Radioprotection in mice following oral administration of WR-1065/PLGA nanoparticles.
OBJECTIVE
N-(2-mercaptoethyl)1,3-diaminopropane (WR-1065), is the active metabolite of amifostine, a broad spectrum cytoprotective agent used in conjunction with both chemo- and radiotherapy of certain cancers. This report describes for the first time an oral formulation of WR-1065 and follows on from our earlier report of a similar oral formulation of amifostine.


METHODS
The nanoparticles of WR-1065 were prepared by spray drying technique using poly lactide-co-glycolide (PLGA) as the polymer matrix. Radioprotection was determined by measuring reductions in radiation-induced: (i) 30-day survival; (ii) bone marrow suppression; and (iii) intestinal injury following 9 Gray (Gy) whole body gamma irradiation in mice. All treatments were given 1 hour pre-irradiation and WR-1065 was tested at the dose of 500 mg/kg.


RESULTS
The WR-1065/PLGA nanoparticles were smooth and spherical with the average diameter of 206 nm and contained 21.7% (w/w) WR-1065. While irradiation markedly reduced 30-day survival in non-treated control mice, and caused significant bone marrow suppression and intestinal injury in surviving mice, oral administration of WR-1065/PLGA nanoparticles resulted in significant radioprotection as evidenced by a marked reduction in all three of the above mentioned parameters of radiation injury.


CONCLUSIONS
These findings clearly demonstrate the feasibility of developing an effective oral formulation of WR-1065 as a radioprotective agent.
Pamujula
Sarala
S
College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Kishore
Vimal
V
Rider
Barbara
B
Agrawal
Krishna C
KC
Mandal
Tarun K
TK
D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D007583:Jejunum / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008624:Mercaptoethylamines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D015996:Survival Rate
D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D011098:Polyglactin 910