Construction And Anti-tumor Research Of Nanoscale Coordination Polymers Based On Fe-polyphenol

Cancer is one of the major public health problems in the world and seriously threatens people’s health.Photothermal therapy(PTT)is an emerging tumor treatment method,which has the advantages of non-invasiveness,high selectivity,and good therapeutic effect.However,the further application of PTT is also subject to certain restrictions.For example,the preparation process of traditional photothermal agent is complicated,and its biosafety needs to be further improved;after achieving the therapeutic function,photothermal agent is difficult to be eliminated from the body quickly,which may cause long-term harm to the body;PTT has a good inhibitory effect on the tumor at the site with light irradiation,but it is powerless to inhibit tumor metastasis,and the PTT is accompanied by inflammation,which may cause tumor recurrence.Therefore,we have performed the following work to overcome the current problems of PTT.First,we selected safe materials to construct a multifunctional theranostics nanoparticle through a simple modular assembly strategy.Although FeⅢ-phenol nanoscale coordination polymers with good biocompatibility and biosafety are often used as photothermal agents for PTT,there is little comparison of the performance of photoacoustic imaging and PTT for different FeⅢ-phenol complexes.Herein,we prepared a series of FeⅢ-phenol nanoscale coordination polymers using FeⅢ and phenols with different structures via a simple one-step method,and the introduction of polyvinylpyrrolidone(PVP)could effectively improve the dispersion and stability of the nanoscale coordination polymers.The research results showed that the nanoscale coordination polymers formed by FeⅢ and polyphenols with ortho-phenolic hydroxyl structure had strong absorbance in the near-infrared region,and exhibited excellent photothermal property and photoacoustic imaging performance.In addition,we performed detailed characterization of the particle size and absorbance in the nearinfrared region of different nanoscale coordination polymers,and compared their photothermal property and photoacoustic imaging performance.Among them,FeⅢ-TA nanoscale coordination polymers are optimal.Therefore,the FeⅢ-TA nanoscale coordination polymers are more suitable for in vivo imaging guided PTT research.In order to further improve the performance of the FeⅢ-TA nanoscale coordination polymers in vivo,we modified them with poly(glutamic acid)-graft-methoxypoly(ethylene glycol).The as-prepared nanoparticles(FeTNPs)had a suitable size(75 nm)and showed a good stability.After being injected into MCF-7 tumor-bearing mice via the tail vein,the nanoparticles showed excellent multi-modal imaging performance,and the PTT guided by imaging had a significant inhibitory on tumor growth.Further study found that during the in vivo circulation,in addition to showing a good enrichment effect at the tumor site,most of the nanoparticles also remained in the liver.To solve this problem,we developed a dynamic disassembly strategy triggered by deferoxamine mesylate(DFO).Due to the stronger binding capacity of DFO and FeⅢ,the nanoparticles showed dynamic disassembly performance after the introduction of DFO,and the particle size was reduced from 75 nm to 3.6 nm,which could accelerate elimination of FeTNPs from the body through the renal clearance pathway.FeTNPs exhibit the following highlighted features:(1)The effective accumulation in the tumor tissue is achieved based on EPR effect;(2)The dual photoacoustic/magnetic resonance imaging capacity can provide guidance for the PTT;(3)FeTNPs can be dynamically disassembled by DFO to accelerate elimination of the nanoparticles,thus reducing the potential toxicity for the body.The DFO triggered dynamic disassembling strategy may open a new avenue to overcome the dilemma between EPR effect and renal clearance.Although PTT shows an excellent inhibitory effect on tumors in the irradiated area,it has poor inhibitory effect on metastatic tumors.In addition,the PTT is accompanied by inflammation,which may cause tumor recurrence.Moreover,in order to realize the clinical transformation of nanoparticles,the biosafety of nanoparticles should be further improved,and safe components should be selected as far as possible.Therefore,we selected endogenous FeⅢ,dietary luteolin and FDA-approved polymer PVP to construct multifunctional nanoparticles(FeLPNPs).The as-prepared nanoparticles exhibit outstanding advantages as follows:(1)The ingredients of FeLPNPs are highly safe,which endows FeLPNPs with good biosafety;(2)FeLPNPs exhibit excellent performance of PAI,magnetic resonance imaging,photothermal imaging,and photothermal property,which can be applied for effective multi-modal imaging-guided PTT;(3)After accomplishing mission of PTT,the as-prepared nanoparticles can be disassembled by DFO via dynamic disassembly strategy to achieve rapid elimination and avoid potential long-term toxicity to the major organs;(4)The luteolin released during FeLPNPs disassembly is expected to perform tumor-specific chemotherapy,down-regulation of PD-L1 expression on tumor cells,and anti-inflammatory functions,which can combine with PTT to achieve potent inhibition of primary tumor,tumor recurrence and metastasis.The experimental results show that imaging-guided PTT can significantly inhibit tumor growth in the subcutaneous 4T1 tumor model.In addition,luteolin released during disassembly could effectively improve the anti-tumor effect of PTT and prevent tumor recurrence.Moreover,in the bilateral tumor model,the combined photothermal/chemo/anti-inflammatory/immunotherapy not only effectively suppressed the primary tumor,but also showed a certain inhibitory effect on the distal tumor.This research demonstrates an innovative method based on highly biocompatible nanoparticles to solve tumor recurrence and metastasis,showing great potential in accelerating clinical translation.We adopt the corresponding scheme to solve the following problems:(1)Using a simple modular assembly strategy to simplify the tedious preparation process of nanoparticles;(2)Using safe components to construct nanoparticles to solve the problem of poor biocompatibility of nanoparticles;(3)The as-prepared nanoparticles are versatile and can be used for multi-modal imaging guided PTT to overcome the problem of frequent drug injection;(4)Developing a dynamic disassembly strategy to solve the potential long-term toxicity of nanoparticles in vivo;(5)Overcoming the bottleneck of PTT through the combination of PTT,anti-inflammatory therapy,chemotherapy and immunotherapy,not only effectively eradicate primary tumors,but also inhibit tumor recurrence and metastasis.The as-prepared nanoparticles have clear structure,safe components and versatility,and are expected to achieve clinical transformation.