Tuning of poly-S-nitrosated human serum albumin as superior antitumor nanomedicine.
Macromolecules have been developed as carriers of low-molecular-weight drugs in drug delivery systems (DDS) to improve their pharmacokinetic profile or to promote their uptake in tumor tissue via enhanced permeability and retention (EPR) effects. We have previously demonstrated that poly-nitric oxide (NO) conjugated human serum albumin (Poly-SNO-HSA) has the potential to be a DDS carrier capable of accumulating NO in tumors. However, the stability of Poly-SNO-HSA in the circulation has to be improved, and its optimal molecular size for using the EPR effects has to be evaluated. In the present study, we performed two tuning methods for refining Poly-SNO-HSA, namely, pegylation and dimerization. We observed that pegylation enhanced the stability of Poly-SNO-HSA both in vitro and in vivo, and that dimerization of Poly-SNO-HSA enhanced the antitumor activity via more efficient delivery of NO in Colon 26 tumor-bearing mice. Intriguingly, dimerization resulted in a 10 times higher antitumor activity. These data suggest that pegylation and dimerization of Poly-SNO-HSA are very important tuners to optimize NO stability and accumulation, and thereby effect, in tumors. Thus, polyethylene glycol-Poly-SNO-HSA dimer seems to be a very appealing and safe NO carrier and thereby a strong candidate as an antitumor drug in future development of cancer therapeutics.
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan.
Yu
Y
Ishima
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
Jun
J
Fang
Department of Biomedicine, University of Aarhus, Aarhus CDK-8000, Denmark.
Ulrich
U
Kragh-Hansen
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
Hongzhuan
H
Yin
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
Long
L
Liao
Pharmaceutical Research Laboratories, Kusatsu, Shiga 525-0055, Japan.
Naohisa
N
Katayama
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan.
Hiroshi
H
Watanabe
Tohoku Nipro Pharmaceutical Corporation, Kagamiishimachi, Iwasegun, Fukushima 969-0401, Japan.
Toshiya
T
Kai
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Ayaka
A
Suenaga
Drug Delivery System Institute, Sojo University, Kumamoto 860-0082, Japan.
Hiroshi
H
Maeda
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan; Drug Delivery System Institute, Sojo University, Kumamoto 860-0082, Japan. Electronic address: otagirim@ph.sojo-u.ac.jp.
Masaki
M
Otagiri
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
Toru
T
Maruyama
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D008297:Male; D008815:Mice, Inbred Strains; D050997:Nanomedicine / Q000379:methods*; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D055503:Protein Multimerization; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000075462:Serum Albumin, Human; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; D009603:Nitroso Compounds; C511514:S-nitrosoalbumin, human; D012709:Serum Albumin; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D000075462:Serum Albumin, Human
antitumor activity; cancer; controlled release/delivery; dimerization; drug delivery system; human serum albumin; macromolecular drug delivery; nanoparticles; nitric oxide; pegylation