Construction Of Reduction-Responsive Polycyclodextrin Supramolecular Nanodrug And Its Application In Tumor Therapy

The development of nanomedicine provides advanced therapeutic strategies for cancer treatment.Nanomaterial delivery platforms based on supramolecular polymers have shown broad application prospects in cancer therapy.Unlike traditional polymers,supramolecular building blocks can be linked by covalent or reversible non-covalent interactions,making it easier and more efficient to integrate biological stimulus response properties into supramolecular polymers.As a class of macrocyclic oligosaccharides,cyclodextrins are food grade natural products with unique advantages such as good biocompatibility,biodegradability and low immunogenicity.In addition,their abundant modified groups can be used to graft drug molecules to optimize their physical and chemical properties,and can also become natural containers for small drug molecules through molecular recognition.Recently,supramolecular nanoplatforms based on cyclodextrin have been reported to improve the bioavailability and stability of drug molecules,thereby enhancing cancer therapy.However,stimuli-responsive functionalized supramolecular nanocapsulers aiming to tumor microenvironment(TME)as a tumor treatment strategy need to be further improved.Nano-carriers that stimulate sensitive response are not only beneficial to the on-demand release or controlled release of active drugs,but also beneficial to the accumulation of drugs at the tumor site.By changing the structure or size conformation,the penetration of drugs can be enhanced,and the side effects can be minimized to achieve the optimal tumor treatment effect for anti-tumor therapy.Therefore,the construction of supramolecular nano-delivery platforms of cyclodextrin with bioresponsive motifs is a promising anti-tumor strategy.In this study,a reduction-responsive polycyclodextrin network supramolecular nanodelivery platform(PDOP NCs)was constructed to improve drug circulation and tumor permeability,as well as intracellular drug release and biosafety.The polycyclodextrin(PCD)molecules were covalently cross-linked to form a polycyclodextrin structure using a reduction-sensitive disulfide cross-linking agent as a connecting network.It can provide a site for the coupling of chemotherapy drug doxorubicin(DOX).Meanwhile,the polycyclodextrin structure could enhance the hostguest interaction between DOX and β-CD to stabilize the nanocage structure.This supramolecular cross-linked structure makes the nanocages highly stable and biosafe.Thanks to this supramolecular structure,it can prolong the drug circulation time and improve the drug tumor aggregation ability.In tumor cells with high GSH levels,disulfide bonds in PDOP NCs are cleaved in response to the tumor cell reducing substance GSH,promoting DOX release within tumor cells and further deplete GSH to alleviate DOX resistance.In vitro and in vivo studies have shown that PDOP NCs exhibit significant anti-tumor effects due to their high cellular uptake,induction of significant DNA damage and strong tumor penetration.This polycyclodextrin-based multifunctional supramolecular nanocage provides a novel and efficient drug delivery strategy for cancer therapy.