Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex.
OBJECTIVE
Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice.


METHODS
Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues.


RESULTS
In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P<0.01) and increased tissue levels up to 7-fold (P<0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P<0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation.


CONCLUSIONS
4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.
Maurer
Barry J
BJ
Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research and Division of Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA. bmaurer@chla.usc.edu
Kalous
Ondrej
O
Yesair
David W
DW
Wu
Xiaqin
X
Janeba
Jitka
J
Maldonado
Vanessa
V
Khankaldyyan
Vazgen
V
Frgala
Tomas
T
Sun
Bee-Chun
BC
McKee
R Travis
RT
Burgess
Stephen W
SW
Shaw
Walter A
WA
Reynolds
C Patrick
CP
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005227:Fatty Acids / Q000737:chemistry*; D017313:Fenretinide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008244:Lysophosphatidylcholines / Q000737:chemistry*; D051379:Mice; D050178:Monoglycerides / Q000737:chemistry*; D009447:Neuroblastoma / Q000188:drug therapy*; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy*; D011208:Powders; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D005227:Fatty Acids; D008244:Lysophosphatidylcholines; D050178:Monoglycerides; D011208:Powders; D017313:Fenretinide