Design And Synthesis Of Near-Infrared Macromolecular Nanotheranostics For Tumor Multimode Imaging And Photothermal Therapy

Molecular imaging is of primary significance for early diagnosis accompanying with timely therapy of cancers and diseases,as well as for fundamental medical and biological research.Rational integration of two or more imaging techniques can provide complementary information and achieve synergistic advantages in cancer diagnosis.The emergence of nanomedicines cooperated with optical imaging and magnetic resonance imaging（MRI）has become one of the hotspots in cancer research over the past decades,largely due to their complementary superiorities for greatly accurate tumor diagnosis.Compared with the conventional optical imaging,the newly developed photoacoustic imaging（PAI）and fluorescence imaging in the second near-infrared window（NIR-II,1000-1700 nm）holds great promise for visualization of physiology and pathology with deeper tissue penetration and unprecedented spatial resolution.Thus,by integrating deep-tissue light-activated imaging technique and MRI functions within a single platform,such multifunctional magnetic phototheranostic platforms have shown supernormal properties for dramatically high-quality cancer theranostics.In this thesis,we designed and synthesized a series of near-infrared macromolecular theranostic platforms for tumor multi-mode imaging,activatable bimodal imaging and photothermal therapy.The thesis mainly includes the following three parts:1.Perylene Diimide-Grafted Polymeric Nanoparticles Chelated with Gd³⁺for Photoacoustic/T₁-Weighted Magnetic Resonance Imaging-Guided Photothermal TherapyHere,we facilely fabricated Gd³⁺-chelated poly（isobutylene-alt-MAnh）framework pendent with perylene-3,4,9,10-tetracarboxylic diimide（PDI）derivatives and polyethylene glycol（PEG）as an efficient theranostic platform for dual-modal photoacoustic imaging（PAI）and magnetic resonance imaging（MRI）guided photothermal therapy.The obtained polymeric nanoparticles chelated with Gd³⁺（PMA-PDI-PEG-Gd NPs）exhibited a high T1 relaxivity coefficient(13.95 mM^-1 s^-1)even at the higher magnetic fields.After 3.5 h tail vein injection of PMA-PDI-PEG-Gd NPs,the tumor areas showed conspicuous enhancement in both photoacoustic signal and T1-weighted MRI intensity,indicating the efficient accumulation of PMA-PDI-PEG-Gd NPs owing to the enhanced permeation and retention（EPR）effect.In addition,excellent tumor ablation therapeutic effect in vivo was demonstrated with living mice.Overall,our work illustrated a straightforward synthetic strategy for engineering multifunctional polymeric nanoparticles for dual-modal imaging to obtain more accurate information for efficient diagnosis and therapy.2.Gadolinium-Chelated Conjugated Polymer-Based Nanotheranostics for NIR-II Fluorescence/Photoacoustic/Magnetic Resonance Imaging-Guided Cancer Photothermal TherapyHerein,we engineered and prepared a water-soluble gadolinium chelated conjugated polymer（PFTQ-PEG-Gd NPs）based theranostic nanomedicine with intrinsic strong NIR absorption,fluorescence emission>1000 nm and powerful positive（T₁）magnetic contrast ability(10.95 mM^-1s^-1)for in vivo tri-mode PA/MR/NIR-II imaging-guided tumor photothermal therapy.The obtained theranostic agent showed excellent chemical and optical stability as well as low biotoxicity.After24 h of systemic administration using PQTF-PEG-Gd NPs,the tumor sites of living mice exhibited obvious enhancement in PA,NIR-II fluorescence and positive MR signal intensities,suggesting the efficacious accumulation of PQTF-PEG-Gd NPs mainly attributing to the enhanced permeation and retention（EPR）effect.Better still,a conspicuous tumor growth restraint was detected under NIR light irradiation after administration of PQTF-PEG-Gd NPs,indicating the efficient photothermal potency of the nano-agent.We expect that such a novel organic nano-platform manifests a great promise for high spatial resolution and deep penetration cancer theranostics.3.Intelligent Polymer-MnO₂ Nanoparticles for Dual-activatable Photoacoustic and Magnetic Resonance Bimodal Imaging in Living MiceActivatable dual-mode probes that combine both photoacoustic（PA）and magnetic resonance imaging（MRI）possess great benefit for tumor visualization with optimized imaging sensitivity.Herein,we designed and prepared an intelligent nanoprobe based on Aza-BODIPY derivative grafted poly（isobutylene-alt-maleic anhydride）（PMA）framework and MnO₂ nanoparticles（NPs）for dual-activatable PA and MR tumor imaging.In this system,the MnO₂ NPs can serve not only as a PA contrast agent at 680 nm,but also as an activatable MRI contrast agent in the presence of peroxide and acidic environment.The peroxide/pH-inert Aza-BODIPY grafted polymer,which possessed strong near-infrared absorption with a peak at 825 nm for PAI,was able to act as a nanocarrier to encapsulate the degradable MnO₂ NPs and formed into structurally stable NPs through a non-covalent adsorption.The obtained polymer-MnO₂ NPs showed ratiometric PA imaging of peroxide/pH and activatable MRI in living mice.We believe the smart platform could facilitate the development of various dual-activatable bimodalities imaging for use in vivo.