Abstract
Synergistic chemo-photodynamic therapy has garnered attention in the field of cancer treatment. Here, a pH cascade-responsive micellar nanoplatform with nucleus-targeted ability, for effective synergistic chemo-photodynamic cancer treatment, was fabricated. In this micellar nanoplatform, 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (Por), a photodynamic therapy (PDT) agent was utilized for carrying the novel anticancer drug GNA002 to construct a hydrophobic core, and cyclic RGD peptide (cRGD)-modified polyethylene glycol (PEG) (cRGD-PEG) connected the cell-penetrating peptide hexaarginine (R6) through a pH-responsive hydrazone bond (cRGD-PEG-N = CH-R6) to serve as a hydrophilic shell for increasing blood circulation time. After passively accumulating in tumor sites, the self-assembled GNA002-loaded nanoparticles were actively internalized into cancer cells via the cRGD ligands. Once phagocytosed by lysosomes, the acidity-triggered detachment of the cRGD-PEG shell led to the formation of R6-coated secondary nanoparticles and subsequent R6-mediated nucleus-targeted drug delivery. Combined with GNA002-induced nucleus-specific chemotherapy, reactive oxygen species produced by Por under 532-nm laser irradiation achieved a potent synergistic chemo-photodynamic cancer treatment. Moreover, our in vitro and in vivo anticancer investigations revealed high cancer-suppression efficacy of this ideal multifunctional nanoplatform, indicating that it could be a promising candidate for synergistic anticancer therapy.
Highlights
Methods of early diagnosis and treatment of cancers have improved in recent years, the treatment of malignant tumors remains an arduous challenge, as deepLi et al J Nanobiotechnol (2021) 19:140Cys668 of the EZH2 field, triggering EZH2 degradation through the COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination, which relies on EZH2 to inhibit cancer growth [9]
2 h, and up to 60% was released after 10 h. These results suggest that the slow release in the first 2 h could ensure the stability of GNA002@cPRP nanoparticles (GNA002)@cPRP in the blood circulation and even cancer cell cytoplasm, causing a slight loss before reaching the nuclei, and that the fast release during the 10 h could improve GNA002 utilization after reaching the cancer-cell nuclei
GNA002, GNA002@cPRP nanoparticles with or without laser irradiation, and cisplatin showed a certain inhibitory effect on the growth of multicellular cancer spheroids (MCSs), especially the MCSs treated with laser-irradiated GNA002@ cPRP nanoparticles, which demonstrated a greater downward trend in volume compared with the other three groups. These results indicated that the GNA002@cPRP nanoparticles enhanced drug penetration, which was consistent with the results of in vitro drug penetration, and that the synergistic chemo-photodynamic therapy could treat deep cancer
Summary
Methods of early diagnosis and treatment of cancers have improved in recent years, the treatment of malignant tumors remains an arduous challenge, as deepLi et al J Nanobiotechnol (2021) 19:140Cys668 of the EZH2 field, triggering EZH2 degradation through the COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination, which relies on EZH2 to inhibit cancer growth [9]. Low bioavailability and poor water solubility of GNA002 and high toxicity of other chemotherapeutic drugs limit their applications in clinical medicine and long-term cancer therapy. In this milieu, photodynamic therapy (PDT) [10,11,12], a cancer treatment mode that can be spatiotemporally controlled, has shown good results in various minimally invasive cancer treatments. The basic principle of PDT is that the half-life of the photosensitizer administered systematically or locally is different in cancerous and normal tissues [13]. PDT cannot eliminate cancer cells owing to limited laser penetration and hypoxia in tumor tissues, presenting insufficient curative effects [16,17,18]
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