Preparation Of Multifunctional Photothermal Nanomaterials Based On Poly(Acrylic Acid) For Cancer Therapy

Photothermal therapy?PTT?is an emerging therapeutic methodology that uses photothermal conversion agents to convert absorbed light energy into heat energy to increase local temperature and cause cancer cell death.PTT has some advantages,such as safety,high efficiency,non-invasive and precise positioning.In order to improve the therapeutic effect and reduce the damage to normal tissues,the absorption of the photothermal agents is usually adjusted to near-infrared?NIR?window?750¹350 nm?.However,single PTT has its limitation,such as insufficient light penetration depth,which may cause the incomplete elimination of deep tumors,leading to recurrence and metastasis of tumors.To further improve the overall therapeutic effect,it is essential to develop new multifunctional photothermal nanomaterials combined with imaging diagnosis and other treatment methods.In this thesis,a series of multifunctional photothermal nanoparticles were designed and synthesized using polyacrylic acid?PAA?as templates.Then,we explore their potential applications in drug loading,photothermal ablation of tumor cells,controlled drug release and synergistic therapy of cancer.The specific contents are as follows:?1?A simple and mild method was developed to prepare hollow gold nanoflowers?Au NFs?using PAA nanospheres as templates.Due to their unique hollow and multi-branched structure,the obtained nanoparticles have excellent drug loading and photothermal conversion capabilities.Moreover,the hollow Au NFs can realize pH/NIR dual-responsive drug delivery.Finally,we test the killing effect on tumors of the nanomaterials by synergistic chemical-photothermal therapy both in vitro and in vivo.?2?Calcium phosphate/small gold nanorod?CaP/Au NR?assemblies were prepared by using poly?acrylic acid calcium salt?nanospheres as templates.The obtained nanoparticles have high photothermal conversion efficiency due to strong plasma coupling between adjacent small Au NRs,and the biocompatibility is significantly improved by the presence of CaP.In addition,the CaP/Au NR assemblies possess high drug loading and pH/NIR dual-responsive drug release capabilities.Finally,CaP/Au NR assemblies are applied in anti-tumor experiments in vivo to test the synergistic effect of chemo-photothermal therapy on tumor elimination.?3?Ternary Janus nanoparticles?JNPs?containing hemispherical MnO₂ at one side and Au core covered with CuS shell at opposite side?CuS-Au-MnO2 ternary JNPs?are fabricated via a selective growth strategy.The obtained ternary JNPs are further modified with poly?ethylene glycol?thiol to enhance the stability and biocompatibility.The MnO₂ domain with mesoporous structures can serve as hydrophobic drug carriers and magnetic resonance?MR?imaging contrast agents.Meanwhile,the Au segment is used for X-ray computed tomography?CT?imaging.Moreover,the obtained ternary JNPs can conduct hyperthermia at 1064 nm in NIR-II window to ablate tumors in deep tissue,which is ascribed to the localized surface plasmon resonance coupling effect of the Au core and CuS domain.According to the results in vivo,PEG-CuS-Au-MnO₂ ternary JNPs provide high chemo-photothermal antitumor efficacy under the guidance of CT/MR imaging,indicating that the PEG-CuS-Au-MnO₂ ternary JNPs can be regarded as a prospective therapeutic platforms for dual-modal imaging-guided synergistic chemo-photothermal cancer therapy in the NIR-II window.?4?A facile approach is explored to fabricate well-dispersed poly?acrylic acid zinc salt??PAA-Zn?/PDA JNPs,which is further used as templates to prepare spherical zeolitic imidazolate framework-8/polydopamine JNPs with hollow structure?H-ZIF-8/PDA JNPs?.The resultant H-ZIF-8/PDA JNPs are further selectively functionalized on PDA sides with heptakis-?6-mercapto-6-deoxy?-?-cyclodextrin?CDs?to gain the capability of loading hydrophobic drug?H-ZIF-8/PDA-CD JNPs?.Meanwhile,the ZIF-8 domains with hollow cavities can serve as reservoirs for loading hydrophilic drug molecules.Moreover,the pH-sensitive ZIF-8 and the strong NIR absorption of PDA make the H-ZIF-8/PDA JNPs possess the conversion capacity from laser energy to heat and pH/NIR dual-responsive drug release behaviors.Finally,H-ZIF-8/PDA-CD JNPs are applied to test the synergistic effect of dual chemo-photothermal therapy on tumor elimination both in vitro and in vivo.Taken together,the H-ZIF-8/PDA-CD JNPs are capable of serving as promising platform for cancer treatment through collaborative photothermal and dual-drug chemical therapy.