Controllable Synthesis Of Tumor Microenvironment Responsive Nanomaterials For Enhanced Cancer Therapy

The microenvironment within solid tumors is characterized with diverse hostile features such as hypoxia,acidity,elevated interstitial pressure,high reactive oxygen species,and immunosuppression.It is well known that the tumor microenvironment(TME)plays a prominent role in promoting tumor progression,invasion and metastasis.Moreover,the complex TMEs would also negatively impair the therapeutic efficacies of various therapies(e.g.chemotherapy,radiotherapy,and immunotherapy).In recent years,the development of TME-responsive nanomedicine systems innovative cancer treatments has attracted wide attention.However,the therapeutic efficacy and biosafety of nanomaterials are still the major obstacles impding their further development.Therefore,in this doctoral dissertation,several types of TME-responsive nanomaterials with excellent biocompatibility and the ability to modulate hostile features within the TME have been developed,aming to achieve more effective cancer treatments without imposing additional side effects.The main achievements are summarized as follows:1.Amplification of tumor oxidative stresses for enhanced cancer chemotherapy and radiotherapy.In this work,ultra-small gallic acid-ferrous(GA-Fe(II))nanocomplexes with high and persistent Fenton catalytic activity were prepared and then encapsulated with the biocompatible liposomes together with L-buthionine sulfoximine(BSO),an inhibitor of glutathione(GSH)synthesis.Upon intracellular internalization,the obtained BSO/GA-Fe(II)@liposome could synergetically amplify intracellular oxidative stress via the GA-Fe(II)mediated generation of·OH from endogenous H₂O₂ and BSO mediated GSH depletion.As a result,such BSO/GA-Fe(II)@liposome could not only directly suppress tumor growth via the effective amplification of intratumoral oxidative stress,but also remarkably enhance the therapeutic efficacies of conventional oxaliplatin chemotherapy and radiotherapy.2.Synthesis of CaCO₃ based hollow nanomedicine for enhanced sonodynamic therapy via amplification of tumor oxidative stress.In this work,we developed a self-templated strategy to synthesize a type of p H-responsive metal-organic coordination polymer of TCPP-Fe coated CaCO₃ hollow nanomedicine via a one-pot coordination reaction.The obtained BSO-TCPP/Fe@CaCO₃ nanoparticles were found to be efficient in amplifying the intracellular oxidative stress via intracellular Ca²⁺-overloading induced mitochondria damage and BSO-mediated GSH depletion.Upon ultrasound exposure,such BSO-TCPP/Fe@CaCO₃-PEG nanoparticles showed efficient sonodynamic efficacy,thereby leading to effective suppression on tumor growth via the triple amplification of tumor oxidative stress.3.Metal-polyphenol-network coated CaCO₃ as p H-responsive nanocarriers to enable ROS-mediated reversal of multidrug resistance for synergistic cancer treatments.In this work,we prepared a type of metal-polyphenol polymer-coated CaCO₃ hollow nanocomposites via the aforementioned self-templated synthesis method.With sequential PEGylation and doxorubicin(DOX)encapsulation,the obtained DOX/GA-Fe@CaCO₃-PEG nanoparticles exhibited p H-responsive size shrinkage,drug release,and Fenton catalytic activity due to the p H-responsive dissociation of CaCO₃.Upon intracellular internalization,DOX/GA-Fe@CaCO₃-PEG exhibited synergistic therapeutic efficacies to multidrug resistance cancer cells,owing to the GA-Fe mediated intracellular oxidative stress amplification that could partially reduce ATP production and ATP-driven drug efflux by inducing mitochondrial damage.Moreover,attributing to its p H-responsive size shrinkage property,such DOX/GA-Fe@CaCO₃-PEG upon tumor accumulation enabled efficient intratumoral penetration of DOX,thereby exhibited a superior anti-cancer effect towards a DOX-resistant 4T1 tumors model.4.p H-responsive reactors enable efficient remodeling of the tumor microenvironment and enhanced cancer immunotherapy.In this work,we prepared a type of p H-responsive microscale assembly of CaCO₃ nanoparticles for efficient encapsulation of catalase and anti-PD-1 antibody via a double emulsion process.It was shown that the obtained a PD1-CAT-CaCO₃@PLGA microscale reactors could enable simultaneous CaCO₃-mediated acidic TME neutralization by reacting with H⁺and catalase mediated hypoxia relief by reacting with endogenous H₂O₂.As a result,such treatment would effectively reverse the immunosuppressive TME by promoting the intratumoral infiltration and activation of effector immune cells,and reducing the proportion of immunosuppressive cells,thereby facilitating the anti-PD-1immunotherapy.Those a PD1-CAT-CaCO₃@PLGA microscale reactors exhibited synergistic inhibition effects on the growth of both subcutaneous CT26 mouse colon tumors and orthotopic 4T1 triple-negative mouse breast tumors,the latter of which is known to be a highly metastatic and poorly immunogenic tumor model.In summary,in this doctoral dissertation,we have developed several multifunctional biocompatible nanomedicine platforms with promising TME responsiveness or/and modulatory functions for enhanced cancer treatment.In particular,we have developed several innovative methods for the construction of CaCO₃based biomaterials and proposed several sequential cancer treatment strategies based on those multifunctional nanomaterials to achieve effective cancer treatment.Considering the biocompatibility and biodegradability of CaCO₃,our nanomedicine systems may hold substantial promises for future clinical translation.