Prostate cancer is the second most common malignancy in men and androgen deprivation therapy is the first-line therapy. However, most cases will eventually develop castration-resistant prostate cancer after androgen deprivation therapy treatment. Enzalutamide is a second-generation androgen receptor antagonist approved by the Food and Drug Administration to treat patients with castrationresistant prostate cancer. Unfortunately, patients receiving enzalutamide treatment will ultimately develop resistance via various complicated mechanisms. This review examines the emerging information on these resistance mechanisms, including androgen receptor-related signalling pathways, glucocorticoid receptor-related pathways and metabolic effects. Notably, lineage plasticity and phenotype switching, gene polymorphisms and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for enzalutamideresistant castration-resistant prostate cancer treatment are suggested, which can help discover more effective and specific regimens to overcome enzalutamide resistance.

Background: Enzalutamide (Enz) has shown limited bioavailability via oral administration. Castration-resistant prostate cancer (CRPC) is frequent among patients receiving 18-24 months of androgen deprivation therapy. The nonsteroidal anti-androgen enzalutamide (Enz) used in the treatment of prostate cancer has shown limited bioavailability via oral administration. Therefore, we developed a multifunctional enzalutamide-loaded graphene oxide nanosystem (TP-GQDss/Enz) for CRPC intravenous treatment, with high drug loading efficiency. Methods: Aminated graphene quantum dots (GQDs) were first cross-linked via disulfide bonds into a graphene quantum dot derivative of approximately 200 nm (GQDss), which was further functionalized with a tumour-targeting peptide and PEG to form TP-GQDss. Enz was loaded into TP-GQDss for in vitro and in vivo study. Results: The results showed that high drug-loading efficiency was achieved by TP-GQDss via π-π electron interaction. TP-GQDss could be rapidly internalized by CRPC cells via endocytosis. Moreover, Enz in TP-GQDss could inhibit the growth of C4-2B and LNCaP prostate cancer cell lines in vitro. Further, TP-GQDss exhibited an enhanced cancertargeting ability and alleviated the side effects of Enz in vivo. Conclusions: The multifunctional nanocarrier constructed here could accomplish controlled Enz release and serve as an intravenous therapy platform for CRPC.

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Background: Enzalutamide (Enz) has shown limited bioavailability via oral administration and is easy for patients to develop into castration-resistant prostate cancer (CRPC) due to resistance to 18-24 months of androgen deprivation therapy (ADT). Moreover, it is hard to delivery Enz for low drug loading (DL) and encapsulation efficiency (EE). Therefore, we developed a multifunctional enzalutamide-loaded graphene oxide nanosystem (TP-GQDss/Enz) for castration-resistant prostate cancer (CRPC) intravenous treatment, with high drug loading efficiency and good biocompatibility.Methods: Aminated graphene quantum dots (GQDs) were first cross-linked via a disulfide bond into a graphene quantum dot derivative of approximately 200 nm (GQDss), which was further functionalized with a tumour-targeting peptide and PEG to form TP-GQDss. Enz was loaded into TP-GQDss for in vitro and in vivo study.Results: The results showed that high drug-loading efficiency was achieved by TP-GQDss via π-π electron interaction. TP-GQDss could be rapidly internalized by CRPC cells via endocytosis. Moreover, Enz in TP-GQDss could promote the inhibition of cell growth in vitro against CRPC cells, while TP-GQDss alone did not show any obvious cytotoxicity on CRPC cells after 24 h of incubation. Further, TP-GQDss exhibited an enhanced cancer-targeting ability and alleviated the side effects of Enz in vivo. Conclusions: The multifunctional nanocarrier constructed here could accomplish controlled Enz release and serve as a intravenous therapy platform for CRPC.

Background: Enzalutamide (Enz) has shown limited bioavailability via oral administration. It is easy for patients to develop into castration-resistant prostate cancer (CRPC) due to resistance to 18-24 months of androgen deprivation therapy (ADT). Moreover, it is hard to delivery Enz in vivo for low drug loading (DL) and encapsulation efficiency (EE).Therefore, we developed a multifunctional enzalutamide-loaded graphene oxide nanosystem (TP-GQDss/Enz) for castration-resistant prostate cancer (CRPC) intravenous treatment, with high drug loading efficiency.Methods: Aminated graphene quantum dots (GQDs) were first cross-linked via disulfide bonds into a graphene quantum dot derivative of approximately 200 nm (GQDss), which was further functionalized with a tumour-targeting peptide and PEG to form TP-GQDss. Enz was loaded into TP-GQDss for in vitro and in vivo study.Results: The results showed that high drug-loading efficiency was achieved by TP-GQDss via π-π electron interaction. TP-GQDss could be rapidly internalized by CRPC cells via endocytosis. Moreover, Enz in TP-GQDss could promote the inhibition of cell growth in vitro against CRPC cells. Further, TP-GQDss exhibited an enhanced cancer-targeting ability and alleviated the side effects of Enz in vivo. Conclusions: The multifunctional nanocarrier constructed here could accomplish controlled Enz release and serve as an intravenous therapy platform for CRPC.