Tumor-Acidity-Cleavable Maleic Acid Amide (TACMAA): A Powerful Tool for Designing Smart Nanoparticles To Overcome Delivery Barriers in Cancer Nanomedicine.

Over the past few decades, cancer nanomedicine has been under intensive development for applications in drug delivery, cancer therapy, and molecular imaging. However, there exist a series of complex biological barriers in the path of a nanomedicine from the site of administration to the site of action. These barriers considerably prevent a nanomedicine from reaching its targets in a sufficient concentration and thus severely limit its therapeutic benefits. According to the delivery process, these biological delivery barriers can be briefly summarized in the following order: blood circulation, tumor accumulation, tumor penetration, cellular internalization, and intracellular drug release. The therapeutic effect of a nanomedicine is strongly determined by its ability to overcome these barriers. However, advances in cancer biology have revealed that each barrier has its own distinct microenvironment, which imposes different requirements on the optimal design of nanocarriers, thus further complicating the delivery process. For example, the pH of blood is neutral, while the tumor extracellular environment features an acidic pH (pHe ≈ 6.5-7.0) and the endosome and lysosome are more acidic (pH 5.5-4.5). The nanoparticles (NPs) should be able to change their properties to adapt to each individual environment for robust and effective delivery. This demand promotes the design and development of smart delivery carriers that can respond to endogenous and exogenous stimuli. It is well-documented that tumors develop acidic extracellular microenvironments with pH ≈ 6.5-7.0 due to their abnormal metabolism in comparison with normal tissues. This provides a unique tool for designing smart NP drug delivery systems. Our studies have revealed that the NPs' physiochemical properties, such as particle size and surface charge, have profound effects on their systemic transport in the body. In different delivery stages, the NPs should possess different sizes or surface charges for optimal performance. We developed a class of stimuli-responsive NPs by incorporating tumor-acidity-cleavable maleic acid amide (TACMAA) as a design feature. TACMAA is produced by the facile reaction of an amino group with 2,3-dimethylmaleic anhydride (DMMA) and its derivatives and can be cleaved under tumor acidity. By virtue of such characteristics, NPs containing TACMAA enable size or surface charge switching at tumor sites so that they can overcome those delivery barriers for improved drug delivery and cancer therapy. In this Account, we systemically review the development and evolution of TACMAA-based delivery systems and elaborate how TACMAA helps the innovation and design of intelligent nanocarriers for overcoming the delivery barriers. In particular, our Account focuses on five parts: TACMAA chemistry, tumor-acidity-triggered charge reversal, tumor-acidity-triggered shell detachment, tumor-acidity-triggered size transition, and tumor-acidity-triggered ligand reactivation. We provide detailed information on how tumor-acidity-triggered property changes correlate with the ability of NPs to overcome delivery barriers.