Presentation

BRAIN TUMOR-TARGETED DRUG DELIVERY STATEGIES

Student name: Doan Hoai Son

7140034

Le Dinh Tuan

7140202

Doan Ngoc Anh Duc

7140010

Supervisor : Prof. Le Thi Hong Nhan

TPHCM, 11/2014

Diagram

CONTENTS
Introduction
Classification of drug carrier system.
Time-Controlled.

Controlled Distribution
Application.
Typical example

1. Introduction
Conventional pharmacotherapy
- Sensibility of conventional pharmacotherapy
- Indiscriminate distribution
- The occurrence of side effects
- Rapid renal clearance
-The need for higher doses of the drug

Smart carrier systems

Current Drug Delivery, vol 253(23-24), p:3042-3066, 2012.

1. Introduction

Time-Controlled

Conventional Formulation
J. Polymer reviews, vol 47, p: 345-381, 2007.

1. Introduction

The bloodbrain barrier (BBB) structure

J. Polymer reviews, vol 47, p: 345-381, 2007.

2. Classification of drug carrier system

Drug-Polymer Conjugates
Therapeutic agents can be
covalently bound to the polymer
backbone
Linkers are labile to certain
digestive enzymes or acidic
conditions
Structure of HPMA copolymer-doxorubicin galactosamine
(PK2)
Biomacromolecules, vol 10, p: 281-290, 2005.

2. Classification of drug carrier system

Carriers in which the drug is embedded or encapsulated
1. The drug is loaded by in situ polymerization

EX : Peppas et al synthesized microparticles of

PEG hydrogels that were prepared by free radical
copolymerization of (PEGDMA) and (PEGMA)

PEG-rich networks containing PEG grafts and bridges

Nano- and Micro-particles

Journal of Controlled Release, vol 62, p:81 87, 1999.

2. Classification of drug carrier system

Nano- and Micro-particles
2. The drug is embedded after the polymer has been synthesized
Drug is absorbed into preformed polymers. This requires the incubation of a
concentrated drug solution with the preformed polymer carrier
EX : Nakamura et al addressed the behavior and kinetics of budenoside release from
microparticles of P(MAA-g-EG).The latter is a copolymer of polymethacrylic acid and
polyethylene glycol.
It is important to optimum conditions of polymer swelling and an
acceptable degree of drug solubility

J. Control. Release , vol 61, 329-335, 1999.

2. Classification of drug carrier system

Carriers in which the drug is embedded or encapsulated

Nano- and micro-capsules are formed by an outer shell that encapsulates the active agent
The drug is encapsulated in the particle and is released by degradation of the polymer
coating
Micro- and nano-capsules are synthesized with hydrophilic polymers.
Gels are the most widely used hydrophilic polymers for this kind of pharmaceutical
formulation
Gels are made either from natural or synthetic polymers
The optimum incorporation strategy for efficient entrapment should be selected on the
basis of the physicochemical characteristics of the drug-carrier pair

Nano- and Micro-Capsules

Current Drug Delivery, vol 253(23-24), p:3042-3066, 2012.

 SMART CARRIER SYSTEMS

Design
Design of
of smart
smart
carrier
carrier system
system

Controlled
Controlled release
release
mechanism
mechanism

TimeTimeControlled
Controlled
mechanism
mechanism

Elimination
Elimination
mechanism
mechanism

Controlled
Controlled
Distribution
Distribution

Renal
Renal
clearance
clearance

Metabolic
Metabolic
clearance
clearance

Current Drug Delivery, vol 253(23-24), p:3042-3066, 2012.

3. Time-Controlled

Extended-Release Formulation

The Science of Dosage Form Design, vol 115, p:87-93, 2002.

3. Time-Controlled

Sustained-Release Formulation

Drug Dev. Ind. Pharm , vol 26, p: 695-708, 2000.

3. Time-Controlled
Pulsatile-Release Formulation

Poly (acrylic acid) (PAA)

Poly(N,N-diethylaminoethyl methacrylate) (PDEAEM)

Advanced Drug Delivery Reviews, vol 53, p: 321 339, 2001.

4. Controlled Distribution
Pathways for the transport of drug across the blood brain barrier

Cancer Res, vol 46, p: 6387-6392, 2014.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)
The delivery of drugs across the BBB by cationic proteins

Cationic bovine serum albumin conjugated, pegylated nanoparticles (CBSA-NP)

structure (6-coumarin was incorporated into nanoparticles)
Int J Pharm, vol 295, p: 247 260, 2005.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process )
The delivery of drugs across the BBB by cationic proteins

Efficiency of CBSA-NP for brain delivery

Int J Pharm, vol 295, p: 247 260, 2005.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)
The delivery of drugs across the BBB by cell penetratingpeptides (CPPs)
Alternative AMT-type cell-penetrating
peptide(CPP)-based delivery systems
show great ability in BBB transport
and deliver a large variety of cargoes
The CPPs are always derived from
natural proteins among which Tat
might be the most frequently used

Acta Pharmaceutica Sinica B, vol 20, p: 148 160, 2014.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)
The delivery of drugs across the BBB by cell penetratingpeptides (CPPs)
The TAT peptide is a non-amphipathic
arginine-rich CPP.
The basic domain of TAT includes a
highly cationic cluster composed of 6
arginine and 2 lysine residues.
The guanidinium head group of
arginine is more potent than other
cationic groups, such as lysine, histidine
Acta Pharmaceutica Sinica B, vol 20, p: 148 160, 2014.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)
The delivery of drugs across the BBB by cell penetratingpeptides (CPPs)

Biologically active polymer core/shell nanoparticles self-assembled from TAT-poly(ethylene

glycol) (PEG)-b-cholesterol (TAT-PEG-b-Chol) (ciprofloxacin was incorporated into NPs)
Biomaterials 29, vol 40, p: 1509-1517, 2008.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)

Efficiency of TAT-PEG-b-Chol for brain delivery

Biomaterials 29, vol 40, p: 1509-1517, 2008.

4. Controlled Distribution
Transporter mediated transcytosis (active process)

Transporter mediated transcytosis is substrate selective, so only

drugs that closely mimic the endogenous substrates will be taken up
and transported into the brain
Glucose transporters(GLUT),which facilitate the transport of
glucose from the blood to the brain, have a broad prospective use in
brain targeting

Journal of Drug Targeting, vol 18(7), p: 536549, 2010.

4. Controlled Distribution
Transporter mediated transcytosis (active process)

New glycosyl derivative of cholesterol(6coumarin was incorporated in NPs)

Journal of Drug Targeting, vol 18(7), p: 536549, 2010.

4. Controlled Distribution
Absorptive-mediated transcytosis (active process)

Efficiency of GLP4 for brain delivery

Journal of Drug Targeting, vol 18(7), p: 536549, 2010.

4. Controlled Distribution
Receptor mediated transcytosis (active process)
Receptor-mediated transcytosis is considered one of the most mature
strategies for brain targeted drug delivery with the characteristics of
high specificity, selectivity and affinity.
One of the most widely characterized receptor-mediated transcytosis
systems for brain targeting is the transferrin receptor(TfR), which is
highly expressed on endothelial cells of the BBB.

Acta Pharmaceutica Sinica B, vol 20, p: 148 160, 2014.

4. Controlled Distribution
Receptor mediated transcytosis (active process)
Transferrin's primary protein structure is made up of about 700 amino acids (80 kDa)

Transferrin's primary protein structure

Journal of Controlled Release, vol 159, p: 429434, 2012.

4. Controlled Distribution
Receptor mediated transcytosis (active process)

Tf-modified paclitaxel-loaded polyphosphoester hybrid micells (TPM) structure

Journal of Controlled Release, vol 159, p: 429434, 2012.

4. Controlled Distribution
Receptor mediated transcytosis (active process)

Efficiency of TPM for brain delivery

Journal of Controlled Release, vol 159, p: 429434, 2012.

4. Controlled Distribution

Temperature-sensitive carriers ( passive process)

Temperature-sensitive polymers are probably one of the most commonly studied
classes of environmentally sensitive polymer systems in drug delivery research.
Temperature sensitive hydrogels are classified into negatively thermosensitive and
positively thermosensitive polymers.

Advanced Drug Delivery Reviews, vol 53, p:321339, 2001.

4. Controlled Distribution
Temperature-sensitive carriers ( passive process)
Positively thermo-sensitive polymers

poly(acrylic acid)

polyacrylamide

poly(acrylamode-co-butyl methacrylate)

Negatively thermo-sensitive polymers

Adv. Drug Deliv. Rev, vol 31, p:197221, 2003.

4. Controlled Distribution
pH-sensitive carriers (passive process)

These polymers are characterized by the presence of groups, which can accept or donate
protons depending on the pH of the medium, leading to ionization variations in their
structure.

Biomaterials, vol 18, p:861872, 2007.

4. Controlled Distribution

Light-sensitive carriers (passive process)

These polymers are characterized by the presence of molecules, which dissociate into
ion pairs under UV light (UV-sensitive polymers) or swell under visible light (visible
light-sensitive polymers)

Structure of bis(4- (dimethylamino)phenyl)(4-vinylphenyl)methylleucocyanide

Macromolecules, vol 23, p:15171519, 2000.

4. Controlled Distribution
Polymeric Nanoparticles (passive process)
It has been shown that NPs coated
with

poly(ethylene

glycol)

(PEG)

accumulate more efficiently in the brain

with a compromised BBB compared to
similar uncoated NPs.

The American Society for Experimental Neuro Therapeutics, vol 2, p:108119, 2005.

4. Controlled Distribution
Polymeric Nanoparticles (passive process)

The American Society for Experimental Neuro Therapeutics, vol 2, p:108119, 2005.

4. Controlled Distribution
Enhanced Permeability and Retention effect (EPR effect)

Cancer Res, vol 46, p: 6387-6392, 1996.

5. Dendrimers
Characteristics of Dendrimers
The chemical structure of a dendrimer
consists of a core or central structure
that contains several branches, leading
to

three-dimensional

globular

structure of concentric layers.

The dendrimeric structure contains two
key features that make them of interest
as drug carriers. One is its interior
hollows. Another important feature of
the dendrimer is that it contains
specific surface functional groups.

Structure of PAMAM dendrimer

Current Drug Delivery, vol 253(23-24), p:3042-3066, 2012.

6. TYPICAL EXAMPLE

Tumor-Targeting and Microenvironment-Responsive Smart Nanoparticles

Design
Target : brain cancer.
Time-Controlled mechanism: size of dendrimers (increasing the generation
of dendrimer) and the use of PEG
Controlled Distribution : Active process based on the combination of cellpenetrating peptide (designated as dtACPP) and shVEG
Elimination mechanism: renal clearance and metabolic clearance

American Chemical Society, vol 6, p:527535, 2013.

6. TYPICAL EXAMPLE
Tumor-Targeting and Microenvironment-Responsive Smart Nanoparticles

Mechanism of dtACPPD/ shVEGFDOX for

brain delivery

American Chemical Society, vol 6, p:527535, 2013.

6. TYPICAL EXAMPLE
Tumor-Targeting and Microenvironment-Responsive Smart Nanoparticles

American Chemical Society, vol 6, p:527535, 2013.

8. CONCLUSION
The chemical nature of the many types of smart drug carriers
available facilitates the distribution and interaction of drugs with
their target tissue.
These carriers also protect their drug cargo from degradation and
prevent their side effects.
Smart drug carriers have presented significant potential as
candidates for drug delivery system for brain.
Smart drug carriers are now used for many treatments, including
tumor , bacterial infection, antiviral, vaccine and gene therapy.

Current Drug Delivery, vol 253(23-24), p:3042-3066, 2012.

Thanks for your attention !