title: Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice.
abstract: Realgar (As4S4) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As4S4. Raw As4S4 (r-As4S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4S4 were evaluated in vivo and in vitro. The results show that e-As4S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4S4. The bioavailability of e-As4S4 was up to 12.6-fold higher than that of r-As4S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4S4, inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice.
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D004195:Disease Models, Animal; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013154:Spleen / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016019:Survival Analysis; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D011108:Polymers; D013440:Sulfides; D014867:Water; C534735:tetraarsenic tetrasulfide