Novel nanoassemblies composed of squalenoyl-paclitaxel derivatives: synthesis, characterization, and biological evaluation.
Using the anticancer compound paclitaxel as a model drug, this study investigates the potential of the squalenoylation technology (i.e., bioconjugation with the natural lipid squalene) in addressing the drug ability and delivery issues of poorly soluble therapeutic agents. In this view, a variety of novel squalene-based prodrugs of the anticancer compound paclitaxel were synthesized, which produced nanoparticles in water. These prodrugs were obtained by covalent coupling of the paclitaxel 2'-hydroxyl group as direct ester, as well as with a succinate or a diglycolate ester as cleavable linker to the 1,1',2-tris-norsqualenoic acid. The hydrophilicity of these paclitaxel bioconjugates was increased by placing poly(ethylene glycol) chains of different lengths between paclitaxel and the squalenoyl moiety. All these prodrugs self-assembled into nanosized aggregates in aqueous solution as characterized by dynamic light scattering, atomic force microscopy, and transmission electron microscopy. The critical aggregation concentration was very low, ranging from 0.09 to 0.4 mg/L. Zeta potential measurements revealed that all squalenoyl-paclitaxel nanoassemblies (NA) held a global negative charge and appeared stable in water for several weeks as determined by particle size measurement. The release of paclitaxel from NA was evaluated in different conditions and in the presence of serum and depended on the nature of the linker used. Preliminary biological assessment showed that these squalenoyl-paclitaxel NA induced the formation of microtubule bundles in HT-29 and KB-31 cells, and additionally displayed notable cytotoxicity on a lung tumor cell line. Furthermore, the cytotoxic activity of these different prodrugs correlated closely with the observed linker stability. Overall, the squalenoylation nanotechnology opens up interesting perspectives for the development of injectable prodrugs of poorly soluble therapeutic compounds by addressing the associated physicochemical and biopharmaceutical challenges.
Dosio
Franco
F
Universita degli Studi di Torino, Facolta di Farmacia, Dipartimento di Scienza e Tecnologia del Farmaco, 10125 Torino, Italy. franco.dosio@unito.it
Reddy
L Harivardhan
LH
Ferrero
Annalisa
A
Stella
Barbara
B
Cattel
Luigi
L
Couvreur
Patrick
P
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000737:chemistry; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013185:Squalene / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013499:Surface Properties; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D011092:Polyethylene Glycols; D013185:Squalene; D017239:Paclitaxel