Surface-modified Black Phosphorus For Cancer Diagnoses And Treatment Applications

Recently,researchers have revealed that the inherent anticancer activities of several kinds of biodegradable inorganic nanomaterials,such as Na Cl nanoparticles and calcium phosphate nanoparticles,exhibit significant cytotoxicity in several types of cancer cells by altering the intracellular osmolarity after rapid dissolution intracellularly.Meanwhile,they cause little cytotoxicity in normal cells because of lower dissolution rate,suggesting the potentials of selective chemotherapeutic application.Black phosphorous nanosheets(BPs),an emerging class of 2D nanomaterials consisting of elemental phosphorus,have been shown to intrigue anticancer bioactivity.The anticancer bioactivity of BPs stems from accelerated intracellular degradation in response to the strong intracellular oxidative stress and energy metabolism in cancer cells,consequently leading to acute elevation of phosphate anions in the cytoplasm,dramatic changes in the intracellular ionic equilibrium,and strong killing effects of cancer cells.Nevertheless,BPs are compatible with normal cells on account of the mild intracellular environment in these cells.Therefore,BPs have great potential in overcoming the challenges confronting traditional small molecule chemotherapeutics with limited selectivity.Based on the above-mentioned researches,a novel surface functionalization strategy by in situ mineralization of BPs with calcium phosphate(Ca₃(PO₄)₂)is raised(designated as Ca BPs).This is mainly because BPs are comprised of phosphorus atoms,which are able to be oxidized into PO₄^3-and then easy to be mineralized with the appearance of Ca²⁺.After mineralization,the selective chemo-therapeutic activities and surface functionalization capabilities of BPs are strengthened.Additionally,the mineralizing process is based on the template of BPs,maintaining the high surface to volume ratio and the initial size.During the process of mineral deposition,various kinds of functional molecules,such as FITC,Ce6 and DOX,etc.,could be loaded with high efficiency,which may achieve fluorescence imaging and combination therapy applications.Meanwhile,the p H of cancer cells microenvironment is lower than the normal ones,leading to the accelerated degradation of Ca BPs and the selective anti-cancer capabilities.The in vitro toxic experiment of Ca BPs present that the highest selective cytotoxicity under the concentration of 0.5?1.0?g/m L and broad-spectrum anti-cancer bioactivities,which are mainly due to the following reasons:1)Ca BPs maintain the p H-responsive degradation behavior and induce intracellular Ca²⁺ overloading in cancer cells.In addition,Ca BPs target mitochondria specifically to cause structural damage and disfunction in these organelles resulting in mitochondrial-mediated apoptosis;2)the intracellular oxidation-reduction and PO₄^3-equilibrium interference caused by the unmineralized BPs.The anticancer efficacy of PLL-PEG-FA modified Ca BPs is assessed in a human breast cancer xenograft model as well as orthotopic model,and effective cancer targeting and enhanced therapeutic efficacy are revealed,as well as the excellent fluorescence imaging capability.Ca₃(PO₄)₂mineralization provides a new functionalization strategy to improve the anticancer bioactivity of BPs and the concept can be extended to the construction of diagnosis/treatment integrating nanotherapeutic platforms...