Solid Lipid Based Nano-particulate Formulations in Drug Targeting DOI: http://dx.doi.org/10.5772/intechopen.88268

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

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

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

potential as well as promising candidate for brain targeting.

brain along with superior in vitro antitumor activity against glioma [33].

developed SLN followed zero-order sustained release profile [35].

4.2.1 Lactoferrin conjugated solid lipid nanoparticles

tion in all the investigated media [34].

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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 degrada-

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

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

4.2 Ligand conjugated solid lipid nanoparticles for passive brain targeting

4.1 Solid lipid nanoparticles for active brain targeting

Role of Novel Drug Delivery Vehicles in Nanobiomedicine

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 showed higher stability, and drug payload.

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

## 4.2.2 Tamoxifen-Lactoferrin cross conjugated solid lipid nanoparticles

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 like MRAPs in cancer cells [38]. Thus, incorporation of Tf could help in preventing a wide range of medication from efflux loss. Lactoferrin (Lf) receptors are overexpressed in BMEC and glioblastoma multiforme (GBM) cells. It is reported that the Lf cause inhibition to the multiplication of malignant GBM cells.

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 antiproliferative action against GBM [39].

#### 4.2.3 PEG conjugated solid lipid nanoparticles for gene delivery

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

siRNA encapsulated SLNs were successfully developed using a combination of titrable cationic lipids. For effective gene delivery, it was PEGylated after

incorporating MMP-cleavable lipopeptide. The in vitro study indicated that the developed SLNs showed higher uptake and gene knockdown efficacy. SLNs also showed low cytotoxicity which was owing to masking of intrinsic positive charge of SLNs by PEGylated cleavable lipopeptide. In in vivo studies, angiopep functionalization played a vital role as a mediator of transport across the BBB and targeting to glioma [41].

in two different ApoE-functionalized SLNs: SLN-DSPE-ApoE and SLN-Palmitate-ApoE. These conjugated SLNs were sufficiently stable and were able to prevail over the issues of RSV like low solubility, degradation but also to help its brain targeted delivery. Brain targeted delivery of RSV by such SLNs follows a bi-stage system. The AP-E-RSV-SLNs mimic lipoprotein particles that are endocytosed into the BBB

List of SLNs and their different ligand conjugated forms for brain cell targeting

Though targeted delivery of a drug to the liver is a challenging task, still, it is an interesting approach in the treatment of various liver disorders. In the treatment of liver disorders, drugs targeting to the liver, face irresistible obstacles from various physiological barriers and processes like uptake by the reticuloendothelial system, mechanical entrapment by the pulmonary vascular bed, and opsonization

Numerous approaches are being proposed to enhance bioaccumulation/ biodistribution of drugs to liver and hepatocytes. These approaches include both active targeting as well as passive accumulations of nanoparticulate formulation due to ligand (carbohydrate, peptide, antibodies conjugation) conjugated nanoparticles. Recently, liver targeted deliveries of drugs by the SLNs are gaining much attention in the treatment of various types of liver disorders. Thus, various liver targeting

Baicalin (BCL), a natural product obtained from Scutellaria baicalensis (Family: Labiatae) popularly used in the treatment of Hepatitis-B and liver fibrosis. BCL loaded SLNs were developed. The prepared SLNs were stable and were able to enhance the therapeutic efficacy of BCL by improving its biodistribution in the liver. In vivo biodistribution, targeting evaluation and in vitro anti-oxidant study reveals that the developed BCL-SLNs have substantial liver targeting, improved anti

Ficus benjamina (Family: Moraceae) is rich in phenolic (chlorogenic, pcoumaric, ferulic and syringic acids) and total flavonoid content that are effective against chronic alcoholism induced fatal liver and cardio-renal injury. Ethanolic

bioaccumulation of the phenolic and flavonoid content in the liver due to lipophilic nature of SLNs. In vivo evaluation of FBSLNs against hepatic and cardio-renal injury revealed its hepatoprotective activity which was further evident from various biological parameters and histopathological photomicrography. In the liver, accumulation of aldehyde level was reduced that validated the detoxifying nature of FBSLN. Moreover, restoration of aberrant cardio-renal biomarkers and histological conse-

Ranunculaceae) have potential pharmacological effects on type-2 diabetes. It has already been validated that BBR enhances glucose and lipid metabolism through the activation of adenosine monophosphate-activated protein kinase (AMPK) and improve insulin sensitivity. BBR loaded SLNs (BBR-SLNs) were developed to improve the beneficial effect of BBR on hepatosteatosis. The effect of BBR-SLNs on lipid metabolism were studied which revealed gaining of body weight and reduction

extract of Ficus benjamina (FB) loaded in SLNs (FBSLNs) helped in

quences revealed the cardio-renal protective potential of FBSLNs [45]. Berberine (BBR), an active constituent of Coptis chinensis (Family:

endothelium via the LDL receptor and then transcytosed to the brain [42].

have been summarized in Table 2.

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

process [43].

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5. Solid lipid nanoparticles for liver targeting

Solid Lipid Based Nano-particulate Formulations in Drug Targeting

strategies using SLNs are enlightened below.

5.1 Solid lipid nanoparticles for active targeting

oxidative and hydroxyl radical scavenging abilities [44].
