Abstract
<jats:p>Curcumin, the principal curcuminoid of turmeric (), has long been recognized for its pleiotropic pharmacological activities, including antiinflammatory, antioxidant, and anticancer effects. Despite extensive preclinical validation, the clinical translation of curcumin has been hampered by its poor water solubility, rapid metabolic inactivation, and low oral bioavailability, resulting in subtherapeutic plasma and tissue concentrations even at high doses. These limitations have prompted the development of advanced formulation strategies, such as nanoparticles, liposomes, micelles, and prodrugs, to improve curcumin’s pharmacokinetic profile. However, these approaches often lack tumor specificity and insufficiently address the need for the specific targeting of malignant cells. Peptide–drug conjugates (PDCs) have emerged as a versatile modality for targeted cancer therapy, offering advantages over antibody–drug conjugates in terms of size, tissue penetration, manufacturing, and immunogenicity. By covalently linking a cytotoxic payload to a tumor-homing peptide via a cleavable or stable linker, PDCs can achieve receptor-mediated internalization and selective drug release within cancer cells, thereby enhancing efficacy and minimizing off-target toxicity. Among the recently emerging cell surface receptors highly expressed in multiple solid tumors, the sortilin (SORT1) receptor, a member of the VPS10p domain family, can mediate rapid endocytosis of its ligands, making it an attractive target for PDC-based tumor-selective targeting. TH1901, a curcumin-peptide conjugate, exemplifies this strategy by leveraging SORT1-mediated uptake to enhance the therapeutic index of curcumin. This chapter explores the rationale, design, and preclinical evaluation of TH1901, highlighting the comparative benefits of peptide-conjugated curcumin over its free form in the context of targeted SORT1 + cancer therapy.</jats:p>