Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

Abstract

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial C of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects.

Dendrimer nanoparticles for colorectal cancer applications

“…Theoretically, a possibility to improve therapeutic index consists on increasing drug exposure in the diseased tissue, without accumulation in the healthy tissues. Dendrimer nanotechnology offers this possibility, as shown by England et al [97]. They modified generation 5 L-lysine dendrimer with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan (Figure -4D).…”

“…View Article Online DOI: 10.1039/C9TB02289A Another anti-cancer drug currently used in the clinics is irinotecan [97]. However, its utility is limited by its narrow therapeutic index.…”

“…The linker with a plasma release half-life of 21 h achieved sustained SN-38 exposure in blood, above the target concentration. Overall, these extensive studies allowed to identify a linker, a dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximized efficacy and minimized adverse side effects [97].…”

Well-defined hyperstar copolymers based on a thiol–yne hyperbranched core and a poly(2-oxazoline) shell for biomedical applications

“…45 Recently, it was shown that POx-based hyperstars show great promise in vivo in the treatment of cancer. 46 In this article, we describe the combination of the beneficial properties of POx with narrow dispersity and high DB of thiolyne based hyperbranched polymers as an easy way to hyperstar copolymers (Scheme 1). Thiol end functionalized POx was produced using a two-step procedure involving end capping of the living polymerization with ethyl xanthate and subsequent aminolysis.…”

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

“…It has been reported that SN-38 had synergistic effect with phototherapy 28–29 . 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 .…”