946821-59-6Relevant articles and documents
Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity
Koseki, Yoshitaka,Ikuta, Yoshikazu,Cong, Liman,Takano-Kasuya, Mayumi,Tada, Hiroshi,Watanabe, Mika,Gonda, Kohsuke,Ishida, Takanori,Ohuchi, Noriaki,Tanita, Keita,Taemaitree, Farsai,Dao, Anh Thi Ngoc,Onodera, Tsunenobu,Oikawa, Hidetoshi,Kasai, Hitoshi
, p. 1305 - 1313 (2019)
In the field of drug delivery, controllability of drug release site and duration are among the most important factors to manipulate the drug efficacy and side effects. In this paper, a series of nano-prodrugs (NPs) composed of anticancer agent SN-38 and various substituent groups were synthesized and fabricated. By increasing the hydrophobicity of the prodrug molecule (calculated logP values exceeded ca. 7) through changing the substituent group, the hydrolysis susceptibility of SN-38 NPs in mouse serum was drastically decreased, thus prolonged the blood retention time of the NPs. In light of this knowledge and the dispersion stability in aqueous media, SN-38 NP modified with cholesterol (SN-38-chol NPs) was selected to be the optimal candidate among the screened NPs. The in vivo pharmacological effect of SN-38-chol NP was about 10 times higher than irinotecan, the clinically used solubilized prodrug analog of SN-38. In addition, SN-38-chol NP has low side effects in evaluating intestinal damage. These NPs possess great potential for clinical application and promise to be a next-generation of drug for cancer treatment.
Lactone Stabilization is Not a Necessary Feature for Antibody Conjugates of Camptothecins
Lau, Uland Y.,Benoit, Lauren T.,Stevens, Nicole S.,Emmerton, Kim K.,Zaval, Margo,Cochran, Julia H.,Senter, Peter D.
, p. 4063 - 4072 (2018)
Camptothecins exist in a pH-dependent equilibrium between the active, closed lactone and the inactive open-carboxylate forms. Several previous reports underscore the need for lactone stabilization in generating improved camptothecins, and indeed, such designs have been incorporated into antibody-drug conjugates containing this drug. Here, we demonstrate that lactone stabilization is not necessary for camptothecin-based ADC efficacy. We synthesized and evaluated camptothecin SN-38 drug linkers that differed with respect to lactone stability and released SN-38 or the hydrolyzed open-lactone form upon cleavage from the antibody carrier. An α-hydroxy lactone-linked SN-38 drug linker preserved the closed-lactone ring structure, while the phenol-linked version allowed conversion between the closed-lactone and open-carboxylate structures. The in vitro cytotoxicity, pharmacokinetic properties, and in vivo efficacy in the L540cy Hodgkin's lymphoma model of the corresponding ADCs were found to be indistinguishable, leading us to conclude that camptothecin-based antibody-drug conjugates possess pronounced activity regardless of the lactone state of the bound drug. This is most likely a result of ADC processing within acidic intracellular vesicles, delivering camptothecin in its active closed-lactone form.
CAMPTOTHECIN PEPTIDE CONJUGATES
-
Paragraph 0324, (2019/10/29)
Provided herein are Camptothecin Conjugates, Camptothecin-Linker Compounds, Camptothecin Compounds, intermediates thereof, and method of preparing the same. Also provided herein are methods of treating cancer and autoimmune diseases with the Conjugates described herein.
