의료용 고분자

Professor, Ph.D. Kim, Hong Sung Biomaterials, Applied Life Science, Pusan National University

http:// 203.232.243.139/bm/, Polymeric Biomaterials Lab., Medical Polymers & Functional Scaffolds, khs@pnu.kr

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Nonviral vector for gene delivery

Chemically modified CTS • N,N,N- trimethylchitosan-galactose conjugate gene delivery by receptor-mediated endocytosis having recognizable saccharide residues polyelectrolyte complex with DNA

• modify by coupling ligands, lactose; lactosylated to target cell, galactose-binding lectin

Successful transfection for a few cell type

Medical Polymers, Functional Polymers, and Biomaterials

Medical Polymers, Functional Polymers, and Biomaterials

Ability to condense DNA • to form homogeneous population of complexes • Smaller than 100 nm

CTS-DNA complex • CTS intravenous injection rapid blood clearance no toxic, no hemolytic complex-ability with DNA

• CTS-DNA intravenous injection protect nuclease degradation low Mw, without liver accumulation

Medical Polymers, Functional Polymers, and Biomaterials

deoxycholic acid-coupling CTS • 5.1 deoxycholic acid/100 glucose • by EDC-mediated coupling reaction • self-aggregates • charge complex with plasmid DNA

CTS-plasmid DNA nanoparticles • oral allergen gene immunization to modulate

peanut antigen-induced anaphylactic response • transduced gene expression in intestinal epithelium • effective in murine anaphylactic response • prophylactic utility in food allergy

Medical Polymers, Functional Polymers, and Biomaterials

refer to next page

Medical Polymers, Functional Polymers, and Biomaterials

EDC (1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide Hydrochloride) 1. crosslinking agent used to couple carboxyl groups to primary amines 2. reacts with a carboxyl to form an amine-reactive O-acylisourea intermediate 3. react with an amine, yielding a conjugate of the two molecules joined by a stable

amide bond 4. intermediate is also susceptible to hydrolysis, making it unstable and short-lived

in aqueous solution 5. addition of Sulfo-NHS (5 mM) stabilizes the amine-reactive intermediate by conve

rting it to an amine-reactive Sulfo-NHS ester 6. thus increasing the efficiency of EDC-mediated coupling reactions 7. amine-reactive Sulfo-NHS ester intermediate has sufficient stability to permit two-

step crosslinking procedures

from 1990, useful excipient optimize in DDS, by modifying of amino

• at C2 of poly-β-(1-4-D-glucosamine) Task for peroral peptide delivery focus on

• overcoming absorption • enzymatic barrier

permeation-enhancing effect for drug • display even unmodified CTS

protective effect from intestinal peptidase • achieve by immobilization of enzyme inhibitor

Medical Polymers, Functional Polymers, and Biomaterials

co-administration of CTS and its derivatives • improve bioavailability of many peroral peptide

drugs – insulin, calcitonin, buserelin phosphonomethyl and carboxymethyl CTS

• dissolve in water at neutral cond. • maintain cosmetic property • increase utility

CTS succinate and phthalate matrices • pH dependent release pH 7.4: maximum drug release pH 2: resist dissolution

Medical Polymers, Functional Polymers, and Biomaterials

CTS

• GnRH(Gonadotropin Releasing Hormone)는 뇌의 배란, 월경, 생식 등에 관여하는 호르몬 분비를 조절하는 시상하부에서 분비되어 LH, FSH 분비를 조절. – Testosterone, Estrogen과 Progesterone 분비와 생성 자극 • GnRH agonist: GnRH 수용체에 강하게 결합 - 성조숙증, 자궁근종, 자궁내막증, 전립성암, 유방암 치료

Carbohydrate glycol CTS • fatty acid pendant group (11-16 mol%) • hydrophobic-hydrophilic polymer self-assembly • biocompatible and hemocompatible • entraping water-soluble drugs • oral and intranasal adm. of gut-labile molecules

CTS citrate as hydrocolloidal matrix N- lauryl-carboxymethyl CTS (LCC)

• lauryl attach to amino, CM attach to hydroxy • taxol-soluble LCC, micell particle size<100nm effective for passive targeting for tumor conc. of taxol in micell, very high, max. 2.37 mg/ml Medical Polymers, Functional Polymers, and Biomaterials

avoid the elimination due to body defence mechanisms • metabolism, excretion, and opsonisation

keep circulating in the blood stream be taken to the target receptor

• pH or warmth or molecular size or shape. critical or important properties

• molecular weight, charge on the surface, hydrophobic or hydrophilic nature of its surface and its size

Medical Polymers, Functional Polymers, and Biomaterials

Molecular Weight: • more than 30 Kda - can escape quick renal

clearance

Molecular Size: • not be more than 200 nm sizes less than 10 nm can filter out in most normal

capillaries of the endothelial cell tissue with big holes and allow upto 200 nm in tumour tissue Under normal circumstances the liver, the spleen and

the bone marrow have capillaries with large pores

Medical Polymers, Functional Polymers, and Biomaterials

Nature of surface: • hydrophilic to avoid removal by the mononuclear

phagocyte system (MPS) looking out for hydrophobic systems as a XENOBIOTIC Opsonization : binding opsonins (body proteins) be imbibed by macrophages in the blood Remove into the reticuloendothelial system

• steric stabilization: must attach hydrophilicity imparting agents such as

polyethylene glycols (PEGylation) stealth or cheating - the body into believing that it is

not a foreign body

Medical Polymers, Functional Polymers, and Biomaterials

Medical Polymers, Functional Polymers, and Biomaterials

Mononuclear phagocyte system 1. a part of the immune system that consists of the phagocytic cells

located in reticular connective tissue 2. consists primarily of monocytes and macrophages

• monocyte is formed in the bone marrow and transported by the blood

• migrates into the tissues and transforms into a histiocyte or a macrophage

• Macrophages are diffusely scattered in the connective tissue and in liver (Kupffer cells); spleen and lymph nodes (sinus histiocytes); lungs (alveolar macrophages); and central nervous system (microglia)

3. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years

4. accumulate in lymph nodes and the spleen 5. important role in defense against microorganisms

Surface Charge: • Negative charge - removed from the circulation

quickly by the Kupffer cells in the liver. • Positive charge - recognized as foreign bodies by

the opsonins • Only neutral systems have a long circulation time in

the blood

to keep it circulating in the blood, and to go to the expected target.

In addition, to attach a protein that can destabilize the natural biomembranes, and penetrate them

Medical Polymers, Functional Polymers, and Biomaterials

Medical Polymers, Functional Polymers, and Biomaterials

Triggered release • pH, temperature or charge in the body in the

target area • releases the drug only in that area and nowhere

else • the triggering mechanism is supplied from

outside the body • Example: On tumor where the temperature is a little bit higher,

the coat melt and release the drug - thermosensitive Drug-attached linker which is labile to a particular

enzyme which is found only in the target tumor Magnetic targeted delivery systems: IV injection to

localize drug in the defect, and apply magnetism from outside

Design for tumor in the liver • proper size and molecular weight • hydrophobic in nature Opsonization, be phagocytosized and will be left in

the liver

Strategy for target in the blood • placebo injection like dextran IV injection opsonins and the phagocytes will all be consumed reticuloendothelial system will be saturated

• real drug-carrier complex injection for staying in the blood for a long time

Medical Polymers, Functional Polymers, and Biomaterials

5-fluorouracil (5FU) • remarkable antitumor activity • reducing side effects, polymeric prodrug of 5FU • CTS derivatives, carrying 5FU, with some spacers hexamethylene spacer and carbamoyl linkage affinity for tumor cell, antitumor activity, prolong life

• Gel nanosphere immobilized 5FU derivatives aminophenyl carbamoyl 5FU, aminopentyl-ester-

methylene 5FU glutaraldehyde crosslinking coated with anionic polysaccharide

Medical Polymers, Functional Polymers, and Biomaterials

prodrug is a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into the active compound.

drug-pendanted 6-O-carboxymethyl chitin • couple enzyme-susceptible bond with chromophore-terminating peptides

Mitomycin C – CTS derivatives conjugate • N-succinyl-CTS and glycol-CTS • exhibit tumor growth suppression

Medical Polymers, Functional Polymers, and Biomaterials

CTS

mitomycins are a family of aziridine-containing natural products isolated from Streptomyces lavendulae. One of these compounds, mitomycin C, finds use as a chemotherapeutic agent by virtue of its antitumour antibiotic activity.

Final step of production before use • Sterilization of biomedical applications

Gamma irradiation at doses (>25 KGB) • main chain scission • decrease Mv with increasing irradiation dose

Irradiation in anoxia, not affect film properties significantly another methods • high pressure vapor, ultraviolet radiation,

ultrasonic, ethylene oxide gas, etc

Medical Polymers, Functional Polymers, and Biomaterials