Applications Of ROS-sensitive Nanomedicine For Enhanced Concurrent Chemoradiation Therapy

Varieties of cancer therapies have been widely studied and applied in clinic treatments,including chemotherapy,radiotherapy,immunotherapy,gene therapy,photodynamic therapy and photothermal therapy.However,single therapy often is difficult to get the expected effect for the limited curative efficacy and drug resistance after repeated treatments.To optimize the anti-tumor performance,combination treatments emerged and acquired gratifying clinical outcomes.To date,chemotherapy and radiotherapy are still the mainstays of cancer treatments,especially,the combined chemoradiation therapy has been set as a standard care in many solid tumor treatments.However,the severe side effects extremely restrict its wide application.Nanocarriers have become a kind of ideal carriers for diagnosis and treatment of cancer,which provide an efficient and safe approach for drug delivery.Hydrophobic polypropylene sulfide（PPS）can be oxidized by reactive oxygen species（ROS）and turn into a hydrophilic compound which contains sulfoxide structures.In this study,ROS-sensitive nanocarrier has been constructed through self-assembly of amphiphilic polymer HA-PPS,which was composed by hydrophobic PPS and hydrophilic hyaluronic acid（HA）.Then,doxorubicin,a broad-spectrum chemotherapeutic agent in clinic was loaded into the inner core of nano micelles,constituting the multifunctional intelligent nanomedicine HA-PPS@DOX.When combined with radiotherapy,the hydrophobic PPS was oxidized by the generated ROS and triggered the destruction of nano vesicles,releasing the DOX.The structural characterization results showed that HA-PPS@DOX nanoparticles has a spherical structure of around 227 nm diameter with good monodispersity as well as stability,and the drug release rate can reach to 78.01%under to the oxidation environment.In vitro cytological studies,the release and action mechanism of nano-drugs in cells were explored through cell uptake experiment,lysosomal co-localization experiment,DNA chain damage experiment,radiotherapy sensitization experiment and cytotoxicity experiment.HA-PPS@DOX entered cells through endocytosis.Uponγray radiation,the endocytosed HA-PPS@DOX released DOX which entered nucleus subsequently and displayed cytotoxicity.Meanwhile,as a radio-sensitizer,DOX has enhanced the radio-sensitization.Compared with free DOX,HA-PPS@DOX combined with radiation has dramatically declined the half maximal inhibitory concentration(IC₅₀)from 2.316 to 0.824μg/m L,preliminarily exhibiting an enhanced efficacy of concurrent chemoradiation therapy.In addition,the radiotherapy sensitization ratio（SER）value has increased from 1.66 to 1.78 after DOX was loaded into nanocarrier HA-PPS,which further confirmed the feasibility of this strategy for synchronously enhancing chemoradiation therapy.In vivo studies,biological distribution experiment were used to explore the passive targeted accumulation of nanomedicines in tumor tissues and the combined effect of radiotherapy and chemotherapy were characterized by tumor inhibition experiment.After intravenous injection,HA-PPS@DOX arrived at tumor sites through systematic circulation and largely accumulated in it due to the enhanced permeability and retention effect（EPR）.Both accumulation amounts and retention time of HA-PPS@DOX nanomedicine had improved compared with free DOX.After an in-situ chemoradiation therapy in tumor sites,an ideal tumor inhibition rate of70.4%was achieved with no harm on main organs and health of animals,fully reflecting the potential of HA-PPS@DOX in concurrent chemoradiotherapy of enhancing anticancer efficiency.