Poly(imidazoyl)-Albumin Nanocarrier Responding to Two Metabolic States of Glycolytic Tumors for Targeted and Traceless Drug Delivery

Altered cellular metabolism is a hallmark of cancer progression, often leading to a chemical microenvironment of solid tumors (TME) that reveals significant differences from that of normal cells. Nanotherapeutics capable of detecting distinctive chemical signals within the disparate metabolic states of invasive cancer phenotypes represents a promising avenue for eliciting a favourable anti-tumor response, thereby enhancing drug efficacy and safety through microenvironment-selective cellular uptake and intracellular release. For instance, triple-negative breast cancer (TNBC), which is notoriously difficult to treat, typically features extracellular acidification and elevated intracellular glutathione (GSH) levels. By leveraging these distinctive metabolic characteristics, we have developed a surface-modified translational human serum albumin (HSA) nanocarrier, termed His-aHSA, which features anionic carboxylic acid and pH-inducible positively charged imidazole groups. This modification endows the nanocarrier with the ability to perceive the acidic TME, responding to a pH change typical for glycolytic, lactate producing tumors, which enables selective uptake into TNBC cells and spheroids. Notably, the nanocarrier His66-aHSA demonstrated a substantial increase in uptake at pH 6.5 of invasive TNBC in comparison to the pH relevant for normal tissue (pH 7.4). Furthermore, the clinically approved chemotherapeutic agent gemcitabine was conjugated via a self-immolative, redox-sensitive linker that responds to the high GSH levels typical of TNBC cancer cells and spheroids, thereby achieving a controlled and traceless intracellular drug release. It is notable that the traceless cleavable analogue (Gem-SS-His66-aHSA) exhibits a comparable IC₅₀ value of 6.1 nM, similar to that of the native drug (4.4 nM). Conversely, the non-cleavable analogue (Gem-His66-aHSA) displays an IC₅₀ that is over 10 times higher (74.6 nm).