Plasma ConcentrationPlasma Concentration

(1)

육 육 순 순 홍 홍 한남대학교 한남대학교

권 권 익 익 찬 찬 KIST KIST

나노 약물 전달

(요약)

(2)

Dept. of Polymer Science & Engineering Chemical Delivery Polymers Lab.

공업화학회 주관 특별심포지엄

“나노:입문에서 응용까지”

Too much agent

Time of dose

Too little agent

Toxic level

Minimum effective level

Time

Plasma Concentration

Toxic level

Minimum effective level

Time

Controlled release

Plasma Concentration

(3)

Low effectiveness of Chemotherapy

LOCALIZATION OF THERAPEUTIC AGENTS

TARGETING

Two different approaches for

“Localization of Therapeutic Agents”

Systemic Administration of Drugs

Drugs spread throughout the body in blood circulation

Drugs reach any part of the body from the head to the feet

Side effects

LOCAL INJECTION

Limiting Dose

(4)

TWO KEY TECHNOLOGIES FOR INJECTABLE DRUG DELIVERY

Depot Systems

Wafers, Liposomes, Microspheres, Injectable Gels

Sustained release of drugs Easily administered

Readily accepted within the body

PEGylation

Optimizing pharmacokinetics Increasing bioavailability Decreasing immunogenicity Decreasing dosing frequency

“Injectable Drug Delivery: Probing the Route to Growth”

reported by Datamonitor (2004)

(5)

o By considering the size of nanosphere, the possibility of the passive targeting to the specific tumor cells is under study based on the enhanced permeation and retention (EPR) effect.

Targeting with Polymeric Nanospheres Targeting with Polymeric Nanospheres

Introduction

(6)

PLGA PLGA

o Copolymer of lactide and glycolide: Poly(D,L-lactide-co-glycolide), Amorphous and water-insoluble polymer

o Biodegradable polymers approved by FDA for medical application such as suture

-- 175~185

175~185 °°CC 225

225 °°CC Melting Temp. (Tm)

Melting Temp. (Tm)

45~55 45~55 °°CC 45~60

45~60 °°CC 35 35 °°CC

Glass Transition Glass Transition Temperature ( Temperature (TgTg))

Amorphous Amorphous Crystalline

Crystalline Crystalline

Crystalline Crystallinity

Crystallinity

6 months 6 months 18~24 months

18~24 months 2~4 months

2~4 months Degradation Time

Degradation Time

PLGA PLGA (75 : 25) (75 : 25) PLLAPLLA

PGAPGA

Materials

(7)

Formation of O/W emulsion

Filtration

PLGA

in Methylene Chloride Water

Sonication with surfactant

Evaporation

Solvent Evaporation Method

Introduction

(8)

Experimental

Paclitaxel Loading Paclitaxel Loading

Powdery State Homogeneous Liquid State Phase-Separated State

Melting at 60 ^oC

Cooling at R.T.

Paclitaxel

PEO-PPO-PEO (F-127) PLGA ( M.W. 90,000 )

Paclitaxel-loaded Nanosphere

(9)

Filtration

&

Freeze dry

Melting

8/2(W/W) F-127/PLGA, Paclitaxel,

Tween 80 Temp. : 60°C

Cooling

At Room Temp.

Experimental

Characterization

SEM, HPLC, Particle Size Analyzer

Washing

D.I.Water

(10)

Paclitaxel Loading Paclitaxel Loading

Encapsulation Encapsulation

Efficiency Efficiency Loading

Loading Amount (wt%) Amount (wt%)

Characteristics Characteristics Polymer

Polymer Mixture Mixture

5/5(w/w)F-127/PLGA 6/4(w/w)F-127/PLGA 7/3(w/w)F-127/PLGA 8/2(w/w)F-127/PLGA 9/1(w/w)F-127/PLGA

¯

¯/{

{ { { 5.7

9.1

10.8 7.4

20.7 21.2 28.4 12.3

- -

Results and Discussion

(11)

Release Pattern of Paclitaxel Release Pattern of Paclitaxel

0 10 20 30 40 50 60

0 20 40 60 80 100

Time (days)

Percent of Released Amount

Results and Discussion

(12)

Core/Shell Polymer System

Introduction Introduction

Core/shell polymer system consisting of a core of one polymer (poly (1,3-bis (p-carboxyphenoxypropane-co-sebacic anhydride)

surrounded by a coating of a second polymer (poly(Lactide) )using a polymer-polymer phase separation

(Pekarek et al. J. Controlled Rel. 1996, 40, 169 )

(13)

Rationale Rationale

A novel method for the preparation of core/shell nanospheres with drug- loaded lipid core was

designed and characterized.

The lipid core is composed of lecithin, which forms a

spherical supramolecular structure (multilamella

vesicles) in the concentrated state.

The polymeric shell is composed of pluronics (poly (ethylene oxide)- poly (propylene oxide)- poly(ethylene oxide)

triblock copolymer, F-127).

(14)

As an effective oil-soluble drug carrier, lipid and mixed micelle have been developed. However, lipid-based drug carriers composed of a single lipid

phase have several inherent problems, including the burst effect and difficulty in achieving zero order release. To overcome these difficulties, the core/shell nanoparticles with drug-loaded lipid core was prepared and characterized as a function of the thickness of polymeric shell.

the burst effect the controlled release

Introduction Introduction

(15)

Results and Discussion Results and Discussion

Cryo-TEM Pictures

(16)

Anionic Lecithin Nanolipid

Proteins with high isoelectric point (>8)

+

Proteins Adsorbrded Lecithin Nanolipid

Protein-loaded Core/Shell Nanoparticles

Rationale Rationale

(17)

Self-Assembly of Amphiphilic Block Copolymers into Polymeric Micelles

core-shell type micelle single polymer chain

hydrophobic block

hydrophilic block

micelle formation

outer shell inner core

Rationale

(18)

Advantage of Micellar Structure for Drug Delivery

• Micelle has unique structure which consist in hydrophilic surface an hydrophobic core.

- Hydrophilic surface : Contact with aqueous millieu

- Hydrophobic core : Contained hydrophobic drug

• Very useful of long blood

circulation and passive tumor targeting

Architecture of block copolymer micelles micelle

formation : drug/nanolipid

Hydrophilic segment

Hydrophobic segment

inner core outer shell Introductions

(19)

Self-assembling acid-sensitive amphiphilic block copolymer

Bae et al., Angew Chem, 2003, 115, 4788 Introductions

(20)

Introductions

Illustration of PIC (polyion complex) Micelle

Oishi et al.,CemBioChem, 2005, 6, 717

(21)

Introductions

Transfection Pathways

of Lipid carrier/DNA Complexes

Nucleus

Local destabilization Fusion Endocytosis

Early endosome

Degradation in lysosome

Endosomal escape (Fusion)

GENE EXPRESSION

Carrier/DNA complexes

Nucleus Transport

(22)

EPR effect에 의한 종양 선택성

Accumulation of Evans blue-albumin complex in tumor tissue and normal skin in tumor-bearing mice. Tumor S-180 was injected into the skin.

INTRODUCTION

(23)

SMANCS의 암조직 선택성

INTRODUCTION

(24)

Suppression of metastatic liver tumor by Lipiodol/SMANCS A: Lipiodol/SMANCS

(0.4mg/0.4ml/kg) B: Lipiodol/SMANCS

plus free lipiodol (0.4mg/0.4ml/kg) C: No drug control

(more than 500 tumor nodule)

암조직 생성의 억제

INTRODUCTION

(25)

INTRODUCTION INTRODUCTION

Blodd Vessels in MCa-IV Tumors

Hashizume et. al., American Journal of Pathology, 156(4), 1365-1380 (2000)

(26)

189 (342) 238 (378) Diameter 전/후(nm)

97.23 38.9

2 5/10 (#2)

94.33 18.9

1 5/10 (#1)

Loading efficiency (%) Actual loading

(w/w,%) DOX(mg)

Polymer(mg)/wa ter(ml)

Physical Loading into Self-Aggregates

Plasma ConcentrationPlasma Concentration

육 육 순 순 홍 홍 한남대학교 한남대학교

권 권 익 익 찬 찬 KIST KIST

나노 약물 전달

(요약)

TARGETING

TWO KEY TECHNOLOGIES FOR INJECTABLE DRUG DELIVERY

Depot Systems

PEGylation

PLGA PLGA

Solvent Evaporation Method

Paclitaxel Loading Paclitaxel Loading

Filtration

&

Freeze dry

Melting

Cooling

Characterization

Washing

Paclitaxel Loading Paclitaxel Loading

- -

Core/Shell Polymer System

the burst effect the controlled release

+

Self-Assembly of Amphiphilic Block Copolymers into Polymeric Micelles

core-shell type micelle single polymer chain

EPR effect에 의한 종양 선택성

INTRODUCTION

INTRODUCTION

SMANCS의 암조직 선택성

INTRODUCTION

INTRODUCTION

Suppression of metastatic liver tumor by Lipiodol/SMANCS A: Lipiodol/SMANCS

(0.4mg/0.4ml/kg) B: Lipiodol/SMANCS

plus free lipiodol (0.4mg/0.4ml/kg) C: No drug control

(more than 500 tumor nodule)

암조직 생성의 억제

INTRODUCTION

INTRODUCTION

INTRODUCTION INTRODUCTION

RESULTS AND DISCUSSION

RESULTS AND DISCUSSION