Application Of Supramolecular Interaction In The Construction Of Multifunctional Nano-drug Delivery System

Thanks for the enhanced permeability and retention effect(EPR)of tumor itself,nano-drug delivery system(DDS)can target tumor sites spontaneously,which sattles the problem of side effects,short cycling time and off-target faced by small-molecular drug.Since the beginning of this century,DDS has been further developed especially in the construction of theranostic platform.However,the following problems also limit the development of DDS.First,the high weight proportion of carrier itself caused the low loading efficiency.The second limination of DDS is biotoxicity.All the DDS should be metabolized when the mission of transportation finished.But in the process of metabolism the heavy metal toxicity and immunoreaction including inflammation and oxidative stress will be caused.To avoid the two problems above,the nanomaterials with better biocompatibility should be chosen as carrier.Besides,to carry the small molecular drug with high loading efficiency and release them in time when DDS arrives at tumor sites,the interation between DDS and small molecular drug should be taken into full consideration.Supramolecular interaction including ?-? stacking,electrostatic interaction,host-guest interaction,coordination and hydrogen bond commonly play the important roles in the construction of multifunctional DDS.Firstly,the assembly process is relatively simple and the structure is concise.Secondly,the strength of supramolecular interaction can be changed in tumor microenvironment and adjusted by external stimulus.As a result,the release process can be controlled easily.We managed to construct multifunctional DDS via simple experiments based on supramolecular interaction.Non-drug ingredients in DDS was discard by self-drug delivery system to enhance the loading efficiency and reduce biotoxicity fundamentally.Meanwhile,to chang the passive target DDS to active DDS,the carrier was facilitate with hyaluronic acid.In this paper,different supramolecular interaction were applied to construct DDS with simple structure,higher loading efficiency and enhanced target ability.The dissertation is mainly divided into following five chapters.Chapter 1: A brief introduction to the function of ?-?,electrostatic,host-guest,coordination hydrogen bond in the construction of multifunctional DDS.Chapter 2: A smart yolk-shell type luminescent nanocomposite for NIR–NIR monitor of drug release in chemotherapy.In this section,A hollow DDS platform(HMSN)based on mesoporous silica was constructed and the biocompatibility was resolved by silica.The structure of mesoporous and hollow is benefitial for the elevation of drug loading efficiency.Meanwhile,the two-photon sensitized Yb(?)complex was synthesized in vivo in mesoporous silica to monitor the releasing process of doxorubicin(DOX).Besides,phenyl group was introduced to further stabilize drug in mesoporous by ?-? interaction.To further prevent pre-release of DOX,carboxylmethyl chitosan(cCTS)was coated onto HMSN.In acid tumor microenvironment the cCTS was protonized and the structure changed,which caused DOX release from DDS.This work has certain significance to solve the problem of low loading efficiency of DDS.Chapter 3: A smart drug-drug nanohybrid for the self-delivery of porphyrin and cis-platinum.Considering the former work still used non-drug ingredients in DDS,the limitation of drug loading efficiency and biocompatibility didn't resolved thoroughly.In this section,a self-delivery system based on the coordination between photodynamic reagent 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin(TCPP)and chemotherapy reagent cis-dichlorodiammine platinum(II)(CDDP)was synthesized.In acidic tumor microenvironment,the coordination bonds can be broken down,which caused the releasement of TCPP and CDDP.Meanwhile,the yield of singlet oxygen was elevated owing to the heavy atom effect of platinum(II)and the photostability of TCPP was reinforced by the self-delivery system itself.At last,the red fluorescence can be used for monitoring the process of drug delivery.By introducing the concept of self-delivery,the drug loading efficiency of DDS has been greatly improved and the biocompatibility has been fundamentally solved.Chapter 4: A multifunctional self-delivery nanovesica based on heptamethine cyanine for precise synergetic therapy and imaging.In this section,we continue to focus on the construction of the self-delivery system.the hydrophobic heptamethine cyanine was transformed into amphipathic Hcy-SS-PEG by covalent linking PEG via cystamine.Hcy-SS-PEG can self-assembly into multifunctional nanovesica(MNV)in water.The cavity in MNV can be used for the delivery of DOX.And DOX can be released when S-S bond is broken down by glutathione overexpressed in tumor sites.The maximum absorbance wavelength of MNV is 539 nm in physiological environment but in acidic environment,the peak value of absorbance wavelength is 850 nm,which is fundmental for photothermal therapy irradiated by NIR light.Menwhile,the NIR fluorescence can be used as monitor for drug delivery process.Chapter 5: CD44 targeted luminescent nanocomposite for NO self-delivery and NIR-NIR monitor of releasing process.Compared with passive targeting drived only by EPR effect,active targeting has more advantages for tumor precise treatment.In this section,a nanocomsite named YbHaL-NO used for the self-delivery of NO based on coordination was constructed.The nanocomposite can release NO when irradiated by UV or 766 nm light.In the process of NO releasing,the ligand L-NO recoved D-?-A configuration and sensitize Yb(?),which caused the NIR fluorescence of Yb(?)to increase.Lastly,hyaluronic acid was used to promote the water solubility of nanocomposite and CD44 target over-expressed by tumor.This work is significant for the precision treatment of tumor.