Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014:2014:963507.
doi: 10.1155/2014/963507. Epub 2014 May 7.

Human serum albumin conjugates of 7-ethyl-10-hydroxycamptothecin (SN38) for cancer treatment

Nima Sepehri  1 , Hasti Rouhani  1 , Ahmad Reza Ghanbarpour  2 , Mehdi Gharghabi  3 , Faranak Tavassolian  2 , Mohsen Amini  4 , Seyed Nasser Ostad  3 , Mohammad Hossein Ghahremani  3 , Rassoul Dinarvand  2
Affiliations

Human serum albumin conjugates of 7-ethyl-10-hydroxycamptothecin (SN38) for cancer treatment

Nima Sepehri et al. Biomed Res Int. 2014.

Abstract

SN38 (7-ethyl-10-hydroxy-comptothecin) is a potent metabolite of irinotecan, which has been approved for treatment of metastatic colorectal cancer. Considering the notable potency of SN38, it has been introduced as an anticancer candidate. In this study, human serum albumin (HSA) conjugates of SN38 were formulated to overcome the solubility problem beside improving the active form stability and tumor tissue targeting. In this target, two different molar ratios of conjugates (SN38 : HSA 15 : 1 and 60 : 1) were prepared by derivatization of 20-hydroxyl group of SN38 with glycine, followed by addition of succinyl group to glycine through which HSA was covalently attached. The conjugates with particle size of about 100 nm revealed enhanced water solubility and were relatively stable in neutral and acidic solutions. For SN38-HSA-15 and SN38-HSA-60 IC50 values were compared with irinotecan in HT-29 human colon cancer cells. Furthermore, biodistribution studies of SN38-HSA conjugate resulted in proper blood concentration level within 4 h. Moreover, blood cytotoxicity assay revealed no toxicity effect on liver and spleen. Collectively, our present investigation offers a water-soluble form of SN38 attached to HSA and suggests using favorable properties as a promising anticancer agent for further preclinical and clinical investigations.

PubMed Disclaimer

Figures

Figure 1
Figure 1
SN38-HSA synthesis scheme. The process consists of phenolic OH protection of SN38 (Compound 2), addition of glycine molecule (Compound 3), OH deprotection (Compound 4), succinyl addition (Compound 5), and HSA conjugation (Compound 6).
Figure 2
Figure 2
The SEM micrographs of the conjugate (SN38-HSA) in different magnification levels.
Figure 3
Figure 3
The release behavior of SN38 from (a) SN38-HSA-15 and (b) SN38-HSA-60 conjugates in pH 7.4 (◆) and 5.2 (■) and (c) SN38-HSA-15 (■) and SN38-HSA-60 (▲) conjugates in rat plasma (n = 3).
Figure 4
Figure 4
SDS-PAGE analysis of free HAS and SN38 conjugates (SN38-HSA-60 and SN38-HSA-15).
Figure 5
Figure 5
In vitro cytotoxicity effect on HT-29 cell line after 48 h incubation time of (a) conjugates and free SN38 with different concentrations. Symbols: ■ as SN38-HSA-15, ▲ as SN38-HSA-60, and ◆ as free SN38. (b) Irinotecan with different concentrations. (c) In vitro cytotoxicity of free SN38, SN38-HSA conjugates at 1.6 SN38 equivalent concentration and irinotecan (1.6 μM) compared to vehicle and HSA (n = 6). ***: significantly different with P value < 0.01.
Figure 6
Figure 6
Biodistribution of free SN38 and SN38-HAS-15, 4 h after i.v. injection in balb/c mice.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Research. 1991;51(16):4187–4191. - PubMed
    1. Saga Y, Mizukami H, Suzuki M, et al. Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells. Clinical Cancer Research. 2002;8(5):1248–1252. - PubMed
    1. van Ark-Otte J, Kedde MA, van der Vijgh WJF, et al. Determinants of CPT-11 and SN-38 activities in human lung cancer cells. British Journal of Cancer. 1998;77(12):2171–2176. - PMC - PubMed
    1. Atyabi F, Farkhondehfai A, Esmaeili F, Dinarvand R. Preparation of pegylated nano-liposomal formulation containing SN-38: in vitro characterization and in vivo biodistribution in mice. Acta Pharmaceutica. 2009;59(2):133–144. - PubMed
    1. Sargent DJ, Niedzwiecki D, O'Connell MJ. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. The New England Journal of Medicine. 2001;345(2):145–146. - PubMed

Publication types

MeSH terms