Multi-Stimul Supramolecular Nanovector Based On Cyclodextrin For Targeted Delivery Of Anti-Tumor Drugs

Malignant tumors are the first major killer of human health.Traditional surgical treatment,radiotherapy,and chemotherapy are the main means of clinical treatment.However,due to the high toxicity and side effects of chemotherapy on normal cells,as well as the non-targeted focus of anticancer drugs in the human body,poor bioavailability,and low accumulation in tumors,the effectiveness of existing clinical anticancer drugs in tumor treatment is not ideal.To address the shortcomings of chemotherapy,scientists are committed to developing various nano carriers.In particular,the development and application of stimulus response nano carriers have received great attention.Stimulation response nanocarriers can utilize the unique microenvironment of tumors to respond to the release of loaded drugs,improving drug efficacy while reducing damage to normal tissues;It can also accurately trigger drug release under external stimuli（light,heat,sound,etc.）in a remotely controllable and spatiotemporal manner.Therefore,designing novel stimulus response vectors that combine multiple endogenous and exogenous stimulus response methods for cancer treatment is more innovative and challenging.In order to further improve the cancer treatment system with stimulatory responsive nanocarriers,a series of stimulatory responsive nanocarriers have been designed to safely and efficiently kill tumor cells.The main content includes the following aspects:（1）A pH-responsive nanoparticles based on sulfobutyl ether-β-CD（SBE₇-β-CD）and cetylbenzyldimethylammonium chloride（HDBAC）were constructed through electrostatic interaction and characterized by UV-vis,FT-IR,XRD,TEM,DLS,Zeta potential.The nanoparticles were adopted to encapsulate the bioactive compound celastrol（CSL）via hydrophobic interactions.The encapsulation efficiency（EE%）and drug-loading content（DLE%）of CSL were obtained as～89.4%and～26.9%,respectively.Based on the in-vitro drug release study,the release rate of CSL/SBE₇-β-CD/HDBAC is only 30.1%at pH=7.4,while could reach up to 86.9%at pH=5.4.The mechanism of CSL sustained release was studied by applying numerous kinetic equations.Hemolysis experiment showed CSL/SBE₇-β-CD/HDBAC NPs have good biocompatibility.In vitro cytotoxicity studies of CSL/SBE₇-β-CD/HDBAC present 2times fewer cytotoxic effects than free CSL on healthy cells（BEAS-2B）.Compared with the positive control group of cisplatin,CSL/SBE₇-β-CD/HDBAC displayed significant cytotoxicity on five human cancer cells.The apoptotic effects of CSL/SBE₇-β-CD/HDBAC is similar to that of free CSL on liver cancer（SMMC-7721）cells（5μg/m L）.The prepared nanoparticles can be used as a novel carrier for the sustained delivery of the anti-tumor drug.The apoptosis rate of liver cancer cells（SMMC-7721）is similar to that of free CSL.（2）A pH and temperature co-responsive supramolecular nanocarrier anchoring with folic acid（FA）ligands,termed PEHA-β-CD-FA/SDS NPs was prepared based on electrostatic interaction between cationic mono-（6-pentaethylenehexamine）-β-CD（PEHA-β-CD-FA）and anionic sodium dodecyl sulfate（SDS）and characterized.Using the anti tumor drug hydroxycamptothecin（HCPT）as a model drug,the EE%and DLE%were 90.6%and 29.5%,respectively.At pH=1.2 and T=45°C,the release rate of HCPT was only 12.4%,while at pH=8.5（simulating the intestinal microenvironment）and T=45°C,the release rate of HCPT achieved 93.6%.Due to the grafting of FA onto HCPT loaded NPs,they have a more precise targeting ability,resulting in a higher cumulative concentration of HCPT in colon cancer cells（SW480）and higher cytotoxic activity,while having a lower toxic activity against BEAS-2B.Compared with free HCPT,HCPT loaded NPs have a better proapoptotic effect on SW480 cells.The prepared NPs will provide a new idea for further enhancing the clinical efficacy of anti colon cancer drugs.（3）A pH/temperature/enzyme three-Stimuli-responsive intelligent nanocarrier drug system based on 7-substituted 6-amino-6 deoxygenationβ-CD（AβCD）and sodium hyaluronate（HA）were constructed through electrostatic interaction and characterized.Doxorubicin hydrochloride（DOX）as the drug model,the EE%and DLE%were 94.6%and 32.4%,respectively.At pH=8.5,T=45℃and HAase were added,the release rate of DOX reached 96.8%.Because HA has CD44 receptors in tumor cells,DOX/AβCD/HA NPs have a more precise targeting ability,resulting in a higher cytotoxic activity against liver cancer cells（SMMC-7721）than free DOX,while their cytotoxic activity against BEAS-2B is only one tenth of that of free DOX.This work has potential application prospects for developing safe and efficient multi stimulus response targeted therapy for liver cancer.（4）By combining the advantages of cyclodextrin derivatives and metal organic frameworks,pentaethylenehexamine was designed and preparedβ-CD grafted Folic Acid（PEHA-β-CD-FA）and polyethylene glycol phosphate modified adamantane（ADA-PEG（2000）-PA）are used to modify metal organic frameworks（MIL-101（Fe）-NH₂）to stimulate responsive nano carriers（FACDMOFs）to achieve efficient drug loading and controlled release.Using methopurine（MTX）as a drug model for adsorption,the EE%and DLE%were 46.48%and 62.32%,respectively.When pH=7.4 and T=45℃,the release amount of MTX is only 10.7%.When pH=5.4,T=45℃,the release amount of MTX reached 94.2%.Compared to free MTX,FACDMOFs have almost no toxicity to normal cells（BEAS-2B）.Because FACDMOFs are grafted with FA,they have a more accurate targeting ability compared to free MTX,MTX@FACDMOFs cytotoxic activity of SMMC-7721 cells was increased by 2.6times.The prepared functionalized MOFs provide potential application value for tumor therapy.