Designed Fabrication Of Acidity-Activatable Nanodrug Systems For Enhanced Tumor Therapy

With the in-depth understanding of tumor microenvironment and development of pharmaceutics research,anti-cancer drug delivery nanosystems have been extensively and deeply studied.How to improve the tumor therapeutic effect and reduce the side effects is one of the great challenges in nano drug delivery systems.In recent decades,metal-based nanomaterials have developed rapidly and are widely used in the tumor therapy and/or diagnosis,due to their unique chemical and physical(e.g.,thermal,optical,acoustic and magnetic)properties.These metal-based nanomaterials can act as an active anti-cancer component,a drug carrier or a medical imaging contrast agent.We here firstly synthesized an acidity-responsive block polymer and loaded anti-tumor active components,for example,the small-sized platinum nanoclusters that can selectively leach toxic Pt2+ on acidic conditions.After modified with liver cancer targeting peptide SP94,an acidity-responsive Pt nanoassembly(Pt-NA)was establised as a acidity-activatable nanodrug.After readily targeting liver tumor tissues and receptor-mediated endocytosis,Pt-NA disassembled into monodispersed Pt nanoclusters in acidic subcellular compartments,which then leached toxic Pt2+ and eventually induced the severe DNA damage.Cell experiment results showed that Pt-NA not only exhibited higher toxicity than cisplatin towards cisplatin-resistant SP+CD24+LM3 hepatoma cells(stem cell-like cells),but also effectively inhibited the sphere formation ability of tumor stem-like cells.The in vivo anti-tumor results demonstrated that the inhibition effect of Pt-NA on the tumor growth was significantly better than that of cisplatin or sorafenib.In addition,the TEM result demonstrated Pt was gradually cleared via the renal route.The HE staining and blood biochemical study results showed that Pt-NA was biocompatible with normal tissues including liver and kidney.In addition,medical imaging is clinically necessary for tumor diagnosis,curative effect evaluation,therapy strategy adjustment,and prognosis monitoring.Integrating targeted delivery,drug therapy,in vivo tracking,and prognosis monitoring into a drug delivery nanosystem is one of the most important research trends.We synthesized renal-clearable ultrasmall bismuth subcarbonate nanoclusters(1.5 nm)as a visual anti-turmor active component.After the solvothermal strategy,hollow bismuth subcarbonate nanotubes(BNTs)was prepared and served as a acidity-triggered function-activatable nanodrug for tumor-targeted computed tomography(CT)imaging guided chemoradiotherapy.BNTs increased the sensitivity of tumor cells to X-rays and were used for radiation sensitization in cancer therapy.Moreover,BNTs can load DOX inside the hollow cavity and accumulate in tumors with high efficiency,thus achieving tumor-specific CT imaging guided combined radio-/chemotherapy.Cell and animal experliments confirmed that BNTs/DOX significantly increased reactive oxygen species(ROS)levels and aggravated DNA damage in tumor cells,whose anti-tumor effect was much greater than those of single radiotherapy or chemotherapy.More interestingly,the TEM and excretion results revealed that BNTs slowly disassembled into nanoclusters in tumor acidic microenvironment and then were cleared via renal excretion,ultimately ensuring the great biosafety.Through controlling the size,shape,and surface structure of metal nanomaterials,we can develop the ultra-small platinum nanoclusters with ion leaching activity,Bi-based nanomaterials with visual radiation sensitization activity,respectively,into a series of acidity-activatable nanodrugs.They amplified the anti-cancer efficacy upon exposure to the tumor microenvironment,while be cleared to keep biocompatible with normal tissues via renal excretion.Taken together,we expect that our approach of exploiting above smart nanosystems can open up an exciting research direction for designing and developing highly efficient and safe drug delivery nanosystems.