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Cytotoxicita a imunostimulace - duální protinádorový útok moderních polymerních léčiv

Blanka Říhová. Cytotoxicita a imunostimulace - duální protinádorový útok moderních polymerních léčiv. Mikrobiologický ústav AV ČR. OD VÝZKUMU K LÉ Č B Ě. 50 000 nové látky 5 000 testy in vitro 500 testy in vivo 5 klinické testy 1 pou ž ití v klinické praxi. Free drug. Targeted drug.

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Cytotoxicita a imunostimulace - duální protinádorový útok moderních polymerních léčiv

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  1. Blanka Říhová Cytotoxicita a imunostimulace - duální protinádorový útok moderníchpolymerních léčiv Mikrobiologický ústav AV ČR

  2. OD VÝZKUMU K LÉČBĚ 50 000nové látky 5 000testy invitro 500testy in vivo 5klinické testy 1použití v klinické praxi

  3. Free drug Targeted drug

  4. ACTIVE x PASSIVE targeting

  5. Active targeting cell-surface receptors on target tumor cells

  6. Targeted drug Free drug Target cell Target cell

  7. Extracellular matrix Plasma membrane Intracellular fluid Endosome Lysosome

  8. Passive targeting (accumulation) EPR effect

  9. a) Normal tissue b) Tumor tissue Intact endothelium Effective lymphatic drainage Discontinuous endothelium Limited lymphatic drainage

  10. Směrované léčivo - pasivní směrování Složení: polymerní nosič + léčivo Enhanced Permeation and Retention effect (EPR) Endotel krevních vlásečnic v nádoru je defektní, kapiláry jsou propustné i pro vysokomolekulární komplexy Ve zdravé tkáni komplex neprojde = cílená terapie Lymfatická drenáž je defektní v nádoru = hromadění léčiva snížením rychlosti eliminace

  11. N-(2-hydroxypropyl)methacrylamide = HPMA = P

  12. STRUCTURE OF PRODRUGS PRODRUGS with ACTIVE TARGETING PRODRUGS with PASSIVE TARGETING

  13. STRUCTURE OF ANTIBODY-TARGETED HPMA COPOLYMER CARRIER-BOUND DOXORUBICIN DOX

  14. STRUCTURE OF (PK1) HPMA COPOLYMER CARRIER-BOUND DOXORUBICIN DOX

  15. STRUCTURE OF PRODRUGS ENZYMATICALLY ACTIVATED PRODRUGS pH-SENSITIVE PRODRUGS

  16. in vivo veritas

  17. ConjugateA Conjugate B

  18. NHN=Dox Dox=NHN NH NH2 X X NH NH2 X NHN=Dox NHN=Dox Dox=NHN Dox=NHN X-biodegradablespacer Hyperbranched conjugate - type A

  19. Hyperbranched conjugate – type B

  20. Survival of mice bearing EL4 T cell lymphoma and treated with hyperbranched conjugates AHYD or BHYD (dose 15 mg/kg) 100 80 60 surviving mice (%) 40 20 0 0 10 20 30 40 50 60 70 days Controls Hyperbranched B Hyperbranched A

  21. Survival of mice bearing EL4 T cell lymphoma and treated with hyperbranched conjugates AHYD or BHYD (dose 5 mg/kg) 100 80 60 surviving mice (%) 40 20 0 0 10 20 30 40 50 60 70 days Controls Hyperbranched B Hyperbranched A

  22. Tumor growth (EL4) afterthetreatmentwithhyperbranchedconjugates A and B (dose 5mg/kg): tumor size in mm3 daysize of tumor size of tumordaysize of tumor size of tumor conjugateAconjugateBconjugateAconjugateB 8288 256 11 726 600 600 320 600 172 726 550 320 600 256 500 256 320 320 320 550 864 405 288 600 500 550 288 221 256 405550550196 15600 196 18 550 126 600 75 486 32 352 108 1080 14 196 172 600 14 365 787 446 108 446 14 1268 787 118614750 7519660

  23. Tumor growth (EL4) after the treatment with hyperbranched conjugates A and B (dose 5mg/kg) ): tumor size in mm3 daysize of tumor size of tumordaysize of tumor size of tumor conjugateAconjugateBconjugateAconjugateB 222025 405 25 3324 1352 1080 4 3726 0 1080 4 2304 14 1080 3240 1960 0 2025 172 5566 4400 256 0 2890 864 1080 0 1437 0 40140 286534 1368 31 6613 2890 5400 256 9216 600 6050 0 8438 0 3468 0 12393 0 10571 6912 12152 9375 2816 2176 4050 3078 5292 0 10816 0 126 0 1099 0

  24. Tumor growth (EL4) after the treatment with hyperbranched conjugates A and B (dose 5mg/kg) ): tumor size in mm3 daysize of tumor size of tumordaysize of tumor size of tumor conjugateAconjugateBconjugateAconjugateB 357497 650 38 10571 0 9464 0 8750 6613 12166 0 9688 0 6534 3564 2432 1014 1470 6200 ex 0 6050 0 ex 0 10140 0 ex 11300 ex ex ex ex 425808 0 45 17100 0 17298 0 7142 0 ex 0 ex 0 ex 0 ex 0 ex 2601 ex 3179 ex 15857 ex ex ex 10206 ex ex ex ex ex ex

  25. Tumor growth (EL4) after the treatment with hyperbranched conjugates A and B (dose 5mg/kg) ): tumor size in mm3 daysize of tumor size of tumordaysize of tumor size of tumor conjugateAconjugateBconjugateAconjugate B 4910571 0 52 ex 0 ex 0 ex 0 ex 0 ex 0 ex 0 ex 0 ex 6613 ex ex ex ex ex ex ex ex ex ex ex ex ex ex 56ex 0 59 ex 0 ex 0 ex 0 ex 0 ex 0 ex 0 ex 0 ex ex ex ex ex ex ex ex ex ex ex ex ex ex ex ex

  26. GENERAL RULES Tumor stop to grow in two - three days after the treatment The first significant shrinkage could be seen in five – six days after the treatment If there is no response until the day 10, the treatment has to be considered as non-effective

  27. The immune system of the host

  28. Equilibrium Elimination (Cancer Immunosurveillance) gd NK Genetic instability/ immune selection Protection

  29. Re-transplantation

  30. Re-transplantation 8 – 12 days 3 – 8 months dead mice surviving mice (up to 100%) strong systemic anti-tumor resistance lethal dose of cancer cells polymer-bound drugs CURED mice lethal dose of cancer cells ! NO TREATMENT!

  31. STRUCTURE OF (PK1) HPMA COPOLYMER CARRIER-BOUND DOXORUBICIN DOX

  32. A B Survival of mice –PRIMARY TREATMENT Dox-HPMAHYD Survival of mice –RE-TRANSPLANTATION Dox-HPMAHYD • controls1x75 mg/kg Dox 1x25 mg/kg

  33. STRUCTURE OF ANTIBODY-TARGETED HPMA COPOLYMER CARRIER-BOUND DOXORUBICIN DOX

  34. A B Survival of mice –PRIMARY TREATMENT Dox-HPMAAM or Dox-HPMAAM-HuIg Survival of mice – RE-TRANSPLANTATION Dox-HPMAAM or Dox-HPMAAM-HuIg • controls Dox-HPMAAM-HuIg Dox-HPMAAM

  35. Polymeric drugs based on HPMA cytotoxic immunomodulation component

  36. Cytotoxicity and immunostimulation double attack on cancer cells with polymeric therapeutics

  37. Protection against the second cancer attack

  38. Systemic antitumor resistance initiated by the treatment with polymeric drugs depends on Dose Time The immune system of the host

  39. Dose

  40. A B Survival of mice –PRIMARY TREATMENT Dox-HPMAHYD Survival of mice –RE-TRANSPLANTATION Dox-HPMAHYD • controls1x75 mg/kg Dox 1x25 mg/kg

  41. More aggressive treatment lower resistance

  42. Too earlythe immune system is not supplied with a sufficient amount of antigens (cancer cells) for effector-cell activation Too latethe effector mechanisms of the cancer-bearing host’s immune system are already exhausted and unable to be activated, resulting in only very limited cancer resistance

  43. Time

  44. RESISTANCE AGAINST BCL1 LEUKEMIA DEPENDS ON THE INTERVAL BETWEEN TUMOR CELL INOCULATION AND APPLICATION OF THE ANTIBODY-TARGETED CONJUGATE (DOX-HPMA-B1MAB) Conjugatesurvival of survival of experimental micere-transplanted mice (day) (n = 10)(1 x 104 BCL1 cells i.p.) 1 100% 0% 17 100% 30% 11 100% 20% 15 60% 0% Control (BPS) 0% 0%

  45. „vaccination window – optimal time frame “ treatment given too early or too late after transplantation of cancer cells induces only a limited resistance

  46. The effect of Dox-HPMAAM/DOX-HPMAHYD mixture (1:2) on the growth of EL4 T cell lymphoma: conventional mice Survival of mice 100 80 60 % of survival 40 20 0 0 10 20 30 40 50 60 days DOX-HPMAAM/Dox-HPMAHYD mixture (1:2) controls

  47. The effect of Dox-HPMAAM/DOX-HPMAHYD mixture (1:2) on the growth of EL4 T cell lymphoma: nu/nu mice Survival of mice 100 80 60 % of survival 40 20 0 0 10 20 30 40 50 60 days DOX-HPMAAM/Dox-HPMAHYD mixture (1:2) controls

  48. Survival of mice bearing EL4 T cell lymphoma and treated with hyperbranched conjugate BHYD or linear conjugate Dox-HPMAAM - conventional mice 100 80 60 surviving mice (%) 40 20 0 10 20 30 40 50 60 80 70 0 days Hyperbranched B/15mg Hyperbranched B/10mg Controls Dox Linear/15 mg Linear/10 mg

  49. Survival of mice bearing EL4 T cell lymphoma and treated with hyperbranched conjugate BHYD or linear conjugate Dox-HPMAAM - nu/nu mice 100 80 60 surviving mice (%) 40 20 0 0 10 20 30 40 50 60 70 days Hyperbranched B/15mg Hyperbranched B/10mg Controls Dox Linear/15 mg Linear/10 mg

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