Targeted anticancer prodrugs that
can be controllably activated
are highly desired for personalized precision medicine in cancer therapy.
Such prodrugs with unique action modes are also promising to overcome
drug resistance. Herein, we report coumaplatin, an oxaliplatin-based
and photocaged Pt(IV) prodrug, to realize nuclear accumulation along
with “on-demand” activation. This prodrug is based on
a Pt(IV) complex that can be efficiently photoactivated via water
oxidation without the requirement of a reducing agent. Coumaplatin
accumulates very efficiently in the nucleoli, and upon photoactivation,
this prodrug exhibits a level of photocytotoxicity up to 2 orders
of magnitude higher than that of oxaliplatin. Unexpectedly, this prodrug
presents strikingly enhanced tumor penetration ability and utilizes
a distinct action mode to overcome drug resistance; i.e., coumaplatin
but not oxaliplatin induces cell senescence, p53-independent cell
death, and immunogenic cell death along with T cell activation. Our
findings not only provide a novel strategy for the rational design
of controllably activated and nucleolus-targeted Pt(IV) anticancer
prodrugs but also demonstrate that accumulating conventional platinum
drugs to the nucleus is a practical way to change its canonical mechanism
of action and to achieve reduced resistance.
We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinum(IV) antitumor prodrug that can be controllably activated by red light. Phorbiplatin maintains its integrity without irradiation, but under irradiation with red light, the prodrug is quickly and efficiently activated, releasing oxaliplatin and PPA. The prodrug shows significant antitumor activity both in vitro and in vivo.
DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA-damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a Pt anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin-induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual-action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin-resistant human cancer cells with an up to 88-fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt-induced DNA damage as a novel strategy to conquer cisplatin resistance.
The efficacy of conventional chemotherapy is hindered by cancer cell escape from the immune system. A multifunctional nanohybrid system is reported for effective immunochemotherapy against cervical cancer. This nanohybrid contains both immune checkpoint inhibitor and cisplatin anticancer prodrug, showing improved cellular accumulation and increased binding of Pt to DNA and resulting in elevated apoptosis than using cisplatin alone when tested in cervical cancer cells. The immune checkpoint inhibitor enables the inhibition of indoleamine-2,3-dioxygenase and reverses immunosuppressive T cells to recognize cancer cells, leading to T cell proliferation and activation, cancer cell cycle arrest, and ultimately increased cancer cell death. The nanohybrid is also active in vivo against the growth of human cervical tumors. Overall, a strategy is provided using a multifunctional nanohybrid system to boost the antitumor activity of cisplatin.
Recently, Pt prodrugs have attracted much attention as the next generation of platinum-based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt prodrug that is among the most cytotoxic Pt prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC values in the nanomolar range in both cisplatin-sensitive and -resistant cells; these IC values are up to 422-fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter-mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.
Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin.
Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in cancer cells, however, remains challenging. Herein, we...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.