Responsive Nanodrug Release Systems:Design And Their Application In Combined Cancer Therapy

Cancer is a disease caused by the mutation of proto-oncogenes and oncogenes in normal cells stimulated by carcinogenic factors such as physical,chemical,and viral factors,and remains a major public health problem that seriously threatens human health.China ranks first in the world in terms of both the number of new cancer cases and the number of deaths.Due to the limitations of drug stability and duration of action,traditional drug delivery means often fail to obtain the desired therapeutic effect.Compared with traditional drug delivery means,nanodrug carriers can effectively improve the stability of clinical drugs,improve the drug absorption ability of patients,prolong the action time of drugs,reduce the toxicity and side effects,and then effectively improve the clinical efficacy of drugs.As research on nanodrug carriers continues to advance,responsive nanodrug release systems are becoming a focus of interest for researchers.Responsive nanodrug release systems allow for targeted drug delivery,sustained drug delivery,and allow for the combination of multiple drugs.In addition,responsive nanodrug release systems can prevent accidental leakage of drug molecules and allow the use of smaller doses,which not only reduces the side effects of drugs but also improves drug utilization at the same time.Based on the above background,we designed two responsive nanodrug release systems:1.A Cu²⁺doped mesoporous polydopamine（CuPDA）Fenton nanoplatform was designed for responsive drug release as well as low-temperature photothermal therapy.The successful modification of Cu²⁺not only provided rich catalytic sites for CuPDA but also enhanced the photothermal effect of polydopamine.After loading the anti-cancer drugβ-lapachone（Lapa）within the pores of CuPDA and coating the surface with hyaluronic acid（HA）,we constructed a dual-response triggered nanodrug release system of hyaluronidase/laser irradiation.The system can induce the production of H₂O₂in tumor cells for chemodynamic therapy under the abundant Cu²⁺catalytic site.Chemodynamic therapy can enhance the thermal sensitivity of cancer cells by inducing oxidative stress,while the increase in temperature can further enhance the Fenton reaction rate in chemodynamic therapy,thus achieving a 1+1>2therapeutic effect between them.Our designed CuPDA Fenton nanoplatform can effectively inhibit the proliferation of cancer cells in vitro and in vivo under low-power near-infrared light irradiation and may be a promising candidate for low-temperature photothermal therapy.2.A cell membrane-anchored two-dimensional covalent organic framework（2D COF）nanosheet was designed for single laser-triggered photodynamic/photothermal/chemotherapy combination therapy.Due to the rigidity,large surface area,and low p H insertion peptide（p HLIP）modification,the 2D COF possesses a cell membrane targeting function.The doxorubicin loaded within the 2D COF pore is released in response to both laser and p H stimulation.Porphyrin-based CAp HD allows for both in situ photodynamic and photothermal therapy,which directly disrupting the integrity of the cell membrane.Furthermore,the cell membrane-anchored combination therapy significantly induced immunogenic death of tumor cells and accelerated the rapid release of cellular contents,then inducing a robust immune response.This work opens up a new idea for integrated cancer therapy systems and provides a novel strategy for designing responsive nanodrug release systems.