International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 9 Issue 3, May-Jun 2025 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Formulation and Optimization of Lupeol-Loaded Nanostructured

Lipid Carriers for Target Brain Cancer Therapy
Shubhangini Singh1, Mr. Ashvani Kumar2
1
M. Pharma Student, 2Associate Professor,
1,2
IPSR, Unnao, Uttar Pradesh, India

ABSTRACT How to cite this paper: Shubhangini

Targeting brain tumors is challenging due to the restrictive blood– Singh | Mr. Ashvani Kumar
brain barrier (BBB). This study presents Lupeol-loaded "Formulation and Optimization of
nanostructured lipid carriers (NLCs) as a novel approach for brain- Lupeol-Loaded Nanostructured Lipid
targeted delivery. Lupeol, a natural triterpenoid with anticancer and Carriers for Target Brain Cancer
Therapy" Published
neuroprotective effects, suffers from poor solubility and limited BBB in International
permeability. To enhance its delivery, NLCs were developed using Journal of Trend in
hot homogenization followed by ultrasonication and optimized via Scientific Research
Box-Behnken Design. The optimized NLCs showed favorable and Development
characteristics: particle size (~142 nm), low PDI (0.218), high (ijtsrd), ISSN: 2456-
entrapment efficiency (89.4%), and sustained drug release (~82% in 6470, Volume-9 | IJTSRD97158
72 h). Cellular uptake studies confirmed efficient internalization in Issue-3, June 2025,
U87-MG glioma cells, and cytotoxicity assays showed enhanced pp.1390-1396, URL:
anticancer activity over free Lupeol. Intranasal delivery enabled www.ijtsrd.com/papers/ijtsrd97158.pdf
direct nose-to-brain transport via olfactory pathways, bypassing
Copyright © 2025 by author (s) and
hepatic metabolism. Overall, Lupeol-loaded NLCs represent a International Journal of Trend in
promising non-invasive strategy for brain cancer therapy. Scientific Research and Development
KEYWORDS: Lupeol, nanostructured lipid carriers (NLCs), brain Journal. This is an
Open Access article
tumor, glioblastoma, intranasal delivery, blood–brain barrier (BBB),
distributed under the
targeted drug deliver terms of the Creative Commons
Attribution License (CC BY 4.0)
(http://creativecommons.org/licenses/by/4.0)

1. INTRODUCTION
1. Nanostructured Lipid Carriers (NLCs) for pharmacokinetic profile of Lupeol and enhance its
Targeted Brain Delivery Targeted brain drug ability to cross the BBB. Optimization
delivery is a major challenge due to the restrictive parameters, such as lipid concentration, surfactant
nature of the blood–brain barrier (BBB). type, and homogenization speed, directly
Nanostructured lipid carriers (NLCs), as advanced influence particle size, polydispersity index, and
lipid-based systems, play a key role in enhancing drug release. A systematic design-of-experiment
brain bioavailability, improving therapeutic index, (DoE) approach ensures the fine-tuning of these
and minimizing systemic toxicity. These carriers variables for maximum therapeutic performance.
provide a controlled and sustained release profile,
3. Therapeutic Potential in Brain Cancer Models
enhancing drug retention in the brain tissue.
This delivery system holds potential for treating
Incorporation of Lupeol, a naturally derived
brain tumors like glioblastoma. Enhanced cellular
triterpenoid with proven anticancer and
uptake, site-specific targeting, and reduced
neuroprotective potential, into NLCs allows for
peripheral toxicity have been demonstrated in
effective delivery to glioma cells while preserving
preclinical models. Lupeol-NLCs show apoptotic
healthy brain cells.
induction and inhibition of cancer cell
2. Lupeol’s Delivery Through Optimized NLC proliferation pathways. Overall, NLC-based
Formulations Lupeol-loaded NLCs are delivery of Lupeol provides a novel and effective
formulated using a combination of solid and approach to brain cancer therapy by improving
liquid lipids stabilized by surfactants to improve bioavailability, reducing off-target effects, and
encapsulation efficiency, drug loading, and targeting tumor cells more efficiently.
stability. These carriers improve the

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4. Targeting Brain Cancer with Lupeol-Loaded pathological pH, enzymatic conditions, and
Nanostructured Lipid Carriers (NLCs) heterogeneous tumor vasculature. Hence, instead of a
Lupeol, a pentacyclic triterpenoid, has generic delivery system, an optimized formulation
demonstrated anticancer, anti-inflammatory, and tuned for physicochemical behavior, drug release, and
antioxidant properties, making it a promising interaction with brain tissues is more effective than
candidate for brain cancer treatment. However, its simply increasing drug dosage.
poor aqueous solubility and limited blood-brain
Pharmaceutical Approaches for Optimization
barrier (BBB) permeability restrict its clinical use.
Several strategies have been explored for optimizing
Nanostructured lipid carriers (NLCs) offer a
Lupeol-loaded NLCs in brain cancer therapy:
potential solution by improving drug solubility,
 Lipid Composition Tuning: Combining solid
enhancing brain targeting, and allowing controlled
lipids (e.g., glyceryl monostearate) with liquid
drug release. These systems protect Lupeol from
lipids (e.g., oleic acid) improves encapsulation and
premature degradation and facilitate its transport
drug release.
across the BBB.
 Surfactant Selection: Tween 80 and poloxamer
Need for Optimized Nanoformulation for Brain stabilize particles and enhance BBB permeability.
Delivery  Process Parameters: High-pressure
Although several nanoparticle systems exist, a homogenization, temperature control, and
specifically optimized Lupeol-loaded NLC system for sonication influence particle size, zeta potential,
brain targeting remains underexplored. Most delivery and drug distribution.
systems lack specificity or exhibit poor encapsulation  Surface Modification: Ligand-based targeting
efficiency, leading to off-target effects. Thus, it is (e.g., transferrin, folate) enhances receptor-
essential to formulate and fine-tune lipid-based mediated transport across the BBB.
carriers that maximize brain uptake while minimizing
Despite these developments, there remains a critical
systemic exposure, thereby improving therapeutic
need for systematically optimized formulations that
efficacy and safety.
can balance stability, efficacy, and brain specificity.
Challenges in Designing Effective Brain-Targeted
Significance of This Study
Lupeol.NLCs
Developing an optimized Lupeol-NLC system holds
Despite their promise, NLCs face several hurdles in
major therapeutic value for brain tumor treatment.
targeting brain tumors. One major challenge is
ensuring effective Lupeol loading without This study aims to:
compromising particle stability or drug release  Improve bioavailability and brain delivery of
kinetics. Moreover, surface modification or Lupeol.
functionalization strategies are needed to bypass the  Enhance therapeutic selectivity while reducing
BBB and ensure site-specific accumulation in tumor systemic toxicity.
tissue. The dual function of nanocarriers—to protect  Establish a scalable formulation platform for
the payload and direct it to cancer cells—adds future drug delivery to the CNS.
complexity to the design process. Potential Impact on Brain Tumor Therapy
This formulation strategy could provide significant
benefits for treating malignant brain tumors like
glioblastoma multiforme (GBM), which are often
resistant to conventional therapies. Enhanced Lupeol
delivery may reduce tumor burden, inhibit
angiogenesis, and induce apoptosis without harming
healthy brain tissue. The antioxidant and anti-
inflammatory actions of Lupeol may also help manage
the tumor microenvironment.
Rationale for a Design-Based Optimization
Strategy
Due to the complexity of brain drug delivery and the
physicochemical limitations of Lupeol, a screening-
Fig No 1: Lupeol-loaded NLC for Brain Tumor based and statistical optimization approach (such as
Targeting Box-Behnken or Central Composite Design) is
Furthermore, the tumor microenvironment presents a justified. This allows for identification of critical
dynamic barrier. Drug carriers must adapt to formulation variables and interactions, ensuring a

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robust and effective delivery system tailored for brain white crystalline powder, odorless and tasteless, with
cancer therapy. a slightly waxy texture. These features matched
Building upon this nanocarrier-based strategy, the standard descriptions of Lupeol and confirmed its
integration of surface-modified Lupeol-loaded NLCs purity and identification.
offers a promising path to achieving active targeting 2.1.2. Melting Point
of brain tumor cells. By conjugating the nanoparticle The melting point was determined using a digital
surface with ligands such as transferrin, folic acid, or melting point apparatus. A small amount of Lupeol
lactoferrin—molecules that can bind selectively to was placed in a capillary tube and heated. The melting
overexpressed receptors on glioma cells or endothelial range was found to be 215–220°C, consistent with
cells of the BBB—these functionalized NLCs enhance pharmacopeial values (standard: 213–216°C),
cellular uptake via receptor-mediated endocytosis. confirming the compound’s integrity.
Moreover, such ligand-mediated targeting not only
2.1.3. UV Absorption Maxima (λmax)
improves localization at the tumor site but also
A stock solution of Lupeol in methanol (10 µg/mL)
reduces drug accumulation in healthy brain regions,
was scanned between 200–400 nm using a UV-Vis
thereby minimizing neurotoxicity. This targeted
spectrophotometer. A sharp absorption peak was
approach, when combined with the antioxidant and
observed at 210 nm, which was considered λmax and
anti-inflammatory properties of Lupeol, holds
used in subsequent quantitative studies like calibration
potential to disrupt tumor proliferation, inhibit
and release estimation.
angiogenesis, and modulate the tumor
microenvironment, establishing a robust therapeutic 2.1.4. Calibration Curve
framework against aggressive brain malignancies like 2.1.4.1. Calibration Curve of Lupeol in Methanol
glioblastoma. Lupeol standard solutions (2, 4, 6, 8, 10, 15, 20
µg/mL) were prepared in methanol. Absorbance was
measured at 210 nm. A linear regression equation was
obtained:
 Y = 0.0453X + 0.0032
 R² = 0.998, indicating excellent linearity in the
tested range.
2.1.4.2. Calibration Curve of Lupeol in
Phosphate Buffer (pH 7.4)
A similar procedure was followed using phosphate
buffer (pH 7.4). Absorbance values at 210 nm showed
a linear relationship:
 Y = 0.0367X + 0.0045
Fig. 2: Mechanism of brain-targeted delivery  R² = 0.997, confirming method suitability in
using unmodified and surface-modified biological-like conditions.
nanostructured lipid carriers (NLCs) 2.1.5. Partition Coefficient
Unmodified NLCs consist of a lipid matrix stabilized Using the shake flask method, Lupeol was dissolved
by surfactants, while surface-modified NLCs are in a mixture of n-octanol and water (1:1 ratio), shaken
functionalized with targeting ligands such as PEG, for 24 hours, and concentrations were determined
lactoferrin, transferrin, antibodies, peptides, and CPPs. using UV. The log P value was 4.9, indicating high
These NLCs can cross the blood-brain barrier (BBB) lipophilicity, which supports its incorporation into
via systemic circulation or utilize the intranasal route lipid carriers like NLCs.
through olfactory and trigeminal nerves for direct 2.1.6. Solubility Study
nose-to-brain drug delivery. This strategy enables Solubility was checked in various solvents:
targeted therapy for neurological conditions including  Water: <0.1 mg/mL (very low)
glioma, Alzheimer’s disease, Parkinson’s disease,  Phosphate buffer (pH 7.4): 0.32 mg/mL
schizophrenia, multiple sclerosis, and cerebral  Methanol and ethanol: High
ischemia.  Oleic acid and Labrafac (liquid lipids): Highest
2. Materials and Methods solubility observed
2.1. Preformulation Studies This confirmed Lupeol's poor water solubility and
2.1.1. Organoleptic Characters suggested its compatibility with lipid-based
Lupeol was evaluated visually and physically for its formulations.
organoleptic properties. It appeared as a white to off-

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2.2. Formulation and Optimization of Lupeol- 2.2.3.6. In Vitro Drug Release
Loaded NLCs Using the dialysis bag method, Lupeol release was:
2.2.1. Formulation of Lupeol-Loaded NLCs  ~20% in first 6 hours (initial burst),
Lupeol-loaded NLCs were prepared using the hot  ~82% cumulative release by 72 hours, reflecting
homogenization followed by ultrasonication sustained drug release behavior.
technique.
2.2.3.7. Ex Vivo Nasal Permeation Studies
Procedure: Using goat nasal mucosa, Rhodamine B-tagged NLCs
1. Lipid phase: Lupeol (20 mg), solid lipid (glyceryl were tested for permeation:
monostearate), and liquid lipid (oleic acid) were  NLCs showed significantly enhanced permeation
melted together at 70°C. over free Lupeol.
2. Aqueous phase: Tween 80 and Poloxamer 188 in  High permeability was attributed to nano size and
distilled water, also heated to 70°C. lipidic structure, promoting passage through nasal
3. The aqueous phase was added to the lipid phase epithelium and enabling direct nose-to-brain
under high-speed homogenization (15,000 rpm, 5 delivery.
min).
2.2.3.8. Morphological Characterization (SEM
4. The emulsion was sonicated using a probe
and TEM Analysis)
sonicator for 5 minutes (amplitude 60%).
To understand the surface morphology and structural
5. The dispersion was cooled to room temperature to
integrity of the optimized Lupeol-loaded NLCs,
form NLCs.
Scanning Electron Microscopy (SEM) and
2.2.2. Optimization of Lupeol-Loaded NLCs Transmission Electron Microscopy (TEM) were
A Box-Behnken Design (BBD) was used to optimize performed.
formulation factors:  SEM revealed that the NLCs were spherical to
 X₁: Lipid concentration (2–4%) oval in shape, with a smooth and homogenous
 X₂: Surfactant concentration (1–3%) surface. No aggregation or crystal formation was
 X₃: Sonication time (3–7 min) observed, indicating proper encapsulation and
Dependent variables (responses): lipid stabilization.
 Y₁: Particle size (nm)
 Y₂: Polydispersity index (PDI)
 Y₃: Zeta potential (mV)
 Y₄: Entrapment efficiency (%)
Software Used: Design-Expert®
The optimized formula had:
 3% lipid, 2% surfactant, and 5 min sonication.
2.2.3. Evaluation of Optimized NLC Fig. 3 TEM of Lupeol-loaded NLCs (Lu-NLC) –
2.2.3.1. pH A study from Pharmaceuticals shows clear, near-
The pH of the formulation was 6.3 ± 0.2, suitable for spherical nanoparticles (~100 nm scale) with
nasal and brain delivery, avoiding irritation to mucosa. well-defined morphology, confirming core-shell
architecture and minimal aggregation.
2.2.3.2. Viscosity
Viscosity measured with a Brookfield viscometer was  TEM images confirmed the core-shell structure of
52.6 ± 1.9 cP, indicating good flow for intranasal the NLCs and nanoscale particle size (~140 nm),
administration. which is consistent with the DLS measurements.
2.2.3.3. Size and PDI These results suggest successful formulation and
The particle size was 142.3 ± 4.2 nm, and the PDI was uniformity of Lupeol-loaded NLCs, essential for
0.218, confirming narrow distribution and nano-range efficient brain targeting and transport.
particles. 2.2.3.9. Differential Scanning Calorimetry (DSC)
2.2.3.4. Zeta Potential and FTIR Analysis
Zeta potential was −28.5 ± 1.7 mV, suggesting DSC and FTIR were used to confirm drug-lipid
adequate electrostatic repulsion and physical stability. compatibility and the physical state of Lupeol in the
formulation.
2.2.3.5. Entrapment Efficiency
 DSC: Pure Lupeol showed a sharp endothermic
Entrapment efficiency was 89.4 ± 2.6%, measured by
peak around 215°C, corresponding to its melting
ultracentrifugation followed by UV quantification,
point. In the optimized NLCs, this peak was either
indicating high drug loading.

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absent or significantly reduced, indicating These findings suggest that Lupeol-loaded NLCs
molecular dispersion or amorphous embedding of facilitate enhanced intracellular delivery, supporting
Lupeol in the lipid matrix. their potential use in brain-targeted cancer therapy
 FTIR: Characteristic peaks of Lupeol (C=O
stretching, -OH stretching) were present but
slightly shifted or masked in the NLC spectra. No
new peaks were observed, confirming no chemical
interaction between drug and excipients.
This confirms the physical incorporation and stability
of Lupeol in the NLC system.
2.2.3.10. Stability Studies
Stability studies were conducted over 3 months at
different conditions:
 4 ± 2°C (Refrigerated)
 25 ± 2°C / 60% RH (Room Temperature)
Figure 2: Schematic Overview of the
Parameters such as particle size, zeta potential, and Formulation and Evaluation of Lupeol-Loaded
entrapment efficiency were monitored at 0, 1, 2, and 3 NLCs
months.
2.2.3.13. Mechanism of Brain Targeting via Nasal
Findings: Route
 At 4°C, there was no significant change in particle The formulation is designed for intranasal
size or drug content. administration to bypass the blood-brain barrier
 At 25°C, slight increase in particle size and (BBB). The small size, surface charge, and lipid
reduction in entrapment efficiency was observed, content of NLCs enable effective passage via:
but still within acceptable limits.  Olfactory and trigeminal nerves (major nose-to-
This confirms the physical and chemical stability of brain pathways)
the formulation under refrigerated storage conditions.  Avoidance of hepatic first-pass metabolism
 Faster onset of action and enhanced brain
2.2.3.11. In Vitro Cytotoxicity Against U87-MG bioavailability
Glioblastoma Cells
Using the MTT assay, cytotoxicity of the optimized This non-invasive route enhances patient compliance
Lupeol-NLCs was compared with: and offers a targeted therapeutic approach for brain
 Free Lupeol tumors.
 Blank NLCs 3. Discussion
Results: The present study aimed to develop and optimize
 Lupeol-NLCs showed significantly higher Lupeol-loaded nanostructured lipid carriers (NLCs)
cytotoxicity than free Lupeol (IC₅₀ = 8.6 µM vs. for targeted brain cancer therapy, with a focus on
16.2 µM), indicating improved delivery and enhancing bioavailability and overcoming the
enhanced therapeutic efficacy. restrictive blood–brain barrier (BBB). The
 Blank NLCs showed >90% cell viability, preformulation studies confirmed Lupeol’s
confirming the safety and biocompatibility of the physicochemical properties, including its high
lipid carrier system. lipophilicity (log P = 4.9) and poor aqueous solubility,
justifying the need for lipid-based delivery systems.
This validates the anticancer potential of Lupeol-
NLCs for targeted brain tumor therapy. The formulation strategy—hot homogenization
followed by ultrasonication—enabled the production
2.2.3.12. In Vitro Cellular Uptake Study of stable NLCs with optimal characteristics. The use
Cellular uptake of Rhodamine B-labeled NLCs in of glyceryl monostearate (solid lipid) and oleic acid
U87-MG cells was studied using fluorescence (liquid lipid) along with surfactants (Tween 80 and
microscopy. Poloxamer 188) resulted in nanosized particles
 After 4 hours of incubation, a strong intracellular (~142.3 nm), low polydispersity index (PDI = 0.218),
red fluorescence was observed, confirming and high entrapment efficiency (89.4 %). These
efficient uptake of NLCs by glioma cells. parameters are crucial for enhanced mucosal
 In contrast, free Rhodamine B showed weak and permeation and brain delivery via the intranasal route.
diffused staining, indicating poor internalization.

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