PLGA nanoparticle formulation of RK-33: an RNA helicase inhibitor against DDX3.
BACKGROUND
The DDX3 helicase inhibitor RK-33 is a newly developed anticancer agent that showed promising results in preclinical research (Bol et al. EMBO Mol Med, 7(5):648-649, 2015). However, due to the physicochemical and pharmacological characteristics of RK-33, we initiated development of alternative formulations of RK-33 by preparing sustained release nanoparticles that can be administered intravenously.


METHODS
In this study, RK-33 was encapsulated in poly(lactic-co-glycolic acid) (PLGA), one of the most well-developed biodegradable polymers, using the emulsion solvent evaporation method.


RESULTS
Hydrodynamic diameter of RK-33-PLGA nanoparticles was about 245 nm with a negative charge, and RK-33-PLGA nanoparticles had a payload of 1.4 % RK-33. RK-33 was released from the PLGA nanoparticles over 7 days (90 ± 5.7 % released by day 7) and exhibited cytotoxicity to human breast carcinoma MCF-7 cells in a time-dependent manner. Moreover, RK-33-PLGA nanoparticles were well tolerated, and systemic retention of RK-33 was markedly improved in normal mice.


CONCLUSIONS
PLGA nanoparticles have a potential as a parenteral formulation of RK-33.
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.|Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, The Netherlands.
Guus Martinus
GM
Bol
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.
Raheela
R
Khan
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.|Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, The Netherlands.
Marise Rosa
MR
Heerma van Voss
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.
Saritha
S
Tantravedi
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.
Dorian
D
Korz
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA. ykato@mri.jhu.edu.|Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ykato@mri.jhu.edu.|Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Science, Shinagawa-ku, Tokyo, Japan. ykato@mri.jhu.edu.
Yoshinori
Y
Kato
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA. vraman2@jhmi.edu.|Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, The Netherlands. vraman2@jhmi.edu.|Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. vraman2@jhmi.edu.
Venu
V
Raman
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004339:Drug Compounding; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000009:adverse effects / Q000737:chemistry*; D061986:MCF-7 Cells; D008819:Mice, Nude; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D010865:Pilot Projects; D011100:Polyglycolic Acid / Q000009:adverse effects / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020365:RNA Helicases / Q000037:antagonists & inhibitors*; D012995:Solubility; D013047:Specific Pathogen-Free Organisms; D014018:Tissue Distribution
C000603512:3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one; D000970:Antineoplastic Agents; D001381:Azepines; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D020365:RNA Helicases
DDX3; Drug release; Nanoparticles; PLGA; RK-33