4. Solid lipid nanoparticles for brain targeting

Targeted delivery of drugs to the brain for is gaining much more interest at the present time, not only for the treatment of brain tumor and other neurodegenerative disorders but also for their diagnosis. Brain targeted delivery of drugs is the most challenging task because of the presence of strongest physiological barrier, i.e., blood brain barrier (BBB). It is a highly selective semipermeable membrane barrier constituted by specialized microvascular endothelial cells, basement membrane and glial cells (astrocytes, neurons, and pericytes). As long as the BBB remains integral, the drugs remain ineffective in the brain. Though BBB is a major issue for it, yet it offers scores of opportunities such as presence of numerous transport proteins and specialized receptors [5].

along with the cell surface of glioblastomas [36]. Keeping it in mind, various researchers tried to target lactoferrin receptor through conjugation of lactoferrin with SLNs for active targeting to brain tumor. Moreover, this conjugated system

Solid Lipid Based Nano-particulate Formulations in Drug Targeting

improved the targeting potential of the DTX for brain tumor [37].

4.2.2 Tamoxifen-Lactoferrin cross conjugated solid lipid nanoparticles

like MRAPs in cancer cells [38]. Thus, incorporation of Tf could help in preventing a wide range of medication from efflux loss. Lactoferrin (Lf)

Lactoferrin (Lf) conjugated SLNs loaded with docetaxel (DTX) were able to show effective brain targeting efficiency. Carbodiimide chemistry was employed for conjugation of Lf on SLN surface (Lf-SLN). Receptor saturation studies and distribution studies of lipidic nanoparticles in the brain indicated brain targeting mechanism for uptake in brain tumor cell and brain respectively. The Lf-SLNs were more stable. It not only showed significantly higher DTX concentration in the brain but also showed superior apoptotic activity when compared with unconjugated SLNs and DTX. Thus it was confirmed that conjugation of Lf to SLN significantly

P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRAPs) are localized on brain microvascular endothelial cells (BMEC) which pump out the substances/drug out from the central nervous system. Tamoxifen (Tf), a selective estrogen receptor modulator possibly reverse the capability of efflux transporters

receptors are overexpressed in BMEC and glioblastoma multiforme (GBM) cells. It is reported that the Lf cause inhibition to the multiplication of malignant

Tamoxifen (Tx) and lactoferrin (Lf) cross-conjugated carmustine (CRM) loaded SLNs were developed. For conjugation of Tx on CRM-SLN, the carbonyl groups of the SLN were first activated with 0.1% (w/v) carbodiimide and 0.05% (w/v) N-hydroxysuccinimide. The suspended SLNs were then crosslinked with 0.05%, 0.1%, 0.15%, or 0.2% (w/v) Tx at 150 rpm and 25°C for 3 h and centrifuged. Further Lf conjugation was done by reacting Lf (0.02%, 0.04%, 0.06%, or 0.08%) (w/v) with the activated CRM-SLNs and Tx-CRM-SLN. The conjugated SLNs were more stable which could be due to inclusion of behenic acid into the lipid core. These were efficiently penetrated through a monolayer of human BMEC and human astrocytes and to target GBM cells. A 10-fold increase in the permeability of BBB and improved the sustained release of CRM was achieved with the help of the developed SLNs as compared to unconjugated CRM-SLNs. Thus, TX and Lf crossconjugated SLNs enhance the BBB permeability of the drug with improved anti-

Treatment of brain tumor through siRNA is preferable, as it can target specifically to one gene and is able to silence it in a post-transcriptional way. Moreover, siRNA can target several functional proteins available at the BBB [40]. Treatment of brain tumor through siRNA, needs a safe, stable, effective carrier which must be able to cross the BBB. The SLNs are mostly preferred as it meets most of the criteria which siRNA needs. Targeted delivery of gene by SLNs is a bi-stage system. Conju-

siRNA encapsulated SLNs were successfully developed using a combination of

gation of angiopep to SLN surface for targeting the low-density lipoprotein receptor-related protein-1(expressed in BBB) is the initial step. The proteolytic cleavage of PEGylated lipopeptide, which releases PEG, glutamic acid residues and

titrable cationic lipids. For effective gene delivery, it was PEGylated after

release of siRNA for high silencing efficiency is the second stage [5].

showed higher stability, and drug payload.

DOI: http://dx.doi.org/10.5772/intechopen.88268

GBM cells.

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proliferative action against GBM [39].

4.2.3 PEG conjugated solid lipid nanoparticles for gene delivery

Conventional approach for the treatment of brain tumor and other brain-related disorders needs a higher dose of the drug that leads to systemic toxicity and substantial adverse effects on CNS and vital normal tissues. However, various researchers have reported SLNs to be a suitable DDS targeting the brain as the SLNs possess numerous unique characteristics, such as improved uptake of SLN by the brain due to lipidic nature, bioacceptability and biodegradability nature, non-toxic, nano sized particles suitable for prolonged circulation time in blood scale up feasibility, absence of burst drug release effect [31]. Thus, SLN could be used as potential as well as promising candidate for brain targeting.

#### 4.1 Solid lipid nanoparticles for active brain targeting

SLNs are the most acceptable brain targeted DDS employed in brain tumor owing to their ability to escape and/or inhibit P-glycoprotein in the blood–brain barrier [32]. Camptothecin (CMP) loaded SLN were successfully developed for the treatment of glioma. Encapsulation of drug in phospholipids and conjugation with the peptide enhances the permeation of drug across BBB, which leads to brain targeted delivery of the drug. The developed SLN was stable in terms of size and charge within a year of storage which might be due to appropriated acidic pH (inclusion of behenic acid into the lipid core of the SLNs). DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) membrane helps in efficient release of the incorporated CMP into the brain parenchyma crossing the BBB. Against glioma, the developed SLNs showed higher cell death or antitumor activity using the lowest maximal inhibitory concentration (IC50) values. Biodistribution study revealed higher accumulation of CMP in the brain in the case of SLNs as compared to other non-encapsulated drugs. However, pharmacokinetics study revealed lower deposition of CMP in peripheral organs indicating lesser toxicological effects in the vital organ. Thus, in short, the SLNs exhibited enhanced accumulation, distribution, and retention of camptothecin in the animal brain along with superior in vitro antitumor activity against glioma [33].

Riluzole (RLZ), a potent neuroprotective agent is useful in the treatment of neurodegeneration including traumatic brain injury and amyotrophic lateral sclerosis. RLZ-SLNs were able to deliver the riluzole successfully to the brain which helps in preventing acute cell damage induced by glutamate in neurodegenerative diseases of motor neurons. Moreover, it also protects dopamine neuron in the case of Parkinson's disease. Stability studies on RLZ-SLNs were also carried out at pH 1.1, 5.5 and 7.4, and in human plasma which revealed the absence of riluzole degradation in all the investigated media [34].

Vinpocetine (VIN), a derivative of vincamine alkaloid, useful against chronic cerebral vascular ischemia. VIN loaded SLN were successfully developed and achieved the objectives of delivering the drugs to the brain. Release kinetics of the developed SLN followed zero-order sustained release profile [35].

#### 4.2 Ligand conjugated solid lipid nanoparticles for passive brain targeting

#### 4.2.1 Lactoferrin conjugated solid lipid nanoparticles

Augmentation of drug uptake into the brain is a subtle mission in the treatment of brain tumor. Lactoferrin (Lf) receptor present on the BBB in different species
