PLGA for drug delivery

1. PLGA for drug delivery Huang Juan Huang Junlian Saskia Huijser Rob Duchateau

2. Introduction • Aliphatic polyesters have been extensively used as important biodegradable biomaterials for a wide variety of drug delivery carriers and biomedical devices. • They have biodegradability, versatile mechanical properties and proven biocompatibility. • Poly(L-lactide)(PLA) and poly(glycolide)(PGA) and poly(lactide-co-glycolide)(PLGA) are the most commonly used biodegradable and biocompatible polymers.

3. Synthesis of PLGA • 1.Melt polycondensation: step growth Lactic acid Glycolic acid PLGA: poly(lactic acid-co-glycolic acid)

4. Synthesis of PLGA • 2. Ring opening polymerization: chain growth Lactide Glycolide PLGA: poly(lactide-co-glycolide) a) Enzyme catalyst b) Metal catalyst

5. Enzymatic polymerization of PLGA • An increase in interest in enzyme-catalyzed organic reactions • Several advantages: • Catalysis under mild reaction conditions (Temperature, pH, Pressure) • Nontoxic natural catalyst • Have the ability to be used in bulk reaction media avoiding organic solvents • Several disadvantages: • Long reaction time • Low molecular weight

6. Enzyme of lipase PS Red site: Histidine Yellow site: Aspartic acid Green site: Serine Serine

7. Postulated Mechanism

8. Results and discussion The results of PLLA and PGA with/without lipase Reaction in bulk in 100 0C and using 8 wt % lipase

9. PLGA prepared by lipase at 100 0C for 7 d

10. PLLGA L/G=80/20using 8 wt% lipase PS at 100 0C The decrease in polymerization rate may be due to the low concentration of monomers and the high viscosity of the system.

11. PLLGA L/G=80/20 using 8 wt% lipase PS-DI at 100 0C Both Mw and polydispersity increase during the reaction time. The reaction rate of glycolide is faster than lactide.

12. 1H NMR spectrum (400 MHz, DMSO-d6) of PLLGA (with 8 wt% lipase PS at 100 0C for 7 d)

13. 13C{1H} NMR spectra (125MHz, CDCl3) of PLLGA (carbonyl region), a) PLLGA with lipase PS-DI at 100 0C for 7 d. b) PLLGA with lipase PS at 100 0C for 7 d

14. LL = (ILL+ILG)/ILG LG = (IGG+IGL)/IGL (nL and nG are lactide and glycolide molar fraction in copolymers respectively ) 13C{1H} NMR sequence analysis of PLLGA copolymers A random copolymer would have an average glycolyl sequence length, LG equal to 2.

15. MALDI-ToF MS spectra of PLLGA with lipase PS at 100 0C. Mass (m/z) = Mend group + mMla + nMga + MK+ (where Mend group = 18 or 0, Mla = 72, Mga = 58, MK+ = 39)

16. Main ion series determined by MALDI-ToF spectrum of PLLGA using lipase Series A Series B Series C

17. PLGA prepared by lipase at 130 0C for 7 d

18. PLLGA L/G=80/20 without catalyst at 1300C PLLGA L/G=80/20 using 8 wt% lipase PS at 1300C Mw decreases after the second day. High temperature increases chain depolymerization. Lipase PS may be denatured at this temperature.

19. PLLGA L/G=80/20 using 8 wt% lipase PS at 1300C PLLGA L/G=80/20 without catalyst at 1300C High temperature at 1300C increases the polymerization rate.

20. 4.Conclusion • Lipase PS works as catalyst to synthesize of PLGA and the conversion gets to 96%. • Transesterfication has occurred during the reaction. • PLGA copolymers obtained by lipase PS and lipase PS-DI at 100 0C are block copolymers. • A higher temperature increases the polymerization rate but also increases the depolymerization rate. • The PLGA copolymers from lipase might contain both linear and cyclic chains.

21. Acknowledgement • Prof. J.L. Huang • Ir. S. Huijser • Dr. R. Sablong • Dr. R. Duchateau • Prof. C.E. Koning • Dr. F.G. Karssenberg • Prof. P. J. Lemstra • Everybody who contributed to my project

22. Thank you for your attention !