Ida Lepistö Helsinki-Kuopio pendolino

Transcription

1 Ida Lepistö Helsinki-Kuopio pendolino

2 OBJECTIVES What are polymer therapeutics? Why and how to conjugate drugs with polymers? How polymer conjugation can affect ADME-properties? in the end there will be questions!

3 POLYMER CONJUGATION is an efficient approach to improve the delivery of drugs and biological agents both by PROTECTING THE BODY FROM THE DRUG and by PROTECTING THE DRUG FROM THE BODY 2013 by Walter de Gruyter Berlin Boston

4 POLYMER THERAPEUTICS Polymer drugs Polymerdrug conjugate Multi component polyplexes Polymer therapeutics Polymer micelles Polymerprotein conjugate

5 PROBLEMS WITH NOVEL DRUGS Small molecules Poor solubility Lipophilic Bioavailability Short plasma circulation time Targeting Toxicity Biological agents Degradation Immunogenicity Poor efficacy Permeability Delivery

6 POLYMER CONJUGATION Backbone = macromolecular - biodegradable - semi-biodegradable - non-biodegradable but able to be eliminated - suitable functional groups Conjugation DIRECTLY to the drug or VIA LINKER/spacer - degradable - non-degradable Targeting moiety Solubilizing agent

7 WHAT PROPERTIES AFFECT THE ABSORPTION?

8 A ABSORPTION Water-solubility Preventing degradation (acidic stomach, gut lumen, metabolizing enzymes etc) Preventing drug from drug resistance mechanisms (efflux) Polymer-drug conjugates Paracellular/transcytosis instead of transcellular Chitosan: Opens tight junctions in intestine BA IDA LEPISTÖ 12/2/2017

9 D DISTRIBUTION Size: nm Shape: Long + flexible (linear) Circulation time Penetration into tissues Short + spherical (branched) Circulation time Cellular uptake Blood vessel penetration Surface charge and decorations Size: nm Shape: Long + flexible (linear) Circulation time Penetration into tissues Short + spherical (branched) Circulation time Cellular uptake Blood vessel penetration Surface charge and decorations

10 D DISTRIBUTION Altered biodistribution (BBB, liver, spleen) Vascular dynamics Uptake Drug release kinetics Degradation Accumulation Immunesystem/serum protein interactions relatively high MW PEG (40 kda) the bigger the size the faster the uptake by MPS Size: nm Shape: Long + flexible (linear) Circulation time Penetration into tissues Short + spherical (branched) Circulation time Cellular uptake Blood vessel penetration Surface charge and decorations

11 TARGETING Targeting moiety (active) Microenvironment Low ph Overexpression of enzymes Oxidative stress Linker Enzymatically cleavable or ph-sensitive Stable until destination Internalization Clathrin-coated vesicles diameter up tp 200 nm (endocytosis) Passive targeting Microenvironment EPR-effect

12 EPR ENHANCED PERMEABILITY AND RETENTION Blood vessels normally impermeable to macromolecules HPMA copolymer-doxorubicin (passive targeting) EPR effect nm Tumors DOXORUBICIN Diabetes, age-related macular degeneration, inflammation, rheumatoid arthritis (RA), psoriasis Lymphatic drainage normal, vascular not

13 M METABOLISM Biodegradable polymers Hydrolytic Enzymatic Natural polymers (collagen, hyaluronic acid amino acids, saccharides) Semi-degradable polymers Linkage breaking Non-degradable PEG, HPMA High MW in tissue after cell death/exocytosis lympha blood kidney (glomerular filtration, if possible)

14 E ELIMINATION IP>SC>IM, lower MW polymers eliminated sooner PEG anti PEG IgM antibodies (rapid clearance when present) allergies also may occur Accumulation into SPLEEN and liver Spleen macrophages responsible for clearance Into feces or urine

15 NAME ONE POLYMER THERAPEUTIC FOR EACH ADME-STAGE and describe how it works with few words. 1) Absorption 2) Distribution 3) Metabolism 4) Elimination

16 SUMMARY By conjugating small drugs or biological agents to polymer carriers one can Improve solubility and dissolution absorption Mask drug from degradation: metabolizing enzymes, immunological cells Improve targeting (active or passive EPR) Prevent systemic side effects or distribution into the CNS Get prolonged circulation in the bloodstream and decrease half-life

17 REFERENCES MARKOVSKY, E., BAABUR-COHEN, H., ELDAR-BOOCK, A., OMER, L., TIRAM, G., FERBER, S., OFEK, P., POLYAK, D., SCOMPARIN, A. and SATCHI-FAINARO, R., Administration, distribution, metabolism and elimination of polymer therapeutics. Journal of Controlled Release: Official Journal of the Controlled Release Society, 161(2), pp Kozlova, Diana and Matthias Epple. "Biological targeting with nanoparticles: state of the art" BioNanoMaterials, (2013): Retrieved 23 Oct. 2017, from doi: /bnm Kobayashi H, Watanabe R, Choyke PL. Improving Conventional Enhanced Permeability and Retention (EPR) Effects; What Is the Appropriate Target?. Theranostics 2014; 4(1): doi: /thno Available from The-intestinal-lining-epithelium-is