TY - JOUR
T1 - Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies
AU - Chung, Chih Kit
AU - Fransen, Marieke F.
AU - van der Maaden, Koen
AU - Campos, Yaima
AU - García-Couce, Jomarien
AU - Kralisch, Dana
AU - Chan, Alan
AU - Ossendorp, Ferry
AU - Cruz, Luis J.
N1 - Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska Curie grant agreement No. 777682 (CANCER), 734684 (CHARMED), 861190 (PAVE), 857894 (CAST), 859908 (NOVA-MRI); 860173 (RISE-WELL); 872860 (PRISAR2), 807281 (ACORN), 852985 (SIMICA), 813834 (pHioniC), 643481 (ELECTOR) and 675743 (ISPIC). This work was also financially supported by the VIDI personal grant (project number 723.012.110 L.J.C.), which was financed by the Netherlands Organization for Scientific Research (NWO).
Funding Information:
This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska Curie grant agreement No. 777682 (CANCER), 734684 (CHARMED), 861190 (PAVE), 857894 (CAST), 859908 (NOVA-MRI); 860173 (RISE-WELL); 872860 (PRISAR2), 807281 (ACORN), 852985 (SIMICA), 813834 (pHioniC), 643481 (ELECTOR) and 675743 (ISPIC). This work was also financially supported by the VIDI personal grant (project number 723.012.110 L.J.C.), which was financed by the Netherlands Organization for Scientific Research (NWO).
Publisher Copyright:
© 2020 The Authors
PY - 2020/7/10
Y1 - 2020/7/10
N2 - Thermosensitive poloxamer 407 (P407) hydrogels were evaluated as slow release system for optimizing CTLA-4 therapy. Slow release reduces systemic antibody levels and potentially mitigates the side effects of CTLA-4 therapy. The 25% P407 hydrogel is injectable at room temperature and depots are established quickly after subcutaneous injection. Scanning electron microscopy revealed the porous structure of the hydrogel, average pore surface was 1335 μm2. Release studies were optimized using the human IgG antibody. IgG was easily incorporated in the hydrogel by simple mixing and no antibodies were lost during preparation. In vitro, hydrogels showed low burst release within the first 24 h. Total IgG load was gradually released within 120 h. In vitro cytotoxicity assays showed that P407 is not cytotoxic and induces no immune activation by itself. In vivo, P407 hydrogels significantly reduced serum IgG levels, were biocompatible and were broken down 1 week after injection. Finally, local hydrogel delivery of anti-CTLA-4 antibodies near established tumors effectively slowed down tumor growth, whilst significantly reduced serum anti-CTLA-4 levels. Altogether, P407 hydrogels represent promising delivery systems for the optimization of CTLA-4 blocking therapy.
AB - Thermosensitive poloxamer 407 (P407) hydrogels were evaluated as slow release system for optimizing CTLA-4 therapy. Slow release reduces systemic antibody levels and potentially mitigates the side effects of CTLA-4 therapy. The 25% P407 hydrogel is injectable at room temperature and depots are established quickly after subcutaneous injection. Scanning electron microscopy revealed the porous structure of the hydrogel, average pore surface was 1335 μm2. Release studies were optimized using the human IgG antibody. IgG was easily incorporated in the hydrogel by simple mixing and no antibodies were lost during preparation. In vitro, hydrogels showed low burst release within the first 24 h. Total IgG load was gradually released within 120 h. In vitro cytotoxicity assays showed that P407 is not cytotoxic and induces no immune activation by itself. In vivo, P407 hydrogels significantly reduced serum IgG levels, were biocompatible and were broken down 1 week after injection. Finally, local hydrogel delivery of anti-CTLA-4 antibodies near established tumors effectively slowed down tumor growth, whilst significantly reduced serum anti-CTLA-4 levels. Altogether, P407 hydrogels represent promising delivery systems for the optimization of CTLA-4 blocking therapy.
KW - Cytotoxic T-lymphocyte-associated protein 4
KW - Hydrogel
KW - Immune checkpoint blockade
KW - Immune related adverse event
KW - Poloxamer
KW - Sustained release
UR - http://www.scopus.com/inward/record.url?scp=85083309446&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2020.03.050
DO - 10.1016/j.jconrel.2020.03.050
M3 - Article
C2 - 32247805
AN - SCOPUS:85083309446
SN - 0168-3659
VL - 323
SP - 1
EP - 11
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -