Exploiting Albumin as a Versatile Carrier for Cancer Theranostics

Conspectus“Theranostics” is a portmanteau that links the fields of therapeutics and diagnostics; it describes a personalized medical approach with the expectation to improve the prognosis for cancer patients while reducing the risk of adverse effects that is currently commonly seen for many systemic cancer therapies. Theranostic radioligands can deliver radionuclides to tumors in a targeted manner, achieving both diagnosis and irreversible damage to tumor cells. Compared with chemotherapy, a therapeutic radioligand that directly damages the DNA sequence of tumor cells is less likely to be impacted by chemotherapy resistance, making the use of a radioligand a promising cancer treatment modality. However, many novel radioligands do not have optimal pharmacokinetics and are rapidly cleared out of the body. Therefore, there has been a long-standing interest in the development of long-acting formulas with prolonged circulation half-life.Albumin, as the most abundant protein in human serum, plays a pivotal role as a physiological carrier protein of, e.g., fatty acids and hormones. Its attributes, including extended circulation time, biodegradability, nontoxicity, and absence of immunogenicity, render it an exceptional candidate as a carrier for various drugs including theranostic agents. In this regard, three prominent albumin-based drug delivery technologies have been developed: (1) coupling small molecule drugs to exogenous or endogenous albumin, (2) employing fusion technology to conjugate bioactive proteins with albumin, and (3) encapsulating drugs within albumin nanoparticles. Of these technologies, the strategy that conjugate radioligands to albumin binding molecules stands out as one of the most widely applied approaches due to its minimal adverse effects and high efficiency in prolonging blood retention time. The utilization of albumin as a carrier for theranostic radioligands holds significant promise in precision medicine and diagnostic procedures.In this Account, we describe the recent development of long-acting radioligands. First, we give a brief introduction to radioligand therapy including its advantages and current challenges, such as fast blood clearance. Subsequently, we briefly summarize the approaches to prolonging blood circulation time with a focus on the albumin binding strategy. We also comprehensively review the structure of human serum albumin, its binders, and efforts in discovering new albumin binders that can be utilized in developing theranostic radioligands. Furthermore, we review the recent progress of PSMA-targeting long-acting radioligands, summarizing the relevant structure–activity relationships (SARs). Lastly, we outline the probable issues in the future development of radioligands. Collectively, the albumin binders, PSMA-targeting radioligands, and relevant SARs from our studies could shed new light on the future development of different theranostic radioligands.