Nucleic acid aptamers have minimal immunogenicity, high chemical synthesis production, low cost and high chemical stability when compared with antibodies. However, the susceptibility to nuclease degradation, rapid excretion through renal filtration and insufficient binding affinity hindered their development as drug candidates for therapeutic applications. In this review, we will discuss methods to conquer these challenges and highlight recent developments of chemical modifications and technological advances that may enable early aptamers to be translated into clinical therapeutics.

Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2′ position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.

Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.

Platinum­(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt­(IV) complexes. In this study, we systematically investigated and compared the properties of Pt­(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt­(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt­(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt­(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt­(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt­(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.

Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum­(II) drugs into more inert platinum­(IV) derivatives is a promising strategy to solve this problem. Some platinum­(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum­(IV) prodrugs, are not easily reduced to active platinum­(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum­(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum­(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt­(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum­(IV) prodrugs.