Multifunctional Hydrogel Construction And Biomedical Applications

Hydrogels are composed of hydrophilic polymers formed by crosslinking.Hydrogels have become very popular due to their unique properties such as high water content,softness,flexibility and biocompatibility.The versatility of hydrogels make them a variety of use in biomedical fields.Although hydrogels have been widely used,there still exist several problems to be solved.For example,the syntheses of most light-response hydrogels are complicated;the composite hydrogels prepared by physically mixing of functional nanoparticles and hydrogels lack stability;and the hydrogels used for photothermal therapy of tumors lack stimuli-responsiveness.How to overcome the problems existing in the biological applications of hydrogels still remains a great challenge in recent years.The aim of this thesis is to construct novel multi-functional hydrogels by using functional molecules or nanoparticles as crosslinking ligands,and investigate their biomedical applications in drug delivery,UV protection and photothermal therapy.The strategies are described as follows:(1)we developed a light-responsive hydrogel composed of four-arm poly(ethylene glycol)bearing thiol terminal groups(PEG-SH)and 3,6-dichloro-1,2,4,5-tetrazine(DT).DT not only functionalized as the light-responsive element,but also the crosslinking compound.And we investigated the light-responsive degradation and drug release behaviors of this hydrogel and evaluated the applications of drug-loaded hydrogel in cancer therapy.(2)We developed a multi-functional hydrogel by using PDA nanoparticles to crosslink thiol containing polymers,and studied the applications of PDA hydrogels in UV protection and drug controlled release.(3)We used dynamic chemical bonds or electrostatic interactions to construct stimuli-response photothermal hydrogels.We investigated the applications of the prepared hydrogels in long-term photothermal cancer therapy and their degradation behaviors in vitro and in vivo.The detailed methods and results are summarized as follows:(1)Photo-responsive hydrogels have been widely used for sustained drug delivery.Traditional photo-responsive hydrogels may acquire photosensitivity by grafting light-sensitive components on the gel network via complicated chemical synthesis.When light irradiated,the light-activated component may generate by-products.In addition,most reported photo-responsive hydrogels in the references respond to UV lights,which has poor penetration ability to reach the deep tissues.This limits the biological application of these light-responsive hydrogels.In the first part,we developed a dual-light responsive hydrogel composed of PEG-SH and DT.Upon UV light irradiation,the hydrogel was gradually degraded and could release the entrapped therapeutic agents in an on-demand manner,and thus the drug release behavior of hydrogel could be controlled without any by-products.In addition,the hydrogel is also responsive to a 532 nm laser,which shows better tissue penetration ability and safety.The hydrogel loaded with doxorubicin efficiently inhibited tumor growth upon irradiation by a 532 nm laser.(2)Composite hydrogels occupied a considerable proportion in the multifunctional hydrogels.Composite hydrogels were generally prepared by physically mixing functional molecules or ligands within the hydrogel network.The synthetic route is facile,but the physically embedded functional materials in the gel are easy to leak during use.Here,we used the PDA nanoparticle to chemically cross-link with thiol containing polymers to form the multi-functional hydrogel.PDA,as a kind of melanin analogues,is now widely used in surface coating,drug delivery,photothermal therapy,and many other fields.The prepared PDA hydrogels were used for UV protection and light-triggered drug delivery.First,inspired by human skin pigmentation-based photoprotection mechanism,we rationally designed and facilely prepared novel sunscreen products based on polydopamine(PDA)hydrogels.The resulting PDA sunscreens are bioadhesive,water resistant,and non-skin penetration,yet could be directly removed by towel wiping.They also perform many promising features including superior UV shielding properties,high in vitro and in vivo UV protection efficiencies,non-phototoxicity,and non-irritating nature.We propose that this class of bioinspired hydrogels will be useful for incident UV protection where simple,safe,and efficient sunscreens are still highly desirable.Besides UV protection,PDA nanoparticles were reported to have high drug loading ability and photothermal conversion effect.Chemical drugs such as SN38 could be loaded on PDA nanoparticles via ?-? stacking,and the loaded drugs could be released by NIR irradiation.In this case,we developed a hydrogel-mediated chemo-photothermal treatment based on PDA-knotted PEG hydrogels.PDA nanoparticles in the hydrogel not only served as a photothermal agent but also played a crucial role to load the chemical drugs such as SN38 and to release the drugs in response to NIR light.(3)Photothermal hydrogels,as novel functional hydrogels,made great contributions in tumor photothermal therapy.Photothermal hydrogels can retain in the tumor site for a long period,but they can't degrade after biomedical use,due to the lack of stimuli-responsiveness.In the third part,we developed two kinds of photothermal hydrogels to solve the biodegradability issue.First,we use dextran-aldehyde and a generation 5 amine-terminated polyamidoamine dendrimer-encapsulated platinum nanoparticles(DEPts)to form a pH-responsive photothermal hydrogels.The hydrogel possessed high photothermal effect and excellent biocompatibility,and could be locally immobilized in tumors for a long time to carry out the repeated photothermal therapy and then be degraded in acidic environments.Considering that patients may bear tumors of different types and different grades of malignancy,which requires different times of photothermal treatments to ablate the tumor,an appropriate duration of photothermal hydrogels in the tumor tissue is desired.To pursue the outcomes for personalized photothermal therapy,we utilized an alginate-calcium hydrogel to immobilize DEPts in its matrix via electrostatic interactions.The hydrogel construct also could be locally immobilized in tumors for a long period and then be degraded in an on-demand fashion upon the injection of calcium chelates.In summary,several multifunctional hydrogels were prepared by using functional molecules or nanoparticles as the crosslinking ligand.This crosslinking strategy is facile for the preparation of stable,versatile and biocompatible hydrogels for biomedical applications.These studies extended the biomedical applications of multifunctional hydrogels.