ABSTRACT
Ephrin A2 targeted immunoliposomes incorporating pH-sensitive taxane prodrugs were developed for sustained delivery of active drug to solid tumors. Here we describe the systematic formulation development and characterization of these immunoliposomes. We synthesized both paclitaxel and docetaxel prodrugs to formulate as ephrin A2-targeted liposomes stabilized in the aqueous core with sucroseoctasulfate (SOS). The optimized lipid formulation was comprised of egg-sphingomyelin, cholesterol, and polyethylene glycol distearoyl glycerol (PEG-DSG). The formulations examined had a high efficiency of prodrug encapsulation (as high as 114â¯mol% taxane per mole phospholipid) and subsequent stability (>3â¯years at 2-8⯰C). The taxane prodrug was stabilized with extraliposomal citric acid and subsequently loaded into liposomes containing a gradient of SOS, resulting in highly stable SOS-drug complexes being formed inside the liposome. The internal prodrug and SOS concentrations were optimized for their impact on in vivo drug release and drug degradation. Cryo-electron microscope images revealed dense prodrug-SOS complex in the aqueous core of the immunoliposomes. Ephrin A2-targeted taxane liposomes exhibited sub-nanomolar (0.69â¯nM) apparent equilibrium dissociation constant toward the extracellular domain of the ephrin A2 receptor, long circulation half-life (8-12â¯h) in mouse plasma, a release rate dependent on intraliposomal drug concentration and stable long-term storage. At an equitoxic dose of 50â¯mg taxane/kg, ephrin A2-targeted liposomal prodrug showed greater antitumor activity than 10â¯mg/kg of docetaxel in A549 non-small cell lung, as well as MDA-MB-436 and SUM149 triple negative breast cancer xenograft models. The lead molecule entered a Phase I clinical trial in patients with solid tumors (NCT03076372).
Subject(s)
Antineoplastic Agents/administration & dosage , Bridged-Ring Compounds/administration & dosage , Drug Carriers/chemistry , Ephrin-A2/metabolism , Nanoparticles/chemistry , Prodrugs/administration & dosage , Taxoids/administration & dosage , A549 Cells , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacokinetics , Bridged-Ring Compounds/pharmacology , Cell Line, Tumor , Drug Compounding , Drug Liberation , Female , Humans , Liposomes , Mice, Nude , Particle Size , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Binding , Taxoids/chemistry , Taxoids/pharmacokinetics , Taxoids/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
One or more methoxy groups on the benzylic carbon at the ortho-position of tricarbonylchromium-complexed aryl aldehydes (2, 3 or 4) permit chelation-controlled addition of nucleophiles to the carbonyl function in the presence of Lewis acids. In the absence of a Lewis acid additive, a complementary set of diastereomeric products are obtained.
ABSTRACT
Formation of distinctly different products from the same alkoxide intermediate indicates a strong dependence of reaction pathways on counterions.
