism to pass BBB [28]. A natural substance wheat germ agglutinin-horseradish peroxide (WGA-hrp) was conjugated to gold nanoparticles (AuNPs) and administered in the IM injection into the mice. Results were remarkable in terms of drug penetration across BBB [29].

Dendrimers are the excellent drug carriers; their surface functionalization with folic acid, peptides, aptamers, amino acids, biotin, antibodies facilitated more site-specific targeting. To penetrate CNS barriers, dendrimers were conjugated with transferrin, lactoferrin, D-glucosamine, and leptin for more effective brain drug delivery [30].

Some other nanoparticulate systems like nanoemulsion and nanogel can be functionalized with targeting moieties (transferrin, insulin, peptides) for CNS drug delivery. Nanogels made up of PEG-polyethylenimine (PEI) and N-vinylpyrrolidone/ isopropyl acrylamide have been tested to ensure CNS drug delivery potential [30].
