Fabrication And Application Of Stimuli-Responsive Polymer Assemblies

Stimuli-responsive polymers,also called smart polymers,are a class of polymers that respond to external environmental stimuli by reversibly or irreversibly changing their physical and/or chemical properties.These external stimuli include pH,temperature,light,electromagnetic fields,mechanical forces,various small molecules and biological molecules,etc.The biological environment of diseased tissues,such as pH,temperature,redox pressure,etc.,is quite different from that of normal tissues in the organism.On the other hand,stimuli-responsive polymers can exist in the form of solutions,gels,self-assembled nanoparticles,(multilayer)films,and bulk solids,which overcome the shortcomings of low stability,poor water solubility,and rapid removal by the organism of small molecular reagents,thus exhibiting potential applications in the fields of biology and medicine.Therefore,it is of great significance to design and develop stimuli-responsive polymers that can be used as sensors and biosensors to control and trigger drug delivery,environmental repair and other functions.This dissertation focuses on the application of stimuli-responsive polymer assemblies in delivery and controlled release of anti-cancer drugs for cancer pain treatment or alleviating pain,which mainly covers the the following three parts:1.The selective activation of nanovectors in pathological tissues is of crucial importance to achieve optimized therapeutic outcomes.However,conventional stimuli-responsive nanovectors lack sufficient sensitivity because of the slight difference between pathological and normal tissues.Traditional stimuli-responsive polymers can only respond to external stimuli in a one-to-one manner,where the input signal determines the output signal,which limits its sensitivity in practical applications.In order to further improve the sensitivity of stimuli-responsive polymers,researchers have developed self-degradable polymers,which can degrade spontaneously after being triggered.Although the output signal can be adjusted by chain structure and degree of polymerization(DPs),stoichiometric triggering is still needed to achieve complete degradation of the polymer,because the triggering process between chains is usually inhibited.However,nature can accomplish sensing events with different range of time and distance through continuous cascade reactions.Inspired by this strategy,the cascade reaction signal amplification strategy based on positive feedback has become an emerging strategy for constructing ultra-sensitive polymers.Compared with the aboved mentioned two types of stimulus-responsive polymers,the self-amplifying polymers based on cascade reactions can amplify the input signal in a positive feedback manner once triggered,thereby significantly improving the sensitivity.To this end,the development of nanovectors capable of responding to weak pathological stimuli is of increasing interest.In the second chapter of this dissertation,we designed and fabricated amphiphilic polyurethane nanoparticles containing both external and built-in triggers.The activation of external triggers leads to the liberation of highly reactive primary amine groups,which subsequently activates the built-in triggers with the release of more primary amine groups in a positive feedback manner,thereby triggering the degradation of micellar nanoparticles in a cyclic amplification model.The generality and versatility of the cyclic amplification concept was successfully verified using three different triggers including reductive milieu,light irradiation,and esterase.We demonstrated that these stimuli-responsive nanoparticles show self-propagating degradation performance even in the presence of trace amounts of external stimuli.Moreover,we confirmed that the esterase-responsive nanoparticles can discriminate cancer cells from normal ones by amplifying the esterase stimulus that is overexpressed in cancer cells,thereby enabling the selective release of encapsulated payloads and killing cancer cells.This work presents a robust strategy to fabricate stimuli-responsive nanocarriers with highly sensitive property toward external stimuli,showing promising applications in cancer therapy with minimized side effects.2.Biodegradable polytrimethyl carbonate(PTMC)is a type of synthetic elastomer,which is amorphous in the relaxed state and crystalline in the stretched state.More interestingly,the crystalline melting temperature(Tm)of PTMC is very close to the temperature of the human body.Nile blue is a very mature photothermal reagent featureing in good light stability,which mainly produces singlet oxygen by photodynamics upon photoirradiation in the dispersed state,while exhibiting photothermal effect in the aggregated state.In view of this,in the third chapter of this dissertation,Polyethylene glycol was used to initiate the ring-opening polymerization of trimethylene carbonate and a small amount of octadecyclic carbonate carbonate with acyl azide side groups to obtain amphiphilic block copolymers with hydrophobic polycarbonate block in the main chain.Then a kind of Nile blue dericative with hydroxy group was post-modified to the polymer side chains.Large vesicles can be fabricated from the synthesized amphiphilic block copolymers through thin-film hydration method,in which the Nile blue moieties are located in the hydrophobic polycarbonate membrane layer,while the hydrophilic drugs or dyes can be loaded into the vesicular lumen.Based on the photothermal effect of Nile blue,the photo-irradiation at the wavelength of 660 nm caused the hydrophobic vesicular membrane layer to melt and changed it from the crystalline to fluid state.Therefore,the hydrophilic small molecules trapped in the vesicular lumen can pass through the hydrophobic membrane layer in fluidic state into the hydrophilic environment outside the vesicles,resulting in the photothermal melting release.It has been confirmed that the prepared vesicles have good photothermal effects in both internal and external environments,and the loaded hydrophilic dye can pass through the hydrophobic layer of the vesicles through the above process.Moreover,after injecting the tetrodotoxin(TTX)loaded large vesicles by peritumoral injection into the vicinity of the tumor transplanted in the mice and followed by laser irradiation at 660 nm,tetrodotoxin flowed out from the vesicles,and showed a good effect of relieving cancer pain.3.Due to their good biocompatibility and biodegradability,aliphatic polycarbonates(PCs)have played a huge role in the fields of biosensing and biomedicine.Different from aliphatic polyesters,aliphatic polycarbonates do not produce acidic by-products when being degraded in the body,thus can avoid local aseptic inflammatory reactions and the inactivation of biologically active substances induced by acid.Generally speaking,the direct hydrolysis or enzymatic hydrolysis of the carbonte bonds in hydrophobic polycarbonates is very slow,which limits their short-term applications in the body.Although the hydrophilic modification of polycarbonates can accelerate their degradation rate,when used in drug or gene delivery,the on-demand and controlled degradation of functional polycarbonate triggered by exogenous stimuli is of more popential application.In the fourth chapter of this dissertation,amphiphilic block copolymers bearing homopolymerzied and copolymerized polycarbonate blocks,respectively,and capable of triggered-cleavage were synthesized via ring-opening polymerization initiated by polyethylene glycol.The copolymerized polycarbonate blocks in the copolymers mainly were composed of trimethylene carbonate and octadecyclic carbonate carbonate with functional side groups responding to light and hydrogen peroxide stimuli,respectively,while the homopolymerzied polycarbonate blocks were totally composed of octadecyclic carbonate units with functional side groups.The synthesized amphiphilic block copolymers with copolymerized polycarbonate blocks can self-assemble into large vesicles via thin-film hydration method,which underwent morphological changes under under different external stimuli.The amphiphilic block copolymers with hopolymerized polycarbonate blocks can be almost completely degraded into small molecular fragments within 48 hours under external stimuli.