Research On The Construction Of High-performance Multi-drug Delivery Vehicles Based On Hydroxycamptothecin Prodrugs

Cancer treatment strategies tend to be diversified,not only in the combination of clinical surgery and chemotherapy and radiotherapy,but also in the construction of multi-functional nanocarriers.Long-term administration of a single chemotherapy drug is likely to cause multiple drug resistance(MDR)of tumor cells.Chemotherapy drugs have a therapeutic effect on some tumors that tend to spread throughout the body or metastasize to advanced stages,but they also inevitably cause damage to normal cells and tissues.Therefore,chemotherapy is usually accompanied by obvious side effects,such as hair loss,diarrhea,and liver/kidney damage.Most chemotherapeutic drugs are hydrophobic,causing the drug molecules to become unstable during circulation in vivo.To improve the above defects,the researchers designed and prepared a series of nanocarriers,such as nanoparticles,micelles,liposomes,polymer prodrugs,etc.The co-delivery vector that can be used to deliver multiple therapeutic agents at the same time is a very efficient new vector due to its ability to achieve coordinated therapy.The purpose of co-delivery is mainly to combine different drugs and different therapy methods,and through synergistic effects,reduce the side effects of tumor MDR,chemotherapy drugs and increase the therapeutic effect.10-Hydroxycamptothecin(HCPT)as a commonly used chemotherapy drug is used to treat various tumor models.We synthesized hydrophobic(keto-)p HCPT chains based on HCPT and ROS-responsive linkers.(keto-)pHCPT chains were modified with hydrophilic polymer PEG to achieve self-assembly in aqueous solution,which formed micelles to load DEX.As a glucocorticoid,DEX can improve the anti-tumor effect of chemotherapeutic drugs and reduce its toxic and side effects.The drug loading,ROS responsive release efficiency,cytotoxicity,cell uptake,and anti-tumor ability of(keto-)Micelle@DEX were tested in detail.The experimental results showed that the HCPT content in(keto-)pHCPT-PEG is 28.6%,and the DEX content in(keto-)Micelle@DEX is 9.7%,which is much higher than the drug loading of conventional micelles.(keto-)Micelle@DEX had a rapid ROS response release rate.(keto-)Micelle@DEX size distribution around 100 nm can be effectively accumulated at the tumor site through the enhanced permeability and retention(EPR)effect.The synergistic treatment of dual drugs can kill tumor cells while reducing side effects on normal tissues.Based on the(keto-)pHCPT-PEG polyprodrug platform for dual drug delivery,we used functional hydrophilic dendrimers(PAMAM)for the hydrophilic segment to construct(keto-)pHCPT-PAMAM,which has amino groups on the outside to provide positive charges for loading nucleic acids.Based on delivering dual drugs,the function of gene delivery was added,and a three-in-one treatment strategy was realized.The designed(keto-)pHCPT-PAMAM has a higher HCPT content and DEX loading than(keto-)pHCPT-PEG.Studies have shown that(keto-)pHCPT-PAMAM had a rapid ROS response release rate and the three-in-one therapy strategy can inhibit the growth of tumor cells.It paved the way for the subsequent in vivo anti-tumor test,and initially verified the feasibility of the three-in-one treatment strategy.In summary,we used different hydrophilic polymers to modify the hydrophobic(keto-)pHCPT,and constructed a series of high-performance multifunctional polyprodrug platforms for tumor therapy,which can ensure the controlled release of the synergistic therapeutic drug HCPT and DEX.DEX improved the therapeutic effect of HCPT while reducing the side effects caused by HCPT,and achieved a reasonable synergistic therapy.The research about the co-delivery strategies of the polyprodrug platforms in this dissertation may provide new strategies to develop promising the design of tumor and other disease treatment.