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Lecture 18:
Drug Delivery: Controlled ReleaseChemically-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
Minimum effective level
Toxic level
. Controlled (or Sustained) ReleaseDrug conc
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 Ratner, et al. Biomaterials Science
4Liposome systems
Chemically-controlled DDS
Drug Bioerodible or biodegradable matrix
time
Drug Deg. conc.
Drug Drug conc. conc.
time time 5
Four major classes of matrix in DDSPoly(lactic acid) and its copolymers with poly(glycolic acid)
O CH C
CH3O
O CH2 C
O
O CH C
CH3O Safe degraded products Acid-induce inflammatory
PLA P(LA-co-GA)
Polyanhydrides
C
O
O C3H6 O C O
O
C C4H8 C O
O O
First degradation rate Hydrolytic instability
Poly(bis-(p-carboxyphenoxy)propane-co-sebacic anhydride)
Polyorthoesters
O
O
O
O
O RO
Well studied by 21st century Good property R: PLGA
Polyphosphoesters
P O R O
O
R'
First degradation rate Hydrolytic instability, high cost6
H
O
O C
O
O
C O
O
H
O
O R
R
Environmentally responsive systems
1. Temperature responsive systemsC O
NH
LCST: 32°C
Poly(N-isopropyl acrylamide)T HO
O
O
O
H
Pluronics® 37°C
T
37°C
Gelation BioerosionPolymer-drug solution
HO C
O
O
C O
O
R O
R
H
Hydrophob
Hydrophilic R: -H, -C H3 7 ic
Environmentally responsive systems
2. pH responsive systems
““Proton SpongeProton Sponge””Endocytosis of drug
Formation of acidsome
Transfer to lysosome
Digestion in lysosomepH 5-6
NH2 NH3+
H+
Poly(L-lysi
HNCH
C
O
(CH2)4
NH2Chitosan
OCH2OH
HONH2
O
ne) 8
Second key point in DDS
1. Controlling release rate
2. Site-specific delivery
Particulate system
Passive targetingActive targeting
Particulate should be between 10 to 200 nm.
Spleen Liver
Lungs
RES Reticuloendothelial system
9
Passive targeting of particulate by EPR effect
Discontinuous endothelialium
Blood vessel
Endothelial cells
Cancer
Enhanced permeability and retention(EPR) effect
Disorganization of tumor vasculaturePoor lymphatic drainage 10
Micro (nano) capsules and spheres 1
Capside vehicle PEO-protein conjugates
protein drug
PEO chain
Capside
RNA Virus
Drug
Immunogenic response Prolong circulationLowering activity
11
Micro (nano) capsules and spheres 2
Polymeric micelles Hydrophilic Hydrophobic
Amiphilic block copolymer
Above CMC Drug
l. , ,
O
NH
CHN
C
HN
H
O
C
OH
O O C
OHO
Yokoyama et a Cancer Res 1991 51, 3229. PEO
Poly(aspartic acid) 12
Paclitaxel incorporating micellar nanoparticle
Hydrophilic shell
Hydrophobic core
HN
PhOH
O
O
O
Ph
AcO
OH
O
AcOH
OBz
OHO
Paclitaxel(Taxol®) or PTX 85 nm
0
0.01
1
100
10000
24
Dru
g co
nc/µ
g/m
L
48 72 0
0 10
4 PTX
PTX
PTX-micelle
PTX-micelle Saline8
20 30
Time after Administration/h Days after Initial Treatment
Rel
ativ
e Tu
mou
r Siz
e
Figure by MIT OCW. Hamaguchi et al. British J Cancer, 2005, 92, 1240. 13
Micro (nano) capsules and spheres 3
Liposomes
CH2
CH
O
H2C
O
C C
O
O O
P
O
CH2
O-O
CH2
N+
CH3
CH3H3C
Hydrophilic head Lipid bilayer
Liposome
Hydrophobic tails C12-C20
Small unilamellar vesicle (SUV): ~ 50 nm Large unilamellar vesicle (LUV): > 1 µm
Multilamellar vesicle 14
15
Preparation of liposomes
1. Lipid thin film preparation
2. Swelling thin film
3. Ultrasound treatment
4. Extrusion
Glass surface
Air
Lipids are cast on a glass surface
Addition of aqueous mediaTearing off from glass
Formation of liposomeswith various shapes and sizes
Reconstruction of lipid membraneSize: ~ 100 nm
16Alfredsson, Current Opinion in Colloid & Interface Science, 2005, 10, 269.
Cryo-TEM image of cationic liposomes
Photo removed for copyright reasons.
Active targeting
Polymer drug conjugate PK2 (Phase I/II)
Poly(N-(2-hydroxypropyl)methacrylamide)Ringsdorf’s model
CH2 C CH2 CH2
CH3 CH3 CH3
C C C
NH
CH2
CHOH
CH3
O O O
Gly Gly
Phe
Leu
Gly
C
NH
Phe
Leu
Gly
C
NH
O O
O
OH
O
O
OH
OH
OCH3
HO
OHO
O
HOOH
HO
Galactosamine
Spacer
Saccharides, Peptides, etc.
Water soluble polymer backbone Doxorubicin
Duncan R and Kopecek J et al., Ringsdorf, J Polym Sci Polymer Symp, 1975, 51, 135 Biochimica et Biophysuca Acta, 1983, 755, 518
17
Biodegradable spacer Drug
Oligoesters, oligopeptides
Targeting residue
Targeting residueO
NH
OH OH
COO-
OHH3C
O
CH2OH
OH Sialic acid or Saccharide determinants Neuramic acid
Terminal residue of carbohydrate chain Gl in
Gl lipi
ycoprote
yco d O
OH
H
H
HO
H
OH
OHHH
OH
Galactose
Saccaride residue next to neuramic acid
3Galβ1Neu5Acα2 4GlcNAcβ1 ±Fucα16
Manα12Neu5Acα2 3Galβ1 4GlcNAcβ1 6 6
Manβ 4GlcNAcβ1 4GlcNAc Asn 3Galβ1Neu5Acα2 4GlcNAcβ1 314Manα1 Typical surface carbohydrate
4GlcNAcβ12
connected to Asn of protein 18 Galβ1
19Julyan et al., J Contr Release, 1999, 57, 281
Tissue distribution of 123I labeled PK2 CH2 C CH2 CH2
CH3 CH3 CH3
C C C
NH
CH2
CHOH
CH3
O O O
Gly Gly
Phe
Leu
Gly
C
NH
Phe
Leu
Gly
C
NH
O O
O
OH
O
O
OH
OH
OCH3
HO
OHO
O
HOOH
HO
Photos removed for copyright reasons.
Third key point in DDS
1. Controlling release rate +
2. Site-specific delivery
3. Drug formulation
H2N R NH2 Cl C
O
R' C Cl
O
NH C
O
R' C
O
RNH
Interfacial polymerization of polyamides
Water soluble Diamine monomer
Drug-loading particle Emulsion formed with 20 Drug and acid dichloride monomer
Emulsification of polymer and drug
+
H2 ilizi lp
l i lAqueous phase
O & stab ng agent Organ c phase Po ymer & drug
drug-oad ng po ymer
i Preci itation of
Coacervation of polymer and drug
-
+
l l l (+) l l l ( )Po ye ectro yte Po ye ectro yte & drug
21
What are the drugs? Typical anticancer drugs
-Cl
Pt
Cl-
NH3++H3N
HN
PhOH
O
O
O
Ph
AcO
OH
O
AcOH
OBz
OHO
O
OOCH3
OH
OH
OH
OCH2OH
O
OH
H2N
O
O
O
OCH3
OH
O
O
NH
OH
OH
CH3
H3C
H
O
O
O
O
Cisplatin Paclitaxel(Taxol®) Doxorubicin Neocarzinostatin chromophore
High molecular weight drugs
Proteins, peptides, hormones, cytokines
DNAs and RNAs etc.
Bioactive compoundsBioactive compounds are not stableare not stable!!22