Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Abstract

Anthracyclines have long been considered to be among the most active agents clinically available for the treatment of breast cancer despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted NC-6300, was synthesized. NC-6300 comprises epirubicin covalently bound to polyethyleneglycol polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure spontaneously in aqueous media with a diameter of 60-70 nm. The block copolymers are partially substituted with hydrophobic benzyl groups to stabilize the micellar structure. The present study was designed to confirm that polymeric micelles incorporating epirubicin through an acid-labile linker improve the therapeutic index and achieve a broad range of therapeutic doses. Pharmacokinetic studies in rats showed highly enhanced plasma retention of NC-6300 compared with native epirubicin. The maximal tolerated doses in mice of NC-6300 and native epirubicin were 25 and 9 mg/kg, respectively, when administered three times with a 4-day interval between each dose. NC-6300 at 15 and 20 mg/kg with the same administration schedule regressed a Hep3B human hepatic tumor with slight and transient bodyweight loss. Remarkably, NC-6300 also inhibited growth of an MDA-MB-231 human breast tumor at the same dosage. In contrast, native epirubicin at 7 mg/kg administered three times with a 4-day interval was only able to slow tumor growth. Tissue distribution studies of NC-6300 showed efficient free epirubicin released in the tumor at 74% by area under the concentration-time curve (AUC) evaluation, supporting the effectiveness of NC-6300. In conclusion, NC-6300 improved the potency of epirubicin, demonstrating the advantage of NC-6300 attributable to the efficient drug release in the tumor. (Cancer Sci 2011; 102: 192-199) A nthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease despite their cardiotoxicity.(1) The aim of increasing their efficacy was first addressed using liposomes.(2) Efforts to design liposomes that are pH-sensitive, temperature-sensitive or antibody-targeted have all been pursued with various degrees of success.(3) However, current clinically approved liposomal formulations have still resulted in only modest increased efficacy for the treatment of cancer.(4) Its actual advantage is reduced toxicity rather than increased therapeutic effect. To increase the efficacy, polymer-based anthracyclines have also been studied extensively. (8,9) Recent strategies have been developed and successfully applied to attain desirable tumor localization through polymeric micelles composed of polyethylene glycol (PEG)-poly (amino acid) block copolymers.(10) These types of strategies involve drug release inside endosomes and lysosomes after cellular internalization, where the slightly acidic pH leads to cleavage of the acid-sensitive linkage.

NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo

“…Of these, polymeric, micelle-based, anticancer drugs were originally developed by Kataoka et al [1][2][3] The assumed bases of higher effectiveness and lower toxicity of anticancer nanoDDSs are the "enhanced permeability and retention (EPR) effect". 4 In addition to the EPR effect, the drug release rate from macromolecular DDSs is also critical to efficacy, 5,6 for the following two reasons: (1) time course of plasma concentration of the naked drug is important, since it is the loaded drug that has toxic effects for both normal and tumor cells; (2) not all nanoDDSs reach their target tissue, releasing the loaded drugs in plasma. The release rate of loaded drugs with polymeric micelles can be optimized by various methods such as redesigning the chemical bond between polymer and drug; however, with liposomes, it is not easy to control release rate, because they have a stable lamella of lipid bilayer on the surface to contain drugs.…”

The Drug Discovery by NanoMedicine and its Clinical Experience

“…The conjugate spontaneously forms a micellar structure with a diameter of 40 -80 nm in aqueous media, as reported previously (53). In vitro findings indicated that it exhibited pH-dependent EPI release, namely, the release of EPI from NC-6300 accelerated under increasingly acidic conditions.…”

Nanomedicine Drug Development: A Scientific Symposium Entitled “Charting a Roadmap to Commercialization”

“…Adaptive designs can provide robust answers to study questions and in the meantime reduce the total number of patients required, resulting in potentially reduced costs and shorter timelines than traditional trials. The session concluded with Iulian Bobe from NanoCarrier sharing his company's experience in clinical development program for nanomedicines (20).…”