Cancer is still a major public health problem and a leading cause of death worldwide. [1] Currently, an increasing number of emerging therapeutic modalities, such as immunotherapy, gene therapy, photodynamic therapy, photothermal therapy, and chemodynamic therapy, have been developed in addition to traditional surgery, radiation, and chemotherapy. [2] In all drug treatments, the tumor accumulation of active pharmaceutical ingredients is a crucial parameter, as it is essential for the concentration of the drug to reach its therapeutic threshold rapidly to produce an effective response. [3] Numerous anticancer formulations have been widely studied and put into clinical practice to improve the tumor accumulation of drugs. Smallmolecular prodrugs are derivatives of active drugs, [4] which undergo biotransformation to release the parent drug by exploiting specific hallmarks of tumor microenvironments (e.g., pH, enzyme expression, reactive oxygen species) or by utilizing external triggers (e.g., light, ultrasound, magnetic energy). [5] Moreover, targeted drugs refer to a new generation of anticancer drugs designed to interfere with a specific molecular target (typically a protein), anticipated to have a critical role in tumor growth or progression. [6] To promote tumor accumulation, targeted drugs have gained importance, including small molecules (e.g., tyrosine kinase, mammalian target of rapamycin and proteasome inhibitors) and macromolecules (e.g., monoclonal antibodies, polypeptides, antibody-drug conjugates, and nucleic acids). [7] In recent decades, nanomedicine has gained ever-growing attention in fighting cancer. [8] Nanomedicine provides an alternate pathway to improve tumor accumulation relying on a wide range of targeting strategies such as active targeting, passive targeting (enhanced permeation and retention [EPR] effect), stimuliresponsive targeting and their combination. [9] Despite these significant achievements, the drawbacks of high tumor accumulation have not yet been addressed well. [3,10] Currently, only a few formulations (e.g., Abraxane, Lapatinib, Telotristat etiprate) (www.clinicaltrials.gov) have been clinically approved to modify the toxicological profile of drugs in patients. [11]
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