Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Abstract

Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C 82 (OH) 22 ] n nanoparticles, that [Gd@C 82 (OH) 22 ] n may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C 82 (OH) 22 ] n not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CPr PC-3-luc cells with [Gd@C 82 (OH) 22 ] n enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C 82 (OH) 22 ] n nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.A s a major chemotherapeutic agent for tumor treatment, cisplatin remains a cornerstone of the present-day chemotherapy regimens against not only epithelial malignancies but also a number of metastatic and advanced malignancies (1, 2). However, because of high toxicity and easy development of drug resistance, successful treatment with cisplatin often is limited (3,4). Following the discovery of ATP-binding cassette (ABC) transporters and their roles in drug resistance in various types of tumors (5), much research has been done to explore the relationship between ABC transporter activity and specific chemotherapeutics, including cisplatin. Because no ABC transporter has been identified for "pumping" cisplatin out of cisplatin-resistant human prostate cancer (CP-r) cells (6-8), it would be difficult to sensitize CP-r cells by using any known strategy that targets resistant cancer cells by inhibiting multidrug resistance (MDR)-associated proteins on plasma membrane of the CP-r cells. Diffusion has been considered as a pathway for cisplatin to penetrate plasma membrane. Recently, studies have indicated that cisplatin entered cells by endocytosis and other mechanisms (9-12).To increase susceptibility of cancer cells to cisplatin, i.e., to reverse drug resistance, many efforts have been made through chemical modification, gene therapy, vector delivery, and other means (2, 9, 13). Combination of traditional chemotherapy with nanotechnology may provide a promising alternative for novel cancer treatments. The use of nanoparticles to sensitize tumor cells to cisplatin in vitro and in vivo has been described recently (14-16). In these studies, cisplatin-encap...

Therapeutic applications of low-toxicity spherical nanocarbon materials

“…Gd@C 82 (OH) 22 nanoparticles can reduce tumor resistance to cisplatin (a major chemotherapeutic agent) in vitro and in vivo. 73 After pretreatment with these particles, the viability of cisplatin-resistive cancer cells was diminished and the growth of tumors was more effectively suppressed. It is known that tumors become resistant to cisplatin, partially because cisplatin uptake is reduced as a result of faulty formation of the endocytic recycling compartment.…”

Current applications and future prospects of nanomaterials in tumor therapy

“…The high antitumor activity may be because the water-soluble NMs can effectively trigger the host immune system to eliminate tumor cells and regulate the angiogenesis and oxidative defense system in vivo. 92 …”

Application of Mixture Design Response Surface Methodology for Combination Chemotherapy in PC-3 Human Prostate Cancer Cells

“…Personalized and targeted therapies, such as immunotherapy, have shown great potential in combating cancer but are still affected by chemoresistance (Bozic et al, 2013). Prostate cancer frequently becomes resistant to commonly used treatments (Theyer et al, 1993;Tilley et al, 1995;Li et al, 2001;Liang et al, 2010) and is the second most commonly diagnosed cancer in men in the United States (Siegel et al, 2018). Of the diagnosed prostate cancers, 10% are metastatic (Jemal et al, 2011).…”