Research On (phenyl) Borate-based Responsive Amphiphilic Polymer

In the past two decades,amphiphilic polymers are being actively investigated as nano-carriers for controlled delivery systems of drugs and other biological substances.Thus,stimuli-responsive polymeric nano-carriers that can be dissociated by various stimuli,such as p H,temperature changes,redox reactions,ultrasonic and light irradiation,are of particular interest.（Phenyl）Borate esters,as the name implies,are the esters of（phenyl）boric acid and alcohols（or phenols）.Moreover,（phenyl）boronate esters are p H and redox-sensitive moieties,allowing polymeric carriers to release the encapsulated cargoes upon p H and redox changes,respectively.Herein,with the continuous interest in smart stimuli-responsive polymeric nano-carriers,our main aim is to develop stimuli-responsive polymeric micelles and polymersomes based on（phenyl）borate esters,reported in three chapters.In the last study,our attention is drawn to the development of light-dissociable copolymer micelles based on photoacid generators.The experiment and main conclusions are summarized as follows:In the first study,photo-cleavable 2-nitrobenzyl derivatives can be conveniently photolyzed and are being widely used in synthetic and biological chemistry,and photo-switchabl polymer materials.Meanwhile,boronic acids can reversibly form chelatesters with cis-diol groups.Obviously,2-nitrobenzy boronates,the combined functional groups of them,would be photo-sensitive moieties,affording 2-nitrobenzy boronates-based polymeric carriers with photo-sensitive properties.Herein,a model photosensitive poly（ethylene glycol）-lipid of NP-B-PEG with a 2-nitrobenzyl2-pyridinylmethyl borate hydrophobic tail is synthesized.The ¹H-NMR and absorption spectra analysis of NP-B-PEG upon 365 nm irradiation in water supports a rapid photocleavage of nitrobenzyl borate.Fortunately,when the polymer aqueous solution is loaded with the hydrophobic doxorubicin（DOX）,the borate hydrolysis can be much retarded.The phototriggered experiment shows a two-stage DOX release:first,the slow leakage as a result of the photocleavage of 2-nitrobenzyl borate before the vesicle disintegration;second,the quick DOX precipitation from the disintegrated vesicles induced by the speeding up hydrolysis of 2-pyridinylmethyl borate.In the second study,due to the biocompatibility and non-contamination of CO₂stimulus,CO₂ is being substantially utilized to trigger the dissociation of p H-responsive polymeric nano-carriers（p H-RPNCs）composed of organic amine bases.However,p H-RPNCs with acid-labile moieties have never been resolved with CO₂.Herein we proposed a novel strategy of CO₂-acidolyzable polymersomes of a star-like polymeric prodrug with dynamic iminoboronate moieties of caffeic acid phenethyl ester（CAPE）.Upon alternative bubbling of CO₂ and N₂,the effective reversibility of iminoboronate moieties in aqueous solution is well demonstrated with 2D COSY NMR analysis.The CO₂-induced hydrolysis of iminoboronates results in disassembling of polymersomes and therefore a tunable release of CAPE molecules.The cellular uptake of polymer prodrug further reveals an enhanced intracellular delivery capability via the endosomal pathway and a satisfactory antitumor efficacy.In the third study,ROS-responsive polymeric nano-carriers（ROS-RPNCs）can controllably deliver encapsulated drugs upon high ROS in tumor tissues.However,ROS-RPNCs may not work due to the complexity in the focus of various periods and different areas and thus it is imperative to improve the sensitivity of ROS-RPNCs.Meanwhile,there are 2-3 times of Cu（II）in tumors than in normal tissues.Based on these facts,we propose a novel strategy of"Fenton-Enhanced Iminoboronate-Based ROS-Responsive Polymeric Nano-Carriers"to improve the responsiveness of ROS-RPNCs.The designed ROS-RPNCs will be incorporated with tertiary amines（TA）ligands in the central position of the synthesized starlike prodrug to form TA-Cu Fenton catalytic system by effectively chelating with Cu（II）,and thus more·OH radicals are generated upon H₂O₂,leading to a more effective cleavage of ROS-responsive groups and a satisfactory antitumor efficacy.In the last study,it was found that the novel PAG-based amphiphilic random copolymer of P（NVP-co-NHPSS）could form polymeric nanoaggregates in aqueous solution.And the photocleavage of the N-O bond within copolymer micelles upon 365nm UV light could be conveniently controlled by changing the irradiation intensity,leading to the disruption of copolymer micelles and the photocontrolled release of Nile red encapsulation.And by encapsulating Na Lu F4:Gd/Yb/Tm UCNPs inside copolymer micelles,the response of the photocleavable N-O bond to the 980 nm laser was much weaker than the response to 365 nm light;however,the photocontrolled release of Nile red could still be effectively triggered by the NIR light of the 980 nm laser.The results showed the interest in developing PAG-based polymer micelles for photocontrolled delivery systems.