| In the past few decades,significant breakthroughs have propelled us to better understand the origins and developments of cancer,in turn,more and better diagnosis and treatment have been worked out.However,cancer is still an important cause of human death.This is mainly because that we cannot simply transport anticancer drugs to the tumor sites without causing adverse side effects on healthy tissues or organs.In addition,due to the limitations of various treatment methods,researches in the past decade have shifted to the development of new-type green therapies(photothermal therapy,photodynamic therapy,gene therapy,immunotherapy,etc.)or in combination with other therapies(integration of diagnosis and treatment)to reduce the side effects of traditional cancer treatment methods.Among them,the most direct way to reduce the side effects of chemotherapy is the construction of drug carriers.The ideal drug carriers can overcome biological barriers,distinguish between benign and malignant cells,be able to specifically recognize targeted cancer cells,respond to the changes of the body microenvironment sensitively,and release appropriate doses of the chemotherapy drugs in appropriate areas.As a kind of polymer colloidal particles with a size of micron or nanometer,various types of microgels can be prepared by incorporating various functional materials to meet various needs in the field of biomedicine.Its inherent nature also lays the foundation for acting as an intelligent drug carrier.Its adjustable physicochemical properties can be effectively prevented them from being rapidly cleared by the body;its deformable properties can effectively enhance its EPR effect and enhance the accumulation at the tumor;its excellent permeability makes the drug loaded can be evenly distributed,and the gentle drug release rate is ensured,which effectively maintains a stable blood drug concentration;its special swelling behavior lays its unique drug release mode,ensuring the controlled release of the drug;its micro-nano scale gives it the ability to respond quickly to external stimuli,making it more responsive to external stimuli than traditional hydrogels,and more "smart";its stability makes it stable in the blood circulation,avoiding early leakage of drugs.These excellent properties make microgels widely used in the field of cancer treatment Although there are many literatures about microgels as drug carriers,microgels still have a large research space as remotely controllable drug carriers.By systematically studying the properties of microgels to improve their therapeutic effects as drug carriers,it is not only beneficial for people to study the essence of life,but also to develop the research systems on biomimetic technology,broaden the ideas on cancer treatment and diagnosis,which is also an important content in the field of soft matter research.Therefore,it is of great scientific significance and application value to carry out the researches on hybrid microgels based on functional materials.Based on the polymer microgel systems,this dissertation mainly constructed the multi-responsive microgel systems by introducing gold nanorods,polymerizable magnetic ionic liquids or functional DNA molecules,and further explored the potential application in the field of cancer treatment,multi-modal combination therapy.The research content of this dissertation is as follows:In Chapter I,we introduced the current difficult situation of cancer treatments and the characters of the ideal drug carriers.The basic concepts,synthetic methods and basic properties of microgels are also briefly introduced.The design ideas of intelligent microgel drug cariers are reviewed in detail:microgels based on internal environment stimulation,microgels based on remote stimulation,and microgels with targeting groups.Finally,we summarized the thesis,research content and significance of this dissertation.In Chapter ?,in virtue of base complementary pairing principle and photo-initiated polymerization,DNA microgels with temperature-responsive properties were synthesized using oligonucleotide chains and polymers as basic building blocks.Unlike conventional microgels,the DNA microgels have a cubic structure,which might be the result from the collapse of the polymer chains and the rigidity of the DNA structure.At room temperature,the anti-cancer drugs can be encapsulated into the network structure of the DNA microgels.When the microgels entered into the cells,the body temperature of 37 ? caused the microgels to shrink and the anti-cancer drugs released.In addition,the targeting of the DNA microgels was endowed with the aptamer.Cell experiments demonstrated that this DNA microgel has excellent biocompatibility and high selectivity and therapeutic effect for targeting cancer cells.In Chapter ?,the microgels synthesized in Chapter ? are only sensitive to temperature and might result in premature release of anticancer drugs in practical applications,thereby causing damage to healthy tissues or organs.Therefore,in this chapter,a dual-responsive DNA microgel built from a photothermal gold nanorods(Au NRs)core,oligonucleotides cross-links,and polymer shells was synthesized for the first time.When irradiated by a near-IR laser beam,Au NRs in the magnetic microgels are the motors causing a rapid rise in the temperature.Once the heat dissipates into the surroundings,the rising temperature causes the DNA cross-links to separate.As a result,the microgel shells break down and the payloads release.DNA not only serves as cross-linking agents for improving the biocompatibility but also takes the role as a valve to control the drugs release.The experiments demonstrated that such light-responsive magnetic microgels can be candidates for a remotely controlled drug delivery platform with excellent biocompatibility and highly therapeutic effect for cancer cells.Our results may provide opportunities for broad new functional nucleic acid-based nanostructures and holds great promise as a candidate for applications in the field of nanomaterials and biomedicine.In Chapter IV,although Au NRs can convert light into heat,its low photothermal conversion performance in practical application still cannot meet the cancer treatment of deep subcutaneous tissue.Plasmonic microgels(PMgels)of self-assembled and in situ growth of Au NRs with side-by-side arrangement piles in ionic liquid microgels were prepared,which were different from the most studied plasmonic nanostructures constructed by self-assembly of amphiphilic polymer grafted nanoparticles.The resultant PMgels possessed unique morphology and enhanced photothermal conversion efficiency,up to 52.8%.This high photothermal conversion efficiency of the PMgels is not only attributed to the well-matched LSPR peak of PMgels and laser,but also to the narrow gaps between the Au NRs in the microgels that induce a strong plasmonic coupling effect.The experiments in vitro and vivo demonstrated that the PMgels can efficiently shield the high toxicity of chemotherapeutic agents,significantly enhance the therapeutic effect and completely inhibit the tumors growth by combing the chemo-and photothermal therapy.We anticipate that the present materials can not only provide new ideas for new functional plasmonic nanostructures,but also hold great promise as a cancer treatment candidate.In Chapter ?,a new type of hydrogel implants was constructed by physiological environment-induced self-assembly of dual-stimuli responsive magnetic microgels.This hydrogel implant exhibits excellent collective behaviors driven by magnetic field and near-infrared laser.The self-organization process can not only realize the structural transformation of the microgel to the hydrogel,but also realize the magnetic enrichment,thereby significantly improving the magnetism of the magnetic materials based on the magnetic ionic liquids.Due to the high controllability and operability of near-infrared light,the hydrogel implant can not only release the drug at a constant rate,but also release a suitable dose of the drug in a suitable area.We anticipate that the present hydrogel implant system could be a local delivery system for the treatment of solid tumor malignancy.The prolonged drug release could ensure that cancer cells take in adequate chemotherapeutic drugs during each cycle of tumor cell division and thoroughly avoid the local recurrence or metastasis of primary tumor.In Chapter ?,we report a multifunctional drug delivery platform based on Au NR@SiO2 for enhancing non-small cell lung cancer(NSCLC)treatment.The nanocomposite can simultaneously achieve drugs to be controlled release,magnetic targeting,and specific targeting cancer cells.This nanocomposite uses polydopamine as a valve for drug release,Au NRs as a local photothermal converter,and porous silica as a container for drugs.In addition,the S6 aptamer endows targeting,and Ce and sodium citrate complexes serve as the primary source of magnetic response.Acid-and photothermal-triggered drug release behavior can be observed after uptake into cancer cells and applied a near-infrared laser.When the target cells are absent,the cellular uptake of the nanocomposite is inhibited,showing a poor therapeutic effect.However,when a target cell is present,more nanocomposites enter into the cells due to specific recognition between the S6 aptamer and the target cells,thereby achieving a good therapeutic effect.In addition,the application of a magnetic field also increases the accumulation of nanocomposites at the tumor sites.Cell experiments have shown that the nanocomposites can effectively shield the toxicity of anticancer drugs,and achieve high sensitivity and high efficiency of cancer treatment.In Chapter ?,ionic liquid microgels with core-shell structure were constructed based on Au NRs and ionic liquids,and electrostatically self-assembled with gold nanoparticles(Au NPs),so that Au NPs can be well immobilized in the network of microgels.Completely different from previous reports,this responsive ionic liquid microgel can act as a "breathing" carrier,and the catalytic activity of Au NPs can be precisely regulated by near-infrared laser.When irradiated by an NIR laser beam,Au NRs in the ionic microgels act as motors,causing a rapid increase in the temperature.Once the heat dissipates into the surrounding microgel shell,the thermosensitive ionic microgels begin to shrink,inducing the aggregation of Au NPs;this leads to a decrease of catalytic activity.When the near-infrared laser is removed,this ionic microgel gradually expands due to heat dissipation,resulting in recovery of catalytic activity.The near-infrared laser acts as a switch throughout the whole process.In addition,the catalytic activity of this self-assembled nanocomposite has a significant competitive advantage over other gold-based catalysts used to reduce 4-nitrophenol reported in the literature.The distinctive accommodation mode may open up an opportunity for the design of intelligent catalysts for tunable catalysis. |
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