Reformulation of etoposide with solubility-enhancing rubusoside.
Etoposide (ETO), a widely used anti-cancer drug, is constrained by its low aqueous solubility and by side effects from both the drug and its solubilizing excipients. In this study, a recently discovered natural solubilizer rubusoside (RUB) was used to achieve the solubilization of ETO. Dynamic light scattering and freeze-fracture transmission electron microscopy studies showed that ETO and RUB formed ETO-RUB nanoparticles (∼6 nm in diameter). The powder of ETO-RUB nanoparticles was completely reconstitutable in water and remained stable in this solution at 25 and 37°C for at least 24h. Under other physiologic conditions, ETO solution was clear and free of precipitation at 25°C, but underwent various structural transformations. In PBS and simulated intestinal fluid, RUB-solubilized ETO underwent epimerization and equilibrated to cis-ETO. In simulated gastric fluid, RUB-solubilized ETO degraded to 4'-demethylepipodophyllotoxin-beta-d-glucoside and 4'-demethylepipodophyllotoxin. Higher temperatures favored epimerization or degradation. Furthermore, a side-by-side comparison with DMSO-solubilized ETO confirmed that the RUB-solubilized ETO showed no significant differences in cytotoxicity in colon, breast and prostate cancer cell lines. RUB effectively solubilized and stabilized etoposide, which sets the stage for further toxicology, bioavailability, and efficacy investigations.
School of Renewable Natural Resources, LSU Agricultural Center, Louisiana State University, Baton Rogue, LA 70803, USA.
Fang
F
Zhang
Gar Yee
GY
Koh
Javoris
J
Hollingsworth
Paul S
PS
Russo
Rhett W
RW
Stout
Zhijun
Z
Liu
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D045786:Diterpenes, Kaurane / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005047:Etoposide / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D005079:Excipients / Q000737:chemistry*; D005260:Female; D005960:Glucosides / Q000737:chemistry*; D006801:Humans; D008027:Light; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D012542:Scattering, Radiation; D012995:Solubility; D013696:Temperature
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D005079:Excipients; D005960:Glucosides; D005047:Etoposide; C056177:rubusoside; D004121:Dimethyl Sulfoxide