Breaking Barriers in Brain Tumor Treatment: Exploring the

Potential of Solid Lipid Nanoparticles.

Abstract
Objective : Brain malignancies continue to present a challenging prognosis,
primarily due to their distinct characteristics that impose limitations on aggressive
multimodal therapeutic strategies. Achieving optimal intratumoral drug delivery is a
key objective in brain tumor therapeutic approaches, aiming to attain effective
concentrations while mitigating systemic undesired toxicity. The development of
various passive and active drug delivery carriers has enabled enhanced control over
drug distribution, metabolism, and elimination post parenteral administration. This
review will delineate the general attributes and assess the effectiveness of Solid
Lipid Nanoparticles (SLN) as carriers for diverse drugs in experimental brain
malignant tumor therapy.
Methods : SLN carrying various types of antineoplastic agents, including
conventional cytotoxic drugs like doxorubicin and paclitaxel, the prodrug
Cholesteryl butyrate, and antisense oligonucleotides targeting anti-VEGF, have
undergone testing in experimental animal models of cerebral gliomas.
Conclusion : Solid Lipid Nanoparticles (SLN) have exhibited notable success in
facilitating the transportation of diverse cytotoxic and gene therapeutic agents
across the Blood-Brain Barrier (BBB). The Blood-Brain Barrier typically poses a
significant challenge for the delivery of therapeutic agents to the brain due to its
selective permeability. However, SLNs have proven their efficacy in overcoming this
barrier.

Inroduction
Brain tumors encompass a diverse group of neoplasms that originate within the
brain or its surrounding structures. These tumors can be classified as either benign
or malignant, with the latter category posing a more significant threat due to their
aggressive nature. The challenges associated with the treatment of brain tumors
are multifaceted and contribute to the often poor prognosis associated with these
conditions. One primary challenge lies in the intricate and sensitive nature of the
brain itself. The brain is a highly organized and vital organ, making surgical
interventions complex and often limited by the potential for damage to healthy
neural tissue. Additionally, the Blood-Brain Barrier (BBB), a protective barrier that
regulates the passage of substances from the bloodstream into the brain, can
impede the delivery of therapeutic agents. Furthermore, the heterogeneity of brain
tumors adds complexity to treatment strategies. Different types of brain tumors
exhibit varied molecular profiles and responses to treatment, necessitating
personalized and targeted therapeutic approaches. The infiltrative nature of certain
tumors, such as gliomas, makes complete surgical removal challenging,
contributing to the likelihood of tumor recurrence.[1-3].
Solid Lipid Nanoparticles (SLNs) serve as a carrier system for poorly water-soluble
drugs and cosmetic active substances. Nanoparticles, colloidal particles within the
size range of 10 to 1000 nm, are incorporated from both synthetic and natural
polymers. These nanoparticles are adept at enhancing drug delivery, utilizing
tailored carriers to reduce toxicity associated with drug formulations.[4]
Solid Lipid Nanoparticles (SLNs) stand out as a promising solution in drug delivery,
particularly for challenging applications like brain tumor therapy. Composed of
biocompatible lipids in a solid state, SLNs offer stability, versatility, and efficient
drug transport. Their nanoscale size enables them to overcome the Blood-Brain
Barrier, enhancing drug delivery to the brain. Tailorable for controlled release, SLNs
show great potential in optimizing therapeutic outcomes with minimized side
effects. In summary, SLNs present a cutting-edge platform for drug delivery, holding
promise for targeted and effective treatments in brain tumor therapy.[5]

Obstacles in Drug Delivery to the Brain

Blood Brain Barrier : The blood-brain barrier (BBB) constitutes a specialized

network of capillary endothelial cells designed to shield the brain from potentially
harmful substances circulating in the bloodstream, all the while ensuring the
provision of essential nutrients necessary for optimal brain function. Unlike
capillaries in peripheral tissues that permit relatively unrestricted passage of
substances between cells, the BBB rigorously controls the entry of substances into
the brain. This regulation occurs through a combination of physical barriers, such as
tight junctions, and metabolic barriers involving enzymes [6]. Consequently, the
BBB frequently acts as the determining factor, setting limits on the permeation of
therapeutic drugs into the brain.

The Architectural Blueprint and Molecular Composition of the Blood-

Brain Barrier :
The Blood-Brain Barrier (BBB) stands as an exceptional and discerning defense
mechanism shaped by endothelial cells lining cerebral capillaries. This intricate
barrier involves not only endothelial cells but also incorporates surrounding
components, including closely linked astrocytic end-feet processes, perivascular
neurons, and pericytes[7,8]. Astrocytic processes surrounding nearly 99% of
capillaries within the central nervous system (CNS) have a restricted impact on the
day-to-day functions of the BBB. Their primary function, however, involves the
secretion of nourishing factors vital for the development, health, and operational
capabilities of endothelial cells in the BBB. Concurrently, pericytes in the vascular
system play a role in regulating the BBB through the release of various soluble
factors essential for the distinctiveness and ongoing support of the BBB [8,9].
The endothelial cells forming the Blood-Brain Barrier (BBB) exhibit distinctions from
their counterparts in peripheral tissues, characterized by heightened mitochondrial
content, the absence of fenestrations, and minimal pinocytotic activity.[10]
Notably, complex tight junctions, facilitated by the interaction of transmembrane
proteins such as occludin, claudins, and junctional adhesion molecules (JAMs),
effectively seal the paracellular pathway [7,8]. These tight junctions also distinctly
divide the membranes of the endothelial cells into two sides: luminal (blood side)
and abluminal (brain side)[11,12].Pericytes are irregularly attached to the
abluminal membrane of the endothelium. Both pericytes and endothelial cells are
surrounded by the basal lamina, a membrane approximately 30 to 40 nanometers
thick. This basal lamina is composed of various components, including collagen
type IV, heparin sulfate proteoglycans, laminin, fibronectin, and other extracellular
matrix proteins. Importantly, the basal lamina maintains continuity with the plasma
membranes of astrocyte end-feet, which encircle cerebral capillaries[10].The
intricate relationship among the endothelium, pericyte, and astrocyte foot
processes stands as one of the most closely intertwined cell-cell interactions in
biology. The space occupied by the basement membrane, situated between the
endothelium/pericyte and the astrocyte foot process, serves as the interface
between the blood and the brain. For the transport of ligands or substrates in
either the brain-to-blood or blood-to-brain direction, the movement must traverse
the capillary endothelial plasma membrane. The transfer of solutes across the
capillary endothelial barrier involves a sequential process through two membranes.
To move from the blood to the brain interstitial space beyond the astrocyte foot
process, a molecule must also navigate the immediate perivascular space, bordered
by the plasma membrane of capillary endothelial cells, pericytes, and astrocyte
foot processes. The transportation of nutrients or drugs across the BBB is likely
orchestrated by a multifaceted interplay involving active efflux systems on the
endothelial plasma membrane, active transporters within the astrocytic foot
process, and ectoenzymes present on the pericyte plasma membrane[13].Brain
endothelial cells house a multitude of membrane transporters, including P-
glycoproteins (P-gp) and the multi-drug resistance-associated protein family (MRP),
situated on both the luminal and abluminal membranes of capillaries. These
transporters play a crucial role in regulating the transcellular traffic of essential
molecules between the brain and blood, while simultaneously facilitating the efflux
of potentially harmful substances and waste products. The Blood-Brain Barrier
(BBB) transporters accommodate a diverse range of molecules, including amino
acids, glucose, micronutrients, electrolytes, hormones, and peptides. Notably,
these transporters exhibit varying efficiencies in the blood-to-brain and brain-to-
blood directions. Structural disparities between brain capillaries and non-brain
capillary endothelium are primarily associated with endothelial tight junctions.
While non-brain capillaries feature fenestrations (openings) between endothelial
cells, allowing for the passive diffusion of solutes, brain capillaries have
unfenestrated endothelium with tight junctions devoid of openings. The
unfenestrated nature of brain capillaries results in the cementation of endothelial
cells through intercellular tight junctions, leading to high electrical resistance across
intraparenchymal endothelial cells. The presence of tight junctions eliminates the
paracellular pathway for solute movement across the BBB, and there is virtually no
pinocytosis across brain capillary endothelium[14]. The existence of the Blood-
Brain Barrier (BBB) gives rise to a considerable clinical challenge in delivering
therapeutic compounds to the Central Nervous System (CNS). Polar drugs face
constraints in freely diffusing into the brain [15], as the absence of a paracellular
pathway prevents the diffusion of aqueous solutes from the blood to the brain
extracellular fluid or in the reverse direction—unlike capillaries in the peripheral
circulation. The scarcity of endocytic vesicles in CNS capillaries further eliminates a
transcellular route for the free diffusion of substances into the interstitium [9].
Additionally, a substantial number of more lipophilic drugs are susceptible to the
activity of efflux transporters. Consequently, a considerable proportion of CNS
diseases lack effective therapy, primarily attributed to the formidable challenge of
delivering drugs across the BBB [16,17]. The existence of the Blood-Brain Barrier
(BBB) gives rise to a considerable clinical challenge in delivering therapeutic
compounds to the Central Nervous System (CNS). Polar drugs face constraints in
freely diffusing into the brain [15], as the absence of a paracellular pathway
prevents the diffusion of aqueous solutes from the blood to the brain extracellular
fluid or in the reverse direction—unlike capillaries in the peripheral circulation. The
scarcity of endocytic vesicles in CNS capillaries further eliminates a transcellular
route for the free diffusion of substances into the interstitium [8]. Additionally, a
substantial number of more lipophilic drugs are susceptible to the activity of efflux
transporters. Consequently, a considerable proportion of CNS diseases lack
effective therapy, primarily attributed to the formidable challenge of delivering
drugs across the BBB [16,17].

The capacity of a specific substance to traverse the Blood-Brain Barrier (BBB) and
gain entry into the brain is contingent upon various factors:

1.Drug-related factors at the Blood-Brain Barrier (BBB) include the concentration

at the BBB, as well as the size, flexibility, conformation, ionization (with the
nonionized form having greater BBB penetration [8]), and lipophilicity of the drug
molecule. Additionally, factors such as cellular enzyme stability, cellular
sequestration, affinity for efflux mechanisms (e.g., P-glycoprotein), hydrogen
bonding potential (i.e., charge), affinity for carrier mechanisms, and the impact of
existing pathological conditions all play a role in determining a substance's ability to
cross the BBB [14,18].

2.Physicochemical characteristics, such as the partition coefficient (log P), play a

pivotal role in the evaluation of therapeutic agents. The "rule of 2" is widely
acknowledged in this context, suggesting that a log P value close to 2 is considered
optimal [18,19]. However, it is essential to recognize that attempts to enhance
permeability through increased lipophilicity may result in an elevation of both the
volume of distribution (Vd) and the rate of oxidative metabolism facilitated by
cytochrome P450 [18,20,21].Peripheral factors, including systemic enzymatic
stability, plasma protein binding affinity, drug uptake clearance rate, and the impact
of existing pathological conditions, are also of considerable significance in assessing
the transport of therapeutic agents.
The hydrophobicity of a given drug or compound exhibits an inverse correlation
with the extent of hydrogen bond formation in the presence of surrounding water.
Certain chemical moieties in the drug, such as terminal amide, primary amines, or
amides, as well as hydroxyl groups, contribute to the promotion of hydrogen bond
formation, resulting in a reduction in hydrophobicity. Consequently, for a
compound to successfully traverse the Blood-Brain Barrier (BBB), the collective
number of hydrogen bonds should ideally not exceed 8–10. Thus, for smaller drugs,
enhancing hydrophobicity (i.e., diminishing hydrogen bonds) positively influences
capillary permeability, facilitating the transfer of the drug to the brain. Conversely,
for larger drug molecules with a molecular weight surpassing 400 Da or those with
pronounced polarity, capillary permeability remains low, regardless of
hydrophobicity [8].While the Blood-Brain Barrier (BBB) effectively seals off the brain
from polar blood-borne solutes, certain polar solutes are crucial nutrients and
metabolites for the brain, including glucose and amino acids. The endothelial cells
of cerebral capillaries maintain a high expression of transporters for these essential
solutes to facilitate their entry into the brain [22]. Tight junctions act as a barrier in
the cell membrane, preventing the free movement of transmembrane proteins and
lipid rafts between the luminal and abluminal surfaces of endothelial cells. This
fence-like property enables the maintenance of a polar expression of many
transporters in the membranes of cerebral endothelial cells, allowing some
transporters to be expressed solely in the luminal membrane and others in the
abluminal membrane. This polarized transporter expression directs the transport of
various solutes primarily from blood to brain or in the opposite direction,
facilitating the removal of certain substances from the Central Nervous System
(CNS). The formation of a tight, polarized BBB by cerebral endothelial cells, as
opposed to the open endothelium seen in other tissues, is believed to result from
close cellular associations with both astrocytes and pericytes. Astrocytes, with cell
bodies situated in the brain parenchyma, have end feet that project down to
cerebral capillaries and spread in a network over the abluminal surface. While
factors inducing the specific differentiation of BBB endothelium are still debated,
both cell surface molecules (cell–cell contact) and soluble factors likely play roles.
Specialized transport mechanisms, such as carrier systems for monosaccharides,
monocarboxylic acids, neutral and basic amino acids, acidic amino acids, amines,
purine bases, nucleosides, vitamins, and hormones, facilitate solute transfer across
endothelial cells into the brain interstitium within the BBB.
More lipophilic substances in the blood can passively diffuse through the lipid of
the cell membrane and enter the endothelial cells and brain. Generally, there is a
correlation between lipophilicity and brain penetration for these solutes, with more
lipid-soluble molecules entering the Central Nervous System (CNS) more readily.
However, certain lipophilic substances, including their metabolites, are actively
removed from the CNS by efflux transporters, such as P-glycoprotein and active
organic acid in choroid plexus, present in the BBB. Conversely, the presence of tight
 junctions and the lack of aqueous pathways between cells significantly restrict the
movement of polar solutes across cerebral endothelium [15].

Guardians of the Neural Realm: Unveiling the Intricate Roles of the

Blood-Brain Barrier -
The blood-brain barrier (BBB) is a crucial component of the central nervous system
that plays a vital role in maintaining the homeostasis of the brain's
microenvironment.
1. Selective Permeability: The BBB selectively allows the passage of essential
substances, such as oxygen, glucose, and certain ions, while restricting the
entry of harmful substances, toxins, and large molecules from entering the
brain tissue [18]
2. Protection: The BBB acts as a protective barrier, preventing the entry of
pathogens, bacteria, and viruses from the bloodstream into the brain, helping
to maintain a sterile environment within the central nervous system[18]
3. Regulation of Brain Microenvironment: It regulates the concentrations of ions,
nutrients, and other molecules in the brain's extracellular fluid, ensuring
optimal conditions for neural function[19]
4. Transport of Nutrients: The BBB facilitates the transport of essential nutrients,
such as glucose and amino acids, from the bloodstream into the brain,
supporting the energy and metabolic needs of neural cells[19].

Exploring Noninvasive Strategies and Novel Drug Delivery Systems to

Surpass the Blood-Brain Barrier =
An Insight into the Novel Drug Delivery System Approach :
Two main reasons for the failure of drug delivery to the brain are:
5. Poor penetration of the drug molecule across the BBB.
6. Back transport (efflux) of drugs from the brain to the blood.

Diverse Colloidal Delivery Systems Explored by Researchers to Overcome

Blood-Brain Barrier Hurdles, Primarily Focusing on Limited Permeation. These
Systems Encompass Liposomes, Microspheres, Lipid Microspheres, Niosomes,
Nanoparticles, and Solid Lipid Nanoparticles (SLNs) [20].
"For an efficacious delivery system, key factors such as high drug loading, robust
physical and chemical stability, and minimal carrier toxicity are imperative.
Additional considerations encompass the in vivo fate of the carrier, scalability of
the production process for the drug delivery system, and overall cost-effectiveness
[21].
The distribution parameters of drugs within the cerebral domain are intricately
influenced by factors including plasma protein binding, cerebral blood flow rate,
influx and efflux rates at the Blood-Brain Barrier (BBB), blood–cerebrospinal fluid
(CSF) barrier, brain parenchyma, drug metabolism rate in the brain, drug–tissue
interactions/binding in the brain, and flow rate. Therefore, meticulous
consideration and optimization of these parameters are essential when selecting
an apt delivery system for brain delivery.
Incorporating cutting-edge techniques such as genomics and proteomics holds
promise in steering novel drug delivery systems toward their target sites. By
unveiling pathways involved in disease pathogenesis, these techniques aid in
identifying brain-specific transport systems. Exploiting these systems could serve
as a noninvasive means of ferrying the drug cargo from the blood to the brain[22].

Solid Lipid Nanoparticles (SLNs): Pioneering the Future of Drug Delivery

Excellence
Chen et al. ( refers to a group of authors who have collaborated on a research paper or
scientific study) have aptly discussed polymeric nanoparticles as suitable delivery
systems for brain [23]. They have outlined various mechanisms for nanoparticle
mediated drug uptake by the brain.

These include:
1.Enhanced retention in the brain–blood capillaries, with an adsorption on to
the capillary walls, resulting in a high concentration gradient across the BBB.
2. Opening of tight junctions due to the presence of nanoparticles.
3. Transcytosis of nanoparticles through the endothelium.
 2. Opening of tight junctions due to the presence of nanoparticles.
3. Transcytosis of nanoparticles through the endothelium.
Furthermore, coating of these polymeric nanoparticles with polysorbate has
been reported to improve the brain bioavailability [15,35]. Some of the proposed
mechanisms by which the polysorbate coating is effective, include.
1.Surfactant Effects: Polysorbate's surfactant properties leading to the
solubilization of endothelial cell membrane lipids and membrane fluidization.
2. Facilitated Endocytosis: Improved interaction with Blood-Brain Barrier (BBB)
endothelial cells, promoting endocytosis of polymeric nanoparticles.
3. Efflux System Inhibition: Notably targeting P-glycoprotein (P-gp) to inhibit efflux
mechanisms.

Despite their promising applications, the use of polymeric nanoparticles presents

various challenges. Issues such as residual contamination from production
processes (e.g., organic solvents, polymerization initiation), the presence of large
polymer aggregates, and the potential toxicity of monomers and degradation
products pose concerns . Additionally, hurdles include the expensive production
methods , a lack of scalable production processes , and the absence of a suitable
sterilization method, such as autoclaving.
Given the success of nanoparticles in traversing the Blood-Brain Barrier (BBB) and
acknowledging their associated limitations, notably in terms of toxicity and stability,
Solid Lipid Nanoparticles (SLNs) emerge as a promising alternative for efficient drug
delivery into the brain[24].
Solid Lipid Nanoparticles (SLNs): A Captivating Colloidal Carrier for Drug Delivery.
SLNs, characterized by spherical solid lipid particles in the nanometer range, form a
versatile system dispersed in water or aqueous surfactant solutions. Comprising a
solid hydrophobic core enveloped by a monolayer of phospholipid coating, these
nanoparticles offer a unique structure. The solid core accommodates the drug,
either dissolved or dispersed in a high-melting fat matrix, with the hydrophobic end
of the phospholipid chains embedded in the fat matrix. This distinctive composition
equips SLNs with the potential to effectively transport lipophilic or hydrophilic drugs
and diagnostics[25-27].

1. Solid Lipid Nanoparticles (SLNs): A Superior Choice Over Polymeric Nanoparticles

and Liposomes – Unveiling the Distinctive Advantages
SLNs combine the advantages of polymeric nanoparticles, fat emulsions and
liposomes while simultaneously avoiding their disadvantages [40]. The advantages of
SLNs include the following:
1.Size Matters: Nanoparticles and SLNs, especially in the 120–200 nm range,
evade rapid uptake by Reticuloendothelial System (RES) cells, bypassing liver and
spleen filtration [23].
2.Prolonged Release: Achieving controlled drug release for several weeks is
feasible . Coating or ligand attachment to SLNs enhances drug targeting possibilities
[28,29,30].
3.Stability Triumph: SLN formulations boast stability for up to three years,
a paramount achievement in comparison to other colloidal carrier systems .
4. Payload Power: High drug payload capabilities.
5.Reproducible Excellence: Employing a cost-effective high-pressure
homogenization method ensures excellent reproducibility [29].
6.Dual Drug Compatibility: SLNs facilitate the incorporation of both hydrophilic
and hydrophobic drugs [25-27].
7. Biodegradable Bliss: Carrier lipids are biodegradable, ensuring safety [31-32].
8. Solvent-Free Solution: SLNs eliminate the need for organic solvents .
9.Scalability and Sterility: Feasibility in large-scale production and
sterilization processes [33].

Strategies for Prolonging Brain Retention of Solid Lipid Nanoparticles

(SLNs)
The distribution of Solid Lipid Nanoparticles (SLNs) within the body is
intricately tied to their surface characteristics, encompassing size, surface
hydrophobicity, and mobility. SLNs emerge as a promising delivery system for
hydrophilic drugs like diminazine and other BCS class IV drugs such as
paclitaxel, vinblastine, camptothecin, etoposide, and cyclosporine [31,32,35].
While these carriers easily access the blood compartment due to their small
size and lipophilic nature, their detection by cells of the reticuloendothelial
system (RES), specifically the mononuclear phagocytic system (MPS) cells of
the liver (Kupffer cells) and spleen macrophages, poses a significant challenge.
The uptake of nanoparticles by RES may lead to therapeutic failure, as it
hinders the accumulation of pharmacologically active drug concentrations in
the plasma and, consequently, at the Blood-Brain Barrier (BBB). To address
these limitations, various researchers have explored methods to enhance the
plasma half-life of SLNs.

1. Optimizing Particle Size for Enhanced Blood Circulation:

1. - Particle size and deformability crucial for clearance by sinusoidal
spleens in humans and rats.
2. - Size must be small or deformable to avoid splenic filtration at
interendothelial cell slits (IES).
3. - IES slit size rarely exceeds 200 to 500 nm, emphasizing the
importance of bulk properties.
4. - Retention at IES depends on factors such as size, sphericity, and
deformability.
5. - Engineered long-circulating particles ideally should not exceed 200
nm or should be deformable to bypass IES filtration.
6. - Larger particles, if rigid, may act as splenotropic agents and be
removed later.
7. - SLNs with a size below 200 nm contribute to increased blood
circulation, extending drug contact with the Blood-Brain Barrier (BBB)
and enhancing brain uptake [23,24,36].
8. - Table 1 provides details on achieved particle sizes with various lipid-
surfactant combinations and preparation methods.
This optimization strategy aims to maximize the circulation time of Solid Lipid
Nanoparticles (SLNs), ensuring prolonged drug interaction with the BBB for
enhanced brain uptake.

2. Surface Coating with Hydrophilic Polymers/Surfactants to Counter RES

Clearance:
1. High RES-mediated detection and clearance in the liver reduce drug
half-life.
 1. Colloidal carriers prone to opsonization, where interaction with plasma
proteins (opsonins) and macrophage membranes leads to clearance.
2. Prevention of RES removal crucial for increased availability at the target site.
3. RES recognition avoidance achieved through coating particles with
hydrophilic or flexible polymers and/or surfactants.
4. Coating serves as a protective shield, reducing opsonization and prolonging
the presence of particles in the bloodstream.
5. This strategy aims to enhance the circulation time of colloidal carriers,
facilitating their journey to the target site and improving drug delivery
efficacy [37].
Table 1 Literature survey of different lipid matrices and methods of preparing SLNs of
different drugs and the resulting particle size distribution and % encapsulation of the
SLNs .

Lipid Matrix Drug Preparation method Particle size[nm] surfactant

Reference

Figure 1: table 1

The RES-mediated detection and clearance process by the liver involves Mononuclear
Phagocyte System (MPS) cells. Opsonins, including complement proteins,
apolipoproteins, fibronectin, and Immunoglobulins (Igs), interact with specific
membrane receptors on monocytes and tissue macrophages, leading to recognition and
phagocytosis. Hydrophobic surfaces generally promote protein adsorption, and negative
surfaces activate the complement system and coagulation factors.
Shielding the hydrophobic character of nanoparticles is crucial for stearic stabilization.
This shielding creates a dense conformational cloud, reducing opsonization and
phagocytosis, as well as uptake by neutrophilic granulocytes. Consequently, this process
increases blood circulation time, enhancing bioavailability . Coating with polyethylene
glycol (PEG), a polymer of hydrophilic nature showed promising results. PEG has high
hydrophilicity, chain flexibility, electrical neutrality and lack of functional groups,
preventing it from interacting unnecessarily with the biological components. It has been
suggested that the PEG's with a molecular weight between 2000 to 5000 are necessary
to suppress plasma protein adsorption; further it has been observed that the thicker the
coat, the slower the clearance, and hence a better protection against liver uptake .
Enlarging the molecule/particle slows down kidney ultrafiltration and, thereby allowing
better accumulation into the brain and other permeable tissues by the passive enhanced
permeation and retention mechanism. It also provides protein shielding which reduces
proteolysis within the serum and tissues, and hinders immune surveillance of surface
epitopes. Pegylation improves the pharmacokinetic profile of molecules by reducing
opsonization, phagocytosis and clearance by the liver and reticulaoendothelial system.
Other hydrophilic molecules which have been tried are Brij 78, Poloxamer F68 and Brij
68. Cavalli et al. found that parenteral administration of nanoparticles of paclitaxel was
more bioavailable than an i.v. injection of the plain drug ., polysorbates are investigated
to have the highest potential to deliver the solid lipid nanoparticles to the brain[38].

Utilizing Ligands: Ligands or homing devices that specifically bind to surface epitopes
or receptors on the target sites can be coupled to the surface of long-circulating carriers.
Certain cancer cells overexpress receptors such as folic acid, LDL, and peptide receptors.
Attaching suitable ligands for these receptors onto nanoparticles enhances their
selectivity [63,64].

Allen et al. hypothesized that the presence of specific ligands on nanoparticles could
increase their retention at the BBB, leading to a higher nanoparticle concentration at the
BBB surface. However, they encountered challenges, including insufficient ligand coating
and a preference for ligand binding to blood thiamine transporters [].

Thole et al. reported improved interaction with brain endothelial cells and higher
intracellular accumulation of stearically stabilized colloidal particles coupled to
cationized albumin compared to bovine serum albumin [66]. Intact antibodies have also
been used as highly specific targeting agents, acting as Trojan horses for delivering
nanoparticles across the BBB. Peptidomimetic antibodies binding to BBB transcytosis
receptors are proposed for brain-targeted pegylated immunonanoparticles [38].

The use of nanoparticulate drug carriers combined with novel targeting principles, such
as "differential protein adsorption (Path Finder Technology)," has been explored. This
technology exploits blood proteins adsorbing onto the carriers' surface for targeting,
with Apolipoprotein E being a targeting moiety for delivering particles to the BBB
endothelials. These approaches could potentially enhance the brain targeting of SLNs
[2].

The Journey of Solid Lipid Nanoparticles after Oral Administration

Utilizing lipid nanoparticles in drug formulation presents an opportunity for improved

bioavailability, as illustrated in Figure 2, leading to more consistent drug levels in the
 bloodstream. These systems offer significant adaptability in shaping the drug release
pattern within the gastrointestinal tract (GIT). Additionally, they serve as a shield,
safeguarding vulnerable drug molecules, such as peptides, against chemical degradation
[23].

Figure 2: Fig. 1. Uncoated SLNs, SLN coated with hydrophilic polymers like polysorbates, SLN coated with
both hydrophilic polymer (like P.E.G.) and a specificuptake linker monoclonal antibodies/thiamine/glucose.
Available SLNs in general circulation immediately after oral administration. SLNs left after 1stmetabolism.
SLNs left after encounter with another RES organ “spleen”. Final S.L.N's made available to the CNS after
passing BBB. This figure shows the fate ofdifferent types of SLNs after oral administration. The SLN can bypass
the RES removal because of their small particle size, moreover their RES detection could befurther decreased
by providing a hydrophilic coat e.g. polysorbates, PEG, Poloxamer F 68, Brig 78. This will result in an
increased circulation time and thus higherchances to be taken up by the target organ. The nanoparticles
statistically keep on circulating until the hydrophilic coating is dissolved; when they are either removedby the
liver or are taken up by the target organ. The hydrophilic coating prevents their interaction with the blood
plasma proteins (opsonins) and thus with themembranes of macrophages. The binding of SLNs to the target site
e.g. the brain can be improved by placing certain ligands e.g. thiamine on to their surface, thesethiamine
ligands could bind to the thiamine receptors and gain access to the brain by receptor mediated transcytosis
Methods of preparation of solid lipid nanoparticles[39-42]

1. High pressure homogenization

A. Hot homogenization B. Cold homogenization
2. Ultrasonication /high speed homogenization
A. Probe ultrasonication B. Bath ultrasonication
3. Solvent evaporation
4. Solvent emulsification-diffusion method
5. Supercritical fluid method
6. Microemulsion based method

7. High-Pressure Homogenization (HPH):

High-pressure homogenization stands as a robust and effective technique, initially

employed in the production of Solid Lipid Nanoparticles (SLNs). Utilizing pressures
ranging from 100 to 2000 bar, high-pressure homogenizers propel a liquid through a
narrow gap, inducing high velocities exceeding 1000 Km/h. The resulting high shear
stress and cavitation forces contribute to breaking down particles into the submicron
range. Typically, 5-10% lipid content is employed, although investigations have explored
up to 40% lipid content.[41]

Types of HPH:

Hot Homogenization: Conducted above the lipid's melting point, resembling

emulsion homogenization. A pre-emulsion, consisting of the drug-loaded lipid melt and
an aqueous emulsifier phase, is created using a high-shear mixing device (Ultra-Turrax).
The final product's quality is significantly influenced by the pre-emulsion quality, with
desired droplet sizes in the range of a few micrometers. Higher temperatures generally
result in smaller particle sizes, albeit at the expense of accelerated drug and carrier
degradation. The homogenization step can be repeated multiple times, with caution due
to increased sample temperature. Nanoemulsion, transitioning to solid particles upon
cooling, is the primary product.

Cold Homogenization:Carried out with solid lipid, representing high-pressure

milling of a suspension. Precise temperature control is essential to maintain the lipid in a
solid state during homogenization. This technique addresses issues encountered in hot
homogenization, such as temperature-induced drug degradation, drug distribution into the
aqueous phase, and complexities in nanoemulsion crystallization. The process involves
solubilizing or dispersing the drug in the bulk lipid melt, followed by rapid cooling to
facilitate homogeneous drug distribution in the solid matrix. Low temperatures increase
lipid fragility, aiding particle comminution. Solid lipid microparticles are then dispersed
in a chilled emulsifier solution and subjected to high-pressure homogenization at or
below room temperature. Generally, cold homogenization results in larger particle
sizes and a broader size distribution compared to hot homogenization.

2. Ultrasonication and High-Speed Homogenization for SLN Preparation:

Solid Lipid Nanoparticles (SLNs) can be effectively prepared using ultrasonication

or high-speed homogenization techniques. For achieving smaller particle sizes, a
combination of both ultrasonication and high-speed homogenization may be necessary.
This approach helps in reducing shear stress, although it comes with certain drawbacks,
including the risk of potential metal contamination and physical instability, such as
particle growth during storage.[41]

Techniques:
Ultrasonication: Involves the use of a probe sonicator or bath sonicator. This method
contributes to the reduction of shear stress, aiding in the achievement of smaller particle
sizes. However, potential drawbacks include the risk of metal contamination and physical
instability over time.

High-Speed Homogenization: Utilizes high-speed homogenization techniques to

efficiently produce SLNs. This method is particularly effective in achieving the
desired particle size.

Combined Approach:
- The combination of ultrasonication and high-speed homogenization proves
beneficial for obtaining optimal particle sizes while mitigating shear stress. However,
it's essential to be mindful of potential challenges such as metal contamination and
physical instability, especially particle growth during storage.

These methods collectively offer flexibility in SLN preparation, allowing researchers

to tailor the technique based on specific requirements and constraints.

3.Solvent evaporation method

The lipophilic material is dissolved in a water-immiscible organic solvent (e.g.

cyclohexane) that is emulsified in an aqueous phase. Upon evaporation of the solvent,
nanoparticles dispersion is formed by precipitation of the lipid in the aqueous medium
by giving the nanoparticles of 25 nm mean size. The solution was emulsified in an
aqueous phase by high pressure homogenization. The organic solvent was removed from
the emulsion by evaporation under reduced pressure (40–60 mbar).[42]

4.Solvent emulsification diffusion method

The particles with average diameters of 30-100 nm can be obtained by this technique.
Voidance of heat during the preparation is the most important advantage of this technique.
In this technique lipid is, are generally dissolved in the organic phase in water bath at50
°C and used an acidic aqueous phase in order to adjust the zeta potential to form
coacervation of SLN, and then easy separation by centrifugation. The SLN
suspension was quickly produced. The entire dispersed system can then be
centrifuged and re- suspended in distilled water.

5. Supercritical fluid method

This is a relatively new technique for SLN production and has the advantage of
solvent- less processing. There are several variations in this platform technology for
powder and nanoparticle preparation. SLN can be prepared by the rapid expansion of
supercritical carbon dioxide solutions (RESS) method. Carbon dioxide (99.99%) was
the good choice as a solvent for this method.

6. Microemulsion based method

Gasco and colleagues innovatively devised techniques for Solid Lipid Nanoparticle
(SLN) preparation based on microemulsion dilution. This method involves stirring a
mixture at 65-70°C until an optically transparent blend is achieved. The blend typically
comprises a low-melting fatty acid (such as stearic acid), an emulsifier (polysorbate 20,
polysorbate 60, soy phosphatidylcholine, and sodium taurodeoxycholate), co-emulsifiers
(sodium monooctylphosphate), and water.

The process unfolds by dispersing the hot microemulsion into cold water (2-3°C)
under continuous stirring. The volume ratios between the hot microemulsion and cold
water typically range from 1:25 to 1:50. Crucially, the composition of the
microemulsion significantly influences the dilution process. Existing literature
suggests that the microemulsion already contains the droplet structure, obviating the
need for additional energy to achieve submicron particle sizes.

Gasco's approach draws parallels with Fessi's method, which involved producing
polymer particles by diluting polymer solutions in water. De Labouret et al. highlighted
the critical role of the velocity of distribution processes in determining particle size.
Notably, nanoparticles were successfully produced using solvents that rapidly distributed
into the aqueous phase (like acetone), while larger particle sizes resulted from more
lipophilic solvents.[41]

In lipid nanoparticle formation, hydrophilic co-solvents within the microemulsion play a

role analogous to acetone in polymer nanoparticle formation. This innovative technique
leverages the inherent structure within the microemulsion, offering a streamlined
process for achieving submicron particle sizes without the need for additional energy
input.[43]

7. Precipitation technique

Solid lipid nanoparticles can also be produced by a precipitation method which is

characterized by the need for solvents. The glycerides will be dissolved in an organic
solvent (e.g. chloroform) and the solution will be emulsified in an aqueous phase.
After evaporation of the organic solvent the lipid will be precipitated forming
nanoparticles
8. Solvent injection technique

This innovative method for Solid Lipid Nanoparticle (SLN) preparation offers several
advantages compared to other production techniques. Notably, it avoids the use of
pharmacologically acceptable organic solvents, making it a more environmentally
friendly option. The process is characterized by easy handling and rapid production,
eliminating the need for technically sophisticated equipment.

The technique is rooted in lipid precipitation from a dissolved lipid in a solution.

Here's an overview of the steps involved:

1.Dissolve the solid lipid in a water-miscible solvent (e.g., ethanol, acetone,

isopropanol) or a mixture of water-miscible solvents.
2.Inject the lipid-solvent mixture through an injection needle into a stirred
aqueous phase, which may or may not contain a surfactant.
3. The resulting dispersion is then filtered using filter paper to remove any excess
lipid.
4.The presence of an emulsifier within the aqueous phase plays a crucial role in
producing lipid droplets at the injection site and stabilizing SLN until solvent diffusion
is complete. This is achieved by reducing the surface tension between water and solvent.

In essence, this method represents a novel and efficient approach to SLN

preparation, offering benefits such as solvent sustainability, ease of operation, and
expedited production timelines without requiring sophisticated equipment.

9.Membrane contractor method

The present study investigates a new process for the preparation of SLN using a
membrane contactor, to allow large scale production. A schematic drawing of the process
is shown in Fig. 3. The lipid phase is pressed, at a temperature above the melting point of
the lipid, through the membrane pores allowing the formation of small droplets. The
aqueous phase circulates inside the membrane module, and sweeps away the droplets
forming at the pore outlets. SLN are formed by the following cooling of the preparation
to room temperature. The influence of process parameters (aqueous phase and lipid phase
temperatures, aqueous phase cross-flow velocity and lipid phase pressure, membrane
pore size) on the SLN size and on the lipid phase flux is investigated. Also, vitamin E
loaded SLN are prepared, and their stability is demonstrated .

Secondary production step

Sterlisation

Sterilization of the nanoparticles is desirable for parenteral administration and

autoclaving which is applicable to formulations containing heat-resistant drugs. Effects
of sterilization on particle size have been investigated and it was found to cause a distinct
increase in particle size. Schwarz investigated the impact of different sterilization
techniques (steam sterilization at 121°C (15 min) and 110°C (15min), g-sterilization) on
SLN characteristics. The results indicate that particle aggregation might occur as a result
of the treatment. Critical parameters include sterilization temperature and SLN
composition. The correct choice of the emulsifier is of significant importance for the
physical stability of the sample at high temperatures. Increased temperatures will affect
the mobility and the hydrophilicity of all emulsifiers to a different extent. Steam
sterilization will cause the formation of an o/w-emulsion due to the melting of the lipid
particles. Solid particles are formed after recrystallization. Schwarz found that lecithin is
a suitable surfactant for steam sterilization, because only a minor increase in particle size
was observed. Experiments conducted by Freitas indicated that lowering of the lipid
content (to 2%) and surface modification of the glass vials prevent the particle increase
to a large extent and avoid gelation. Additionally, it was observed by Freitas that purging
with nitrogen showed a protective effect during sterilization. That observation suggests
that chemical reactions could contribute to particle de-stabilization. ỵirradiation could be
an alternative method to steam sterilization for temperature sensitive samples .

Lyophilisation

Lyophilization is a promising way to increase the chemical and physical stability over
extended periods of time. Lyophilization had been required to achieve long term
stability for a product containing hydrolysable drugs or a suitable product for per -oral
administration. Transformation into the solid state would prevent the Oswald ripening
and avoid hydrolytic reactions. In case of freeze drying of the product, all the lipid
matrices used, form larger solid lipid nanoparticles with a wider size distribution due to
presence of aggregates between the nanoparticles. The conditions of the freeze drying
process and the removal of water promote the aggregation among SLNs. An adequate
amount of cryoprotectant can protect the aggregation of solid lipid nanoparticles during
the freeze drying process .

Spray drying

It is an alternative and cheaper technique to the lyophilization process. This recommends

the use of lipid with melting point more than 70oC. The best results were obtained with
SLN concentration of 1% in a solution of trehalose in water or 20% trehalose in ethanol-
water mixture. The addition of carbohydrates and low lipid content favor the preservation
of the colloidal particle size in spray drying. The melting of the lipid can be minimized
by using ethanol–water mixtures instead of pure water due to cooling leads to small and
heterogeneous crystals, the lower inlet temperatures.

Determination of incorporated drug (Loading Efficiency and

Entrapment Efficiency) .

Accurately measuring the drug content incorporated in Solid Lipid Nanoparticles

(SLNs) is crucial as it significantly impacts release characteristics. The quantification of
drug
encapsulation per unit weight of nanoparticles involves separating free drug and solid
lipids from the aqueous medium. This separation can be achieved through methods
such as centrifugation, filtration, or gel permeation chromatography.

In centrifugation filtration, filters like U'trafree →MC (Milipore) or Utrasart→10

(Sartorious) are employed in conjunction with classical centrifugation techniques. The
degree of encapsulation can be indirectly assessed by determining the drug
concentration in the supernatant after centrifugation filtration/ultracentrifugation of the
SLN suspension. Alternatively, dissolution of the sediment in an appropriate solvent
followed by analysis can provide information on encapsulation.

Standard analytical techniques such as UV spectrophotometry, spectrofluorophotometry,

high-performance liquid chromatography, or liquid scintillation counting can be utilized
for drug assay. Gel permeation chromatography involves using Sephadex® and
Sepharose® gels to remove free drug from SLN preparations. The column is
preliminarily calibrated using SLNs and free drug. SLN preparations are then applied to
the column, washed with a suitable buffer, and fractions containing SLNs are collected
for analysis of the actual drug content after dissolution/extraction with an appropriate
solvent.
Another approach involves determining drug content directly in SLNs by extracting
the drug with a suitable solvent under optimized conditions and subsequently
analyzing the aqueous extract. This meticulous measurement is essential for
understanding the drug release dynamics of SLNs.[45,47]

In vitro and ex vivo methods for the assessment of drug release from SLN .

A large number of drugs including very hydrophilic molecules have been postulated to
be incorporated into SLN.
Various methods used to study the in vitro release of the drug are:
• Side by side diffusion cells with artificial or biological membrane20.
• Dialysis bag diffusion technique.
• Reverse dialysis bag technique .
• Agitation followed by ultracentrifugation or centrifugal ultra filtration.

In vitro drug release

Dialysis tubing

In vitro drug release could be achieved using dialysis tubing. The solid lipid nanoparticle
dispersion is placed in pre - washed dialysis tubing which can be hermetically sealed.
The dialysis sac then dialyzed against a suitable dissolution medium at room
temperature; the samples are withdrawn from the dissolution medium at suitable
intervals, centrifuged and analyzed for the drug content using a suitable analytical
method.

Reverse dialysis
In this technique a number of small dialysis sacs containing 1 mL of dissolution
medium are placed in SLN dispersion. The SLN’s are then displaced into the medium.

Ex vivo model for determining permeability across the gut

Ahlin et al. demonstrated the passage of enalaprilat SLN’s across rat jejunum. In short
the rat jejunum (20 – 30 cm distal from the pyloric sphincter) was excised from the rats
after sacrificing the animal used for the study. Qing Zhi Lu et al. excised 10 cm long
segments of duodenum (1 cm distal to pyloric sphincter); jejunum (15 cm to pyloric
sphincter), ileum (20 cm proximal to cecum) and colon (2 cm distal to cecum) were
immediately cannulated and ligated on both sides used for their permeability studies .

Ex Vivo Model for Assessing Antitumor Drug Permeability Across the Blood-
Brain Barrier (BBB):[48]

Tissue Source:
- Obtain fresh rodent brain tissue.
- Ensure ethical compliance.

-Brain Tissue Preparation:

- Slice into thin sections.
- Maintain in physiological buffer.

BBB Integrity Confirmation:

- Assess BBB integrity using TEER( Transendothelial Electrical Resistance)
measurement.

Drug Application:
- Apply antitumor drugs to brain tissue slices.
- Maintain physiological conditions.

-Sampling and Analysis:

- Collect samples at specific intervals.
- Utilize HPLC for drug concentration analysis.

Permeability Measurement:
- Calculate permeability coefficients.
- Assess drug penetration kinetics.

Controls and Validation:

- Include positive and negative controls.
- Perform duplicate experiments.

-Data Interpretation:
- Analyze data for permeability characteristics.
- Consider drug properties and tissue factors.
-Optimization:
- Adjust parameters for improved relevance.
- Optimize drug concentration and exposure time.

Actual Study:
Assessing the BBB permeability of [Antitumor Drug X] in rodent brain tissue slices
to understand its potential for treating brain tumors.[48]

Analytical methods for characterizing SLNs

Particle Size:

Particle size analysis is crucial for assessing the efficacy and stability of Solid Lipid
Nanoparticles (SLNs). Techniques such as Dynamic Light Scattering (DLS) are
commonly employed for determining the average size and size distribution of SLNs in
a colloidal suspension. DLS measures the Brownian motion of particles in a solution,
providing information on their hydrodynamic diameter[37].

Molecular Weight:

The molecular weight of SLNs can be determined through various methods, and Gel
Permeation Chromatography (GPC) is frequently used in this context. GPC separates
and analyzes particles based on their size and molecular weight, offering insights into the
distribution of molecular sizes within the SLN formulation.[43]

Surface Element Analysis:

Surface element analysis is essential for understanding the composition and chemistry of
the outer layer of SLNs. Techniques like X-ray Photoelectron Spectroscopy (XPS) can
be employed to analyze the elemental composition of the SLN surface. XPS provides
information on the elements present on the nanoparticle surface and their respective
concentrations.[44]

Density:
Density, a critical parameter for SLN characterization, can be determined using
techniques like the Archimedes' principle. Archimedes' principle involves measuring the
buoyant force experienced by SLNs immersed in a fluid, allowing for the calculation of
their density. This information contributes to a comprehensive understanding of the SLN
formulation.[46]

Molecular Analysis:
For molecular analysis of SLNs, techniques such as Nuclear Magnetic Resonance (NMR)
spectroscopy can be employed. NMR provides insights into the molecular structure,
allowing researchers to verify the composition of lipid components within the
nanoparticles. This analysis aids in confirming the integrity of the lipid matrix
and assessing any potential interactions or modifications.

Each of these characterization techniques plays a unique role in providing detailed

information about different aspects of SLNs, contributing to the overall assessment
of their quality, stability, and suitability for drug delivery applications.

Conclusions:

Solid Lipid Nanoparticles (SLNs) present a promising and innovative approach for
delivering molecules to the brain, potentially addressing challenges related to solubility,
permeability, and toxicity of certain drug molecules. This method offers advantages over
conventional invasive brain drug delivery approaches. The high physical stability of
SLNs adds to their appeal.

Unlike polymeric micro or nanoparticles, which face limitations due to cytotoxicity and
lack of large-scale production methods, SLNs utilize solid lipids known from oral drug
delivery. The simplicity and cost-effectiveness of large-scale production using techniques
like high-pressure homogenization or microemulsion contribute to the widespread
adoption of SLNs by the pharmaceutical industry, as seen with companies like Skye
Pharma and Vector Pharma AG.
SLNs accommodate both lipophilic and hydrophilic molecules, supporting various
administration routes, making them a versatile delivery system. This technology is
expected to revolutionize drug delivery, encompassing analgesics, antitubercular,
anticancer, antiaging, antianxiety, neuroleptics, antibiotics, and antiviral agents into
the brain.
Although our understanding of the molecular biology and genomics of the Blood-Brain
Barrier (BBB) is evolving, there's a need to complete the knowledge base on carrier
and receptor-mediated transport systems at the BBB. This information is crucial for
developing targeted brain drug delivery strategies. Formulating neuroactive drugs into
SLNs is anticipated to enhance their pharmacokinetic profiles, allowing for increased
concentrations in the brain. Further modifications like pegylation may be necessary to
optimize CNS delivery of therapeutics. The continuous exploration of these
advancements is vital for the future of effective brain drug delivery.

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