TY - JOUR
T1 - Poly-isoprenylated ifosfamide analogs
T2 - Preactivated antitumor agents as free formulation or nanoassemblies
AU - Skarbek, Charles
AU - Delahousse, Julia
AU - Pioche-Durieu, Catherine
AU - Baconnais, Sonia
AU - Deroussent, Alain
AU - Renevret, Patrice
AU - Rivard, Michael
AU - Desmaele, Didier
AU - Martens, Thierry
AU - Le Cam, Eric
AU - Couvreur, Patrick
AU - Paci, Angelo
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/11/5
Y1 - 2017/11/5
N2 - Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.
AB - Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.
KW - Cancer drug delivery
KW - Ifosfamide
KW - Nanoassemblies
KW - Prodrug
UR - http://www.scopus.com/inward/record.url?scp=85019846374&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2017.05.044
DO - 10.1016/j.ijpharm.2017.05.044
M3 - Article
C2 - 28546071
AN - SCOPUS:85019846374
SN - 0378-5173
VL - 532
SP - 748
EP - 756
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 2
ER -