Targeted Treatment of Sarcomas by Single Protein Encapsulated Doxorubicin with Undetectable Cardiotoxicity and Superior Efficacy

Simple Summary Doxorubicin (DOX) is one of the main options for treating soft tissue sarcomas. However, a cumulative lifetime limit of <450 mg/m2 DOX has restrained its applications. Various formulation strategies have been developed to increase DOX’s efficacy and reduce toxicities but with limited success. We recently developed single-protein-encapsulated DOX, SPEDOX-6, a novel approach for improving DOX’s efficacy and reducing its side effects. Rat model studies demonstrated superior toxicokinetic properties and undetectable cardiotoxicity for SPEDOX-6 at high doses. Since the neonatal Fc receptor (FcRn) plays an essential role in maintaining the long half-life of IgG and human serum albumin (HSA), we also investigated the relationship between SPEDOX-6’s efficacy and FcRn level. In mouse models, SPEDOX-6 remarkably suppresses HT-1080 (lowest FcRn), compared to DOX, and is significantly better than Doxil/DOX in inhibiting SK-ES-1 (highest FcRn). Combined with a study on MB-MDA-231 (medium FcRn), SPEDOX-6’s antitumor efficacy displays an inverse relationship with FcRn levels in three tumor mouse models, thereby providing a potential mechanism for SPEDOX-6 to effectively target tumors with low FcRn levels.