Intra and inter-molecular interactions dictate the aggregation state of irinotecan co-encapsulated with floxuridine inside liposomes.
OBJECTIVE
The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (copper gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio.


METHODS
Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro-release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV-Vis were used to characterize the aggregation state of the drugs within the liposomes.


RESULTS
Coordinated release of the drugs from liposomes was disrupted by removing copper gluconate. Approximately 45% of the total irinotecan was detectable in the copper-containing CPX-1 formulation by NMR, which decreased to 19% without copper present in the liposomal interior. Formation of higher order, NMR-silent aggregates was associated with slower and uncoordinated irinotecan release relative to floxuridine and loss of the synergistic drug/drug ratio. Solution spectroscopy and calorimetry revealed that while all formulation components were required to achieve the highest solubility of irinotecan, direct drug-excipient binding interactions were absent.


CONCLUSIONS
Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.
Dicko
Awa
A
Celator Pharmaceuticals Corp., 1779 W 75th Avenue, Vancouver, British Columbia V6P6P2, Canada.
Frazier
April A
AA
Liboiron
Barry D
BD
Hinderliter
Anne
A
Ellena
Jeff F
JF
Xie
Xiaowei
X
Cho
Connie
C
Weber
Tom
T
Tardi
Paul G
PG
Cabral-Lilly
Donna
D
Cafiso
David S
DS
Mayer
Lawrence D
LD
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry*; D002151:Calorimetry; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D002784:Cholesterol; D003300:Copper; D004337:Drug Carriers; D004339:Drug Compounding; D005079:Excipients; D005467:Floxuridine / Q000008:administration & dosage / Q000737:chemistry*; D005942:Gluconates; D000077146:Irinotecan; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005079:Excipients; D005942:Gluconates; D008081:Liposomes; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D005467:Floxuridine; C084352:distearoyl phosphatidylglycerol; D000077146:Irinotecan; D003300:Copper; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D002166:Camptothecin