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

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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

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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

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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