title: Targeted cancer therapy with novel high drug-loading nanocrystals.
abstract: A novel nanocrystal formulation of hydrophobic drugs has been developed for cancer therapy. The new method, called a three-phase nanoparticle engineering technology (3PNET), includes three phases: phase 1, amorphous precipitate; phase 2, hydrated amorphous aggregate; and phase 3, stabilized nanocrystal. The 3PNET has been applied to two anticancer drugs, paclitaxel (PTX) and camptothecin (CPT), using Pluronic F127 (F127) polymer as a single excipient. The nanocrystals encapsulated over 99% of the drug with a high ratio of drug to excipient. The nanocrystal formulation of PTX did not induce hemolysis at pharmacologically relevant concentrations. Antitumor activity in two tumor models, human lung cancer and murine breast cancer, demonstrated that intravenously injected nanocrystals significantly inhibited the tumor growth. The nanocrystals also showed significant therapeutic effects via oral administration. In addition, the nanocrystals could be further modified for targeted delivery of PTX by conjugating a folate ligand to F127. The new nanomedicine formulations show clear potential for clinical development because of the excellent antitumor activity, low toxicity, and the ease of scale-up manufacture. The formulation method may apply to other hydrophobic drugs.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. fliu@email.unc.edu
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Conwell
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Surendar Reddy
authors.initials: SR
authors.lastname: Bathula
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use* / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage; D002352:Carrier Proteins / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D005079:Excipients; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005990:Glycerol / Q000031:analogs & derivatives; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D020442:Poloxamer; D011956:Receptors, Cell Surface / Q000187:drug effects; D013501:Surface-Active Agents
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D005079:Excipients; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D013501:Surface-Active Agents; D020442:Poloxamer; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol; D002166:Camptothecin