Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

Abstract

7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C 10 -OH)SN38 and chitosan-(C 20 -OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C 10 -OH)SN38 (CS-(10s)SN38) and chitosan-(C 20 -OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC) 0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P <0.01). A larger AUC 0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 ( P <0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg ( P <0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C 20 -OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

High Potency of SN-38-Loaded Bovine Serum Albumin Nanoparticles Against Triple-Negative Breast Cancer

“…For the in vivo qualitative analysis, the HPLC-FL L-2000 series (Hitachi, Tokyo, Japan) was used at λ ex = 368 nm, λ em = 515 nm with an encapped Discovery HS C18 (150 × 4.6 mm, 5 µm) column at 30 °C [18,19]. The mobile phase was identical to that of the in vitro analysis, except that the duration was extended from 15 min to 19 min to ensure no flatulence before the next injection.…”

Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy

“…SN-38 is the active metabolite of irinotecan hydrochloride (CPT-11), which is 100- to 1000-fold more cytotoxic than CPT-11 30,32–35 . The conversion rate from CPT-11 to SN-38 by carboxylesterases after administration is typically inefficient and usually yields only 2–8% 30,36–38 . Direct administration of SN-38 instead of CPT-11 would bypass the inefficient enzymatic activation, and therefore improve anticancer efficacy of this drug.…”