Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.
MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.
a Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , Texas Southern University , Houston , TX , USA .
Su
S
Liang
a Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , Texas Southern University , Houston , TX , USA .
Xiaomei
X
Bian
a Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , Texas Southern University , Houston , TX , USA .
Dong
D
Liang
b Department of Biological Sciences, Border Biomedical Research Center , University of Texas at El Paso , El Paso , TX , USA , and.
Jeffrey C
JC
Sivils
c Urologic Oncology Branch , National Cancer Institute , Bethesda , MD , USA.
Leonard M
LM
Neckers
b Department of Biological Sciences, Border Biomedical Research Center , University of Texas at El Paso , El Paso , TX , USA , and.
Marc B
MB
Cox
a Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , Texas Southern University , Houston , TX , USA .
Huan
H
Xie
D000813:Anilides / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019999:Pharmaceutical Solutions / Q000138:chemical synthesis / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D051381:Rats; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000813:Anilides; D000970:Antineoplastic Agents; D003510:Cyclohexanes; C000611744:N-(2,3-dichlorophenyl)cyclohexanecarboxamide; D019999:Pharmaceutical Solutions
Androgen-independent; MJC13; castration-resistant prostate cancer; efficacy; formulation; preformulation