Platinum Drug‐Incorporating Polymeric Nanosystems for Precise Cancer Therapy

Abstract

made great progress in the field of medicinal inorganic chemistry. [2] They have been extensively applied in various types of cancers such as bladder cancer, ovarian cancer, breast cancer, endometrial cancer, neck cancer, and lung cancer. [3] Generally, Pt-based anticancer drugs interact with gene nucleobases and cause DNA damage. For example, after cellular uptake, cisplatin will hydrolyze along with the dissociation of chloride ion, which is ascribed to relatively lower concentration of chloride ion in cytoplasm (4-10 mm) than that in blood (≈100 mm). The hydrolyzed cisplatin can further conjugate with N7 position of adenine (A) and guanine (G), distort the structure of DNA and inhibit G2/M transition of cell cycle, leading to cell apoptosis in the end. [4][5][6] However, Pt(II) analogue drugs face various side effects, such as vomiting, neurotoxicity, nephrotoxicity, ototoxity, and cardiotoxicity. [7] These severe side effects greatly limit their efficacy and have become huge obstacles for further clinical applications. Though great efforts have been devoted to improve the efficacy of Pt-based anticancer drugs. Up to now, there is no Pt(II)-based drug that fully solves the problems despite of years of research. [8,9] Meanwhile, drug resistance is another major challenge for Pt-based drugs. Further, the anticancer efficacy of these Pt(II)-based drugs is greatly compromised by the inactivation of intracellular coppertransporting proteins, such as glutathione (GSH) and metallothioneins (MT), through forming stable Pt(II)-S bond. Later, copper transporter ATP7A and ATP7B are involved in the efflux or translocation Pt(II)-S complex as well as multidrug resistance-associated protein MRP2. What's more, it is noteworthy that DNA damage caused by Pt lesions can be recovered by the nucleotide excision repair (NER) machinery, in which DNAadduct repair enzymes play the critical role, such as excision repair cross complementation 1. [10,11] To minimize side effects of Pt(II) drugs, Pt(IV) prodrug have drawn more and more attention for cancer therapy. [12][13][14][15][16] Compared to Pt(II) drugs, these Pt(IV) drugs have a six coordinate octahedral geometry with an inert d 6 electronic configuration. The two additional ligands can endow Pt(IV) prodrugs with additional lipophilicity, tumor targeting property, and enhanced cellular uptake. [17] After endocytosis, these Pt(IV) drugs can be reduced to active Pt(II) drugs by intracellular GSH, resulting in enhanced therapeutic efficacy and reduced side effects. [18] Ideally, Pt drugs should kill cancer cells exclusively without damaging the normal ones. However, the tumor selectivity of Platinum (Pt) drugs are widely used in clinic for cancer therapy, but their therapeutic outcomes are significantly compromised by severe side effects and acquired drug resistance. With the emerging immunotherapy and imaging-guided cancer therapy, precise delivery and release of Pt drugs have drawn great attention these days. The targeting delivery of Pt drugs can greatly increase the accumulation...

Nanoscale Ion-Exchange Materials: From Analytical Chemistry to Industrial and Biomedical Applications

“…Nanomedicine is arguably the most rapidly emerging application of nanotechnology, and one of its pillars, controlled or targeted drug delivery, has received a great deal of interest from oncologists and medicinal chemists [79,80]. Over the past decade, a wide variety of drug carriers have been synthesized from different types of nanomaterials, of organic, inorganic, or biological nature, and their composites [81], as well as synthetic and natural polymeric nanosystems [82][83][84]. This does not impede, however, the discovery of alternative nanoscale vehicles.…”

Antitumor Effect of Platinum-Modified STING Agonist MSA-2

“…), and nonclassical Pt­(II) drugs (picoplatin, BBR3464, 56MESS) and Pt­(IV) prodrugs (satraplatin and Pt­(IV)-azide complexes) . Various modalities and recent advances in combination with platinum-based antitumor therapy were developed, for instances, platinum drugs combined with surgery, chemotherapy, radiation therapy, thermal therapy, gene editing, ROS-based therapy, and immunotherapy. , The platinum-based drug not only caused tumor cell death and remodeled the immunosuppressive microenvironment but also activated the cGAS-STING pathway in immune cells to enhance the antitumor immune response. , Therefore, we first synthesized a platinum-modified STING agonist MSA-2 (MSA-2-Pt) and supposed that it could induce cell death by Pt and activate the STING pathway by MSA-2.…”