Lecture 18:
Drug Delivery: Controlled Release
Chemically-controlled Devices
3.051J/20.340J Materials for Biomedical Applications,
Spring 2006
1
Drug Delivery System (DDS)
Controlling delivery rate and Site-specific delivery of drugs
Current drug administration
Toxic level
Drug conc.
Controlled (or Sustained) Release
Minimum effective level
Time
2
Even though controlled release can be achieved…
Spread over body
Site-specific delivery
Active or passive
targeting
might cause side effect.
3
Table Controlled Release DDS
Diffusion-controlled DDS
Reservoir and monolithic systems
Water penetration-controlled DDS
Osmotic and swelling-controlled systems
Chemically-controlled DDS
Biodegradable reservoir and monolithic systems
Biodegradable polymer backbones with pendant drugs
Responsive DDS
Physically- and chemically-responsive systems
Mechanical, magnetic- or ultrasound-responsive systems
Biochemically-responsive; self-regulated systems
Particulate DDS
Microparticulates
Polymer-drug conjugates
Polymeric micelle systems
Liposome systems
Ratner, et al. Biomaterials Science
4
Chemically-controlled DDS
Drug
Bioerodible or biodegradable matrix
time
Deg.
Drug
conc.
Drug
conc.
Drug
conc.
5
time
time
Four major classes of matrix in DDS
Poly(lactic acid) and its copolymers with poly(glycolic acid)
CH3 O
O
O
CH C
CH3 O
O
CH C
O CH2 C
Safe degraded products
Acid-induce inflammatory
P(LA-co-GA)
PLA
Polyanhydrides
O
C
O
O C3H6 O
O
C
O
O
C C4H8 C
O
First degradation rate
Hydrolytic instability
Poly(bis-(p-carboxyphenoxy)propane-co-sebacic anhydride)
Polyorthoesters
O
O
O
O
O
O
R
Well studied by 21st century
Good property R: PLGA
Polyphosphoesters
O
P
R'
O
R
O
First degradation rate
Hydrolytic instability, high cost6
Environmentally responsive systems
1. Temperature responsive systems
C
O
LCST: 32°C
NH
T
Poly(N-isopropyl acrylamide)
HO
O
Pluronics®
Polymer-drug solution
O
O
37°C
Bioerosion
Gelation
T
37°C
R
HO
R
O
C
O
O
O
C
O
R
H
H
O
O
Hydrophilic
Hydrophobic
O
C
O
O
O
C
O
O
H
R
R: -H, -C H3
H
7
Environmentally responsive systems
2. pH responsive systems
Endocytosis of drug
“Proton Sponge”
Formation of acidsome
Transfer to lysosome
pH 5-6
Digestion in lysosome
H+
NH3+
NH2
O
HO
O
H
N
CH2OH O
CH
C
(CH2)4
NH2
Chitosan
NH2
Poly(L-lysine)
8
Second key point in DDS
1. Controlling release rate
2. Site-specific delivery
Reticuloendothelial system
RES
Particulate system
Lungs
Passive targeting
Active targeting
Liver
Spleen
Particulate should be
between 10 to 200 nm.
9
Passive targeting of particulate
by EPR effect
Discontinuous endothelialium
Cancer
Endothelial cells
Blood vessel
Enhanced permeability and retention
(EPR) effect
Disorganization of tumor vasculature
Poor lymphatic drainage
10
Micro (nano) capsules and spheres 1
Capside vehicle
PEO-protein conjugates
Capside
PEO chain
RNA
Virus
Drug
Immunogenic response
protein drug
Prolong circulation
Lowering activity
11
Micro (nano) capsules and spheres 2
Polymeric micelles
Hydrophilic Hydrophobic
Amiphilic block copolymer
Drug
Above CMC
O
O
PEO
C
N
H
O
C
H
N
H
N
C
O
HO
C
H
O
OH
Yokoyama et al. Cancer Res, 1991, 51, 3229.
Poly(aspartic acid)
12
Paclitaxel incorporating micellar nanoparticle
AcO
Hydrophilic shell
Ph
O
HN
O
Hydrophobic core
O OH
O
Ph
OH
H
AcO
OH OBz
O
Paclitaxel(Taxol®)
or PTX
85 nm
10000
Relative Tumour Size
Drug conc/µg/mL
PTX-micelle
100
1
PTX
8
Saline
PTX
4
0.01
0
24
48
Time after Administration/h
Figure by MIT OCW.
72
0
PTX-micelle
0
10
20
30
Days after Initial Treatment
Hamaguchi et al. British J Cancer, 2005, 92, 1240.
13
Micro (nano) capsules and spheres 3
H3C
Liposomes
Lipid bilayer
-O
H2C
O
O C
CH3
N+ CH3
CH2
CH2
O
P O
O
CH2
CH
O
C O
Hydrophilic head
Hydrophobic tails
C12-C20
Small unilamellar vesicle (SUV): ~ 50 nm
Large unilamellar vesicle (LUV): > 1 µm
Liposome
Multilamellar vesicle
14
Preparation of liposomes
Air
1. Lipid thin film preparation
Lipids are cast on a glass surface
Glass surface
2. Swelling thin film
Addition of aqueous media
Tearing off from glass
3. Ultrasound treatment
Formation of liposomes
with various shapes and sizes
4. Extrusion
Reconstruction of lipid membrane
Size: ~ 100 nm
15
Cryo-TEM image of cationic liposomes
Photo removed for copyright reasons.
Alfredsson, Current Opinion in Colloid & Interface Science, 2005, 10, 269.
16
Active targeting
PK2 (Phase I/II)
Polymer drug conjugate
Poly(N-(2-hydroxypropyl)methacrylamide)
Ringsdorf’s model
CH3
CH3
CH2 C
C
Biodegradable spacer
Drug
Oligoesters, oligopeptides
CH3
CH2
O
CH2
C
O
C
NH
Gly
Gly
CH2
Phe
Phe
CHOH
Leu
Leu
CH3
Gly
Gly
C
O
OH C
NH
Spacer
Water soluble
polymer backbone
Targeting residue
Saccharides,
Peptides, etc.
Ringsdorf, J Polym Sci Polymer Symp, 1975, 51, 135
O
HO
O
HO
OH
Galactosamine
O
O
NH
OH
O
OH
O
OCH3
HO
HO
O
Doxorubicin
Duncan R and Kopecek J et al.,
Biochimica et Biophysuca Acta, 1983, 755, 518
17
O
Targeting residue
CH2OH
H3C
NHOH
OH
Saccharide determinants
Sialic acid or
O
COOOH
OH
Glycoprotein
Neuramic acid
Terminal residue of carbohydrate chain
Glycolipid
OHOH
H O
H
HO
H
H
H
OH
Galactose
OH
Saccaride residue next to neuramic acid
Neu5Acα2
3Galβ1
4GlcNAcβ1
6
Neu5Acα2
Neu5Acα2
3Galβ1
3Galβ1
4GlcNAcβ1
2
Manα1
6
Manβ
31
4GlcNAcβ1
4
2
Galβ1
± Fucα1
4GlcNAcβ1
Manα1
4GlcNAcβ1
6
4GlcNAc
Typical surface carbohydrate
connected to Asn of protein
Asn
18
Tissue distribution of 123I labeled PK2
CH3
CH3
CH2 C
C
CH3
CH2
O
CH2
C
O
C
NH
Gly
Gly
CH2
Phe
Phe
CHOH
Leu
Leu
CH3
Gly
Gly
C
O
OH C
NH
O
HO
OH
O
NH
O
HO
O
OH
O
OH
O
HO
HO
O
Photos removed for copyright reasons.
Julyan et al., J Contr Release, 1999, 57, 281
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OCH3
Third key point in DDS
1. Controlling release rate
2. Site-specific delivery
O
H2N
3. Drug formulation
R
NH2
+
Cl
C
O
R'
O
NH R NH C
C
Cl
O
R'
C
Interfacial polymerization of polyamides
Water soluble
Diamine monomer
Drug-loading particle
Emulsion formed with
Drug and acid dichloride monomer
20
Emulsification of polymer and drug
Aqueous phase
Organic phase
H2O & stabilizing agent
Polymer & drug
Precipitation of drugloading polymer
+
Coacervation of polymer and drug
Polyelectrolyte (-)
& drug
Polyelectrolyte (+)
+
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What are the drugs?
O
O
O
Typical anticancer drugs
O
OH
O
CH2OH
O
OH
H
O
OH
AcO
-Cl
O
HN
Pt
+H N
3
Ph
ClNH3+
Cisplatin
O
O
O OH
OCH3 O
O
Ph
OH
OH
O
H
AcO
OH OBz
O
Paclitaxel(Taxol®)
O
O
H2N
OH
Doxorubicin
OCH3
H3C
CH3
O
NH
OH
OH
Neocarzinostatin
chromophore
High molecular weight drugs
Proteins, peptides, hormones, cytokines
DNAs and RNAs etc.
Bioactive compounds are not stable!!
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Summary
1. Controlling release rate
Degradable matrix
Environmentally responsive matrix, Proton sponge
2. Site-specific delivery
Passive targeting
EPR effect, RES
Active targeting
Targeting residue
3. Drug formulation
Denature or deactivation
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