Novel disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate/human serum albumin nanoparticles for breast cancer therapy

Abstract

7-Ethyl-10-hydroxyl camptothecin (SN38), a semisynthetic derivative of camptothecin, exhibited extreme pharmacological activities in treating a range of cancers. However, its poor aqueous solubility and low stability hinder its clinical applications. Hence, a redox-responsive SN38 prodrug encapsulated human serum albumin (HSA) nanoparticle is developed to realize its potential in the clinic. First, a disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate (SN38-SS-COOH) was synthesized and characterized structurally. After that, SN38-SS-COOH/HSA nanoparticles (SNH NPs) were prepared by the desolvation method. The SNH NPs with a feed molar ratio of 9 : 1 of SN38-SS-COOH : HSA showed a spherical structure with a diameter range of approximately 120–150 nm revealed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Fluorescence quenching confirmed the formation of SNH NP complexes by dual hydrophobic force and electrostatic interaction. The SNH NPs have a high drug loading of 10.44% and an encapsulation efficiency of 89.59% with good stability. Moreover, the redox responsiveness was validated by glutathione (GSH)-triggered accelerated release of parent drug SN38. In an in vivo pharmacokinetic study, the SNH NPs exhibited a significantly prolonged circulation time (t_1/2, 3.77-fold) compared with free SN38. Finally, the in vivo antitumor efficacy and systemic toxicity of SNH NPs in a breast xenograft model were thoroughly evaluated. The inhibition rate of tumor growth induced by the SNH NPs reached 70.1%, while only 50.1% was achieved for irinotecan at an equivalent SN38 dosage of 10 mg kg⁻¹. More importantly, the SNH NPs achieved a higher level of tumor growth inhibition (85.3%) by increasing the dosage to 60 mg kg⁻¹ SN38 without obvious adverse effects. Taken together, the use of redox-responsive SN38 prodrug/HSA NPs could be a promising strategy to deliver highly active SN38 for breast cancer chemotherapy.