Drug delivery – By Menna Hazem – From dr Abdulhakeem powerpoint and record Lec 7

Solid nanoparticles
Solid constructs in the nanometer range

Manufacturing method
(Top-Down approach) (Bottom-Up approach).
Size reduction of particles (e.g. by milling) Molecular agglomeration (e.g. by precipitation methods)
to within the nanoparticle range to form nanoparticles
Used to prepare drug particles in the nanosize more commonly used to prepare nanoparticle carriers
range where there is no carrier material added in which drug is loaded.

bottom‫ طريقة الـ‬، ‫ بتكون حاجة كبيرة بطحنها ل حجم النانو‬top‫طريقة الـ‬
‫ واكبرها بيها للنانو‬carrier ‫بتكون حاجة أصغر من النانو بجيب‬

Nanosized drug particles and drug nanocrystals Problem of nanosized drug particles
Reducing drug particles to within the nanosize Due to their high surface area and subsequent high
range → ↑ total area of the system → ↑ dissolution interfacial energy tend to be unstable and prone to
and bioavailability of drugs delivered by the oral particle aggregation.
route → The use of nanosized drug particles in oral bulk ‫ وبتكون عايزة تتجمع مع بعضها تاني وتعمل‬unstable ‫الحاجات الصغيرة دي بتكون‬
drug delivery can also avoid variations in drug To reduce this problem, surface active agents can be
bioavailability caused by the fed/ fasted state used, as in the case of NanoCrystal Technology,
of a patient. developed by Elan Corporation.
‫الصيام للمريض‬/‫تجنب االختالفات ف وصول الدواء للدم الناجمة عن حالة التغذية‬

What is nanocrystals
• NanoCrystals are prepared from 100% drug with
no carrier, and stabilizers (non-ionic and
anionic surfactants) are added during the size-
reduction process to improve stability.
• Within nanoparticle system, drug can be either
crystalline or amorphous.
• The small particle size, increase dissolution.
• For oral delivery, nanocrystals are normally
formulated into tablets or capsules.

• There are several drug nanoparticle products on the market which exploit this NanoCrystal Technology
Product Attributes Uses
• oral capsule form of the poorly soluble drug, Aprepitant, which is Treatment of nausea
Emend® only absorbed in upper GIT. and vomiting
(Aprepitant) • Therefore, the rapid dissolution offered by the nanocrystals, associated with
supports fast absorption and increased bioavailability. chemotherapy
• oral tablet of the poorly soluble drug sirolimus which is an
Rapamume® immunosuppressant.
immunosuppressant
(Sirolimus) • oral tablet offers higher bioavailability and can be more user
friendly compared to a liquid product
• Generally, fenofibrate uptake is from the gut lumen region therefore bioavailability is
TriCor ®
influenced by the patient’s fed/non-fed state.
(Fenofibrate) • By formulating as nanocrystals, the lipophilic drug has improved solubility therefore
uptake of the drug is not influenced by solubilization of the drug in food components.

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Drug delivery – By Menna Hazem – From dr Abdulhakeem powerpoint and record Lec 7

Solid polymeric nanoparticles

In addition to their production by size reduction of drug particles, solid nanoparticles can be formed from
polymers.
1- with the drug incorporated within the polymer matrix
2- or associated onto the particle surface.
As such, the delivery system can be loaded with a wide range of drugs (e.g. water-soluble and low-solubility
drugs, small and large molecular weight drugs) and can offer protection to the drug.

Role of polymer
• Incorporation of the drug into solid polymeric nanoparticles also allows for modified drug biodistribution
as the drug pharmacokinetic profile will be dictated by the properties of the nanoparticle attributes rather
than those of the drug.
• In terms of drug delivery, the main areas in which polymeric nanoparticles are being considered is for their
ability to promote passive targeting of drugs to tumor sites via the EPR effect.
‫ ف بالتالي خليته موجود في الدم فترة أطول‬phagocytosis ‫ بتاعي ويعمله‬drug‫ إنه يتعرف على الـ‬immune system‫البوليمر بيمنع الـ‬

Polymeric nanoparticles are generally formulated from

natural polymer synthetic polymers
chitosan 1- poly(lactide-co-glycolide) (PLGA)
2- polylactic acid (PLA)
3- polycaprolactone (PCL)

PLGA the commonly used one due to:

1- Biodegradable
2- Biocompatible (not cause immune response)
3- Its MWt can be controlled to provide sustained drug release

Stealth’ nanoparticles
• the surface coating of PEG to these nanoparticles produces so
called ‘stealth’ nanoparticles with the hydrated PEG surface coating
prohibiting protein and antibody binding, thereby reducing
recognition and clearance from the circulation.
‫ بيه بالتالي بطول مدة بقاؤه في الدم‬Antibody‫ بمنع ارتباط الـ‬PEG ‫لما بحط‬
• By increasing plasma circulation time of the polymeric
nanoparticles, this supports their accumulation at sites of leaky
vasculature including tumor sites.
• To formulate these ‘stealth’ systems, PEG-PLGA copolymers are often employed.
• Alternatively, active targeting of these systems can be achieved by the attachment of targeting groups to the
nanoparticles.
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Drug delivery – By Menna Hazem – From dr Abdulhakeem powerpoint and record Lec 7

Solid-lipid nanoparticles
‫ له مواصفات معينة‬lipid ‫ بستخدم‬polymer ‫بدل ما بستخدم‬
• Nanoparticles made from solid (high melting point) lipids dispersed in an aqueous phase.
• solid-lipid nanoparticles can be used as drug delivery systems with the drug being incorporated within the
lipid matrix of the particle or by attaching the drug to the lipid nanoparticle surface.

Examples of lipids used

1- solid triglycerides,
2- saturated phospholipids
3- fatty acids which are well tolerated by the body

Methods of dispersion of drug in lipids

Matrix Drug enriched core Drug enriched shell

Rigid matrix Gel matrix • Provide controlled release. • Provide immediate release
provide high provide lower • The shell is degraded in • Degradation of matrix not
degree of degree of plasma. important
controlled drug controlled drug
release release

• Due to their composition, they are sometimes described as solidified o/w

emulsions in which the oil globule is replaced by solidified lipid.
• Lipid particles normally have a size greater than 50 nm and can be
prepared on a large-scale by homogenization to disperse the lipid into an
aqueous environment.
• Solid lipid nanoparticle dispersions have been developed for parenteral, oral, ocular, dermal and cosmetic
applications.
• PEG coating of these systems has been shown to passively target tumor sites via the EPR effect
• To actively target cancer cells, covalent coupling of targeting groups such as ferritin or galactose to the
lipids used in the formulation has been investigated
• Currently, there are a range of cosmetic products which use lipid nanoparticles loaded with cosmetic
components such as: ascorbyl palmitate, beta-carotene, and co-enzyme Q 10. As these are all lipophilic
in nature, they are efficiently incorporated within lipid nanoparticles.

N.B:
➢ Each 1gm of cream or 1 ml of preparation contain at least 107 nanoparticle.
➢ The Matrix form very thin transparent translucent sheet, which achieve about 80% vitality of the skin.
➢ Provide controlled release on skin
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Drug delivery – By Menna Hazem – From dr Abdulhakeem powerpoint and record Lec 7

Protein nanoparticle
• Nanoparticles prepared from proteins.
• The first commercial product based on protein nanotechnology was:
Abraxane® (nabTM-paclitaxel).
• Approved for the treatment of breast cancer in patients who do not respond to combination chemotherapy
for metastatic disease or relapse within 6 months of adjuvant chemotherapy.
• consists of 130 nm particles of albumin-bound paclitaxel
• paclitaxel has a low water solubility → requires addition of solubility-enhancing agents to allow its clinical use.
• Prior to the development of Abraxane®, paclitaxel was only available as Taxol®.
• This is a liquid product with paclitaxel solubilized in polyethoxylated castor oil (Cremophor® EL) and
ethanol. ‫كده حسنت ذوبانيته‬
• Problems of taxol
1- this formulation requires special infusion sets,
2- prolonged infusion times
3- has toxicity issues associated with its use.

• By incorporating paclitaxel into albumin nanoparticles, albumin function:

1- coat the paclitaxel
2- provide colloidal stabilization to the drug.
• This circumvents both ‫يؤدي إلى التغلب على‬
1- low solubility
2- Cremophor®-associated side effects. taxol ‫اللي كنا بنستخدمه في ال‬

• Targeting mechanisms of Abraxane®

The albumin within the nanoparticle-albumin technology used in Abraxane
a- serves as more than a solubility enhancing agent
b- albumin also promotes active targeting of the paclitaxel to tumor cells.

1- drug targeting of nanoparticles to tumors may be enhanced as a result of the EPR effect;
- The dense and highly permeable endothelial microvascular structure of tumors (which is a result of
angiogenesis) allows large macromolecules and nanoparticles to leak into the underlying tumor tissue.
(Permeation) ‫الخلية السرطانية الفتحات فيها بتكون واسعة وسهلة االختراق من الكبير والصغير‬
- The impaired lymphatic drainage at the tumor site slows drainage of these nanoparticles from the tumor
site, resulting in the particles becoming trapped. (Retention)
‫الميكانيزم ده بسبب إنه بحجم النانو مش بسبب األلبيومين‬
2- In the case of Arbaxane®
• a second mechanism has also been associated with the targeting and uptake of the albumin nanoparticles
to tumor sites.
• This is the Albumin-activated (glycoprotein) gp60 pathway. ‫ده بقا بسبب األلبيومين‬
• Within the body, albumin is able to transport hydrophobic molecules, such as vitamins, hormones and
other plasma constituents, across the endothelial lining and out of the blood circulation. ‫ده في الطبيعي‬
• This is achieved by albumin binding to gp60 albumin receptors found on the surface of vasculature
endothelial cells.
• These gp60 receptors are then responsible for the transport of albumin across blood vessel walls.
• The binding of albumin to the gp60 receptors, activates the membrane protein caveolin-1 → subsequently
results in the internalization of the cell membrane and the formation of transcytotic vesicles (known as
caveolae) → These caveolae then transport their contents across the endothelial cell cytoplasm and
release their contents into the cell’s interstitium. ‫كده األلبيومين والباكليتاكسل هيدخلوا الخلية‬

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Drug delivery – By Menna Hazem – From dr Abdulhakeem powerpoint and record Lec 7
In the case of tumors
• This transport system is thought to be upregulated.
• Therefore Abraxane® is able to exploit this albumin-activated gp60 transport mechanism to target the tumor
site. After entering the systemic circulation, the albumin-bound paclitaxel can bind to the gp60 albumin
receptors and be carried across the endothelial cells via transcytosis in the same way as albumin.
.‫ وينتقل عبر الخاليا البطانية عن طريق النقل الخلوي بنفس طريقة حمل األلبومين‬gp60 ‫ يمكن للباكليتاكسيل المرتبط باأللبومين أن يرتبط بمستقبالت األلبومين‬، ‫ بعد دخوله الدورة الدموية‬.‫ المنشط باأللبومين الستهداف موقع الورم‬gp60 ‫أبراكسان® قادر على استغالل آلية نقل‬

3- After crossing the endothelial lining

• The drug must cross the tumor cell membrane and enter the tumor cells.
1- Once the albumin-bound paclitaxel reaches the interstitium, the albumin may bind to an extracellular matrix
glycoprotein known as SPARC (secreted protein acid and rich in cysteine) which is also overexpressed in
tumor cells. ‫ده بروتين موجود بكثرة في الورم لما األلبيومين بيمسك فيه بينفصل عنه الباكليتاكسيل‬
2- This can trigger the release of the paclitaxel from the albumin, allowing the free drug to diffuse to the nucleus
of tumor cells initiating cell death.
• Given that this mechanism of tumor targeting is an attribute of the albumin carrier system and not the drug,
it is conceivable it may be applied to the delivery of other low solubility anti-cancer agents.
.‫ فمن الممكن تصور أنه يمكن تطبيقها على توصيل عوامل أخرى مضادة للسرطان منخفضة الذوبان‬،‫بما أن هذه اآللية الستهداف الورم هي سمة من سمات نظام حامل األلبومين وليس الدواء‬

Inorganic nanoparticles
Nanoparticles can be fabricated from inorganic materials including
• metal oxides,
• metal sulphides,
• carbon nanotubes,
• calcium phosphate
• ceramics
These nanoparticles are generally not biodegradable and so have a more limited application.

Abdoscan
an example of a metal oxide nanoparticle product
• used for magnetic resonance imaging (MRI) diagnostics of the bowel, ‫ بدل حقن الصبغة‬as it is a
superparamagnetic iron oxide nanoparticle formulation which is administered orally.
• The particles have a mean diameter not less than 300 nm.
• It is a negative contrast agent utilized for peroral bowel MRI diagnosis due to its high magnetic signal
strength and decreased cytotoxicity.
• The particles are suspended in viscosity increasing agents, such as starch, to prevent aggregation of the
particles. in-vivo.
‫ ال‬.‫ حيث أنه عبارة عن تركيبة جسيمات متناهية الصغر من أكسيد الحديد ذات مغناطيسية فائقة والتي يتم تناولها عن طريق الفم‬،‫• يستخدم لتشخيص التصوير بالرنين المغناطيسي لألمعاء‬
‫ وهو عامل تباين سلبي يستخدم لتشخيص التصوير بالرنين المغناطيسي لألمعاء حول الفم بسبب قوة اإلشارة المغناطيسية العالية وانخفاض‬.‫ نانومتر‬300 ‫يقل متوسط قطر الجسيمات عن‬
.‫ لمنع تراكم الجسيمات في الجسم الحي‬،‫ مثل النشا‬،‫ يتم تعليق الجسيمات في عوامل زيادة اللزوجة‬.‫السمية الخلوية‬

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