Design And Synthesis Of Organic/Inorganic Hybrid Theranostic Platform Based On Conjugated Polymer For Biological Application

Optical theranostic ustilizes optical means to achieve disease diagnosis and treatment with high resolution,high sensitivity,precise control and easy integration of diagnosis and treatment.It is becoming an important means for early diagnosis and precise treatment of major diseases.The key to develop high-performance theranostic agents is balancing the advantages and disadvantages of payload,carrier and surface modification to design a smart nano-theranostic platform.For example,select an excellent carrier providing protection for the payload during transport,increases cycle time,and specifically respond to the tumor microenvironment.The surface modification of the carrier further provides additional properties for the theranostic agents,such as strong ability to penetrate tumour,specific binding to target sites,and the like.Therefore,optical theranostic agents are the key to the development of optical diagnostic technology in biomedical applications.It is well known that inorganic materials have excellent photophysical properties such as high stability and high quantum efficiency,making them excellent optical imaging platforms.The polymer semiconductor is usually a conjugated polymer having a large conjugated main chain or a polymer having a large conjugated structure.Due to its excellent semiconductor optical properties,there is great potential in optical diagnosis and treatment.In recent years,organic/inorganic hybrid nano-theranostic platforms have gradually become a hot topic of research.At present,the nano-theranostic platform based on organic/inorganic hybrid combines the advantages of organic and inorganic materials.However,there are still some problems and deficiencies in the research.In terms of design,how to skillfully design the structure of the platform to weigh the relationship between nano transport,delivery,targeting,penetration and toxicity.This paper aims to develop an organic/inorganic hybrid nano-theranostic platform based on conjugated polymer with near-infrared absorption through structural design.The specific researches are as follows:1.Tandem Activated Photodynamic and Chemotherapy:Using p H-Sensitive Nanosystems to Realize Different Tumour Distributions of Photosensitizer/Prodrug for Amplified Combination TherapyHerein,we used the semiconducting polyelectrolyte-based zwitterionic photosensitizer?PFNS?to modify the surface of upconversion nanoparticles?NPs?and prepare near-infrared?NIR?light-responsive PDT agents?UCNP@PFNS?.A p H-sensitive Mn-Ca₃?PO₄?₂?Mn Ca P?layer was further coated onto UCNP@PFNS with the hypoxia-activated prodrug AQ4N incorporated inside.The final nanocomposites exhibited a diameter of 73 nm with high stability in the blood and a remarkably enhanced permeability and retention?EPR?effect in tumours.Importantly,when these nanoparticles reached the tumour site,the acidic tumour microenvironment?p H 6.5-6.8?decomposed the Mn Ca P layer,releasing both UCNP@PFNS?30 nm?and AQ4N.The relatively small size of UCNP@PFNS and AQ4N satisfied the different distribution requirements in tumour and achieved a high therapeutic effect,thereby reaching an inhibition rate of as high as 83%.In addition,Mn²⁺ions can be released during the decomposition of Ca P,leading to a significantly increased magnetic resonance?MR?signal in the tumour site.Overall,we report a nanoparticle guided by MRI and fluorescence imaging possesses of tandem active pattern of PDT and chemotherapy,which is promising for future clinical diagnosis and treatment.2.Conjugated Polyelectrolyte Brush Templated Gold Nanoparticles for Photoacoustic Imaging-Guided Photothermal TherapyGold nanoparticles?GNPs?that are designed to efficiently convert near-infrared light to heat hold great promise for preclinical phototheranostics including photoacoustic imaging?PAI?and photothermal therapy?PTT?;however,the low photothermal conversion efficiencies???greatly restrict their practical applications in photothermal-related phototheranostics.Therefore,new designed approach and mechanistic study are urgently required to improve conversion efficiencies.Herein,a conjugated polyelectrolyte brush-templated approach is reported to prepare GNPs with enhanced?for PAI and PTT in vivo while the underlying mechanisms for the enhanced?is deciphered.Firstly,polymer-templated GNPs?PTGs?of different size?30,45,60,and 75 nm?are prepared by employing monodispersed conjugated polyelectrolyte brush?PFNBr?as template.Notably,the 30 nm PTGs display the strongest photothermal effects,which exhibit a 3.5-fold enhanced?relative to the pure GNPs with same size that are prepared using traditional approach.Further mechanistic study using femtosecond transient absorption?fs-TA?spectroscopy reveals that PTGs accelerate electron-phonon interaction,which accounts for the 3.5-fold enhanced?relative to pure GNPs.At last,in vivo studies using the optimal sized PTGs demonstrate the excellent PAI and PTT inhibition of tumor in living mice.This study not only introduces the first conjugated PTGs but also present a deeper fundamental understanding of ultrafast excited state dynamics,both of which would inspire the future fabrication of high-performance PTGs.3.Cationic poly-L-lysine-encapsulated melanin nanoparticles as efficient photoacoustic agents targeting to glycosaminoglycans for the early diagnosis of articular cartilage degeneration in osteoarthritisHerein,we introduce endogenous melanin nanoparticles?MNPs?encapsulated by poly-L-lysine?PLL?as positively charged contrast agents for the accurate photoacoustic?PA?imaging of cartilage degeneration through its strong electrostatic interaction with anionic glycosaminoglycans?GAGs?in the cartilage.PLL–MNPs presented high PA intensity,photostability and biocompatibility.In vitro PAI studies showed that PLL–MNPs with a zeta potential of+32.5±9.3 m V had more cartilage uptake and longer retention time than anionic MNPs and generated a positive relationship with the GAG content in the cartilage.After administration via intra-articular injection in living mouse models,PLL–MNPs exhibited about a two-fold stronger PA signal in a normal joint?with high GAG content?than an OA joint?with low GAG content?.Furthermore,the obtained PAI results provided accurate information of the GAG content distribution in the OA knee joint.Consequently,by detecting and analyzing the changes of the GAG content in OA cartilage using PAI,we can clearly distinguish early OA from late OA and monitor the therapeutic efficacy in OA after drug treatment.All PAI results were examined histologically.