Several Supramolecular Systems Based On Macrocyclic Arenes For Drug Delivery Application

Supramolecular macrocycles are capable of selectively constructing supramolecular complexes with guest molecules through noncovalent interactions.The noncovalent binding strategies mainly include?-?interactions,hydrogen bonding interactions,coordination interactions,electrostatic interactions,van der Waals force,charge transfer,etc.,which indicate that the interactions between supramolecular macrocycles and guests are dynamic and reversible,endowing them with various stimuli response.The dynamic binding properties give supramolecular materials used for drug delivery in a specific environment to induce active therapeutic agents in a controllable manner under unique stimuli conditions,such as pH,reducing force,temperature,light,ions,ultrasound,and external magnetic fields,realizing the on-demand drug delivery.As a new type of supramolecular macrocycles,pillar[n]arenes(n=5-15),especially pillar[5,6]arene and their derivatives,are widely used in the drug delivery fields due to their suitable cavity sizes,unique host-guest properties,and good biocompatibility.On the other hand,porous materials have become suitable nanocarriers for increasing the drug loading capacities,improving the drug solubilities,and achieving the afficient drug delivery effects,which is on account of their prominent physicochemical features including easy synthesis and functionalization,tailorable pore sizes,variable structures,high surface areas and loading capacities,good biocompatibility and biodegradability.Porous materials functionalized by supramolecular macrocycles combine the advantages of recognition,binding,and dynamic release of supramolecular macrocycles,which enable guests combined with supramolecular macrocycles to be efficiently selected,recognized,and released under specific conditions,achieving the purpose of controllable drugs release.Moreover,they possess the superiorities of high porosities and easy functionalization of porous materials,which provide a strong guarantee for the efficient loading of drug molecules and enhanced targeting of supramolecular carriers.Based on the aforementioned fascinating features,this paper is summarized as the following three parts:(1)Owing to the advantages of tunable noncovalent interactions of supramolecular macrocycles for specific recognition,interaction,and controlled release of chemotherapeutic drugs,two water-soluble macrocyclic hosts,i.e.,carboxylated leaning tower[6]arene(CLT6)and carboxylated[2]biphenyl-extended pillar[6]arene(CBpP6),were designed and synthesized as a molecular-scale drug delivery system to load chemotherapy drug oxaliplatin(OxPt)by fabricating inclusion complexes(OxPt(?)CLT6 and OxPt(?)CBpP6)through host-guest interactions.CLT6 and CBpP6hosts possessed eight carboxylated groups and could be synthesized with satisfactory yields.Through the host-guest interactions,OxPt guest was spontaneously encapsulated in the cavities of CLT6 or CBpP6 host to construct host-guest complex of OxPt(?)CLT6 or OxPt(?)CBpP6 with a stoichiometry of 1:1.The association constants were calculated as(1.15±0.08)×10³ M^-1 and(2.29±0.19)×10² M^-1,respectively.In addition,spermine(SPM),overexpressed in MCF-7 cancer cells,could also be encapsulated into CLT6 and CBpP6 cavities to develop 1:1 SPM(?)CLT6 or SPM(?)CBpP6 complex.Moreover,because of the stronger binding abilities between two macrocycles and SPM with a binding constant of(4.59±0.82)×10⁴ M^-1 for SPM(?)CLT6 and(2.64±0.61)×10⁴ M^-1 for SPM(?)CBpP6,respectively,OxPt could be released from OxPt(?)CLT6 or OxPt(?)CBpP6 complex,and SPM was simultaneously bound in the corresponding cavities of hosts,causing enhanced cytotoxicity on MCF-7cells.Interestingly,compared with free OxPt,such two complexes also exhibited a reduced toxicity on human normal liver L02 cells,which was attributed to the low SPM content in normal L02 cells,decreasing the side effect of chemotherapy drugs on normal cells during the process of supramolecular chemotherapy.(2)By integrating the advantages of supramolecular macrocycles and mesoporous silica nanomaterials using the host-guest interactions as a magpie bridge,a multifunctional supramolecular nanomaterial drug delivery system based on macrocycle host,namely Fa-m PEG@CP5-CuS@HMSN-Py(Fa PCH),was constructed,consisting of a pyridinium(Py)-modified hollow mesoporous silica nanoparticles-based drug reservoir(HMSN-Py)with high loading capacity,a layer of NIR-operable carboxylatopillar[5]arene(CP5)-functionalized CuS nanoparticles(CP5-CuS)on the surface of HMSN-Py connected through supramolecular host-guest interactions between CP5 rings and Py stalks,and another layer of folic acid(Fa)-conjugated polyethylene glycol(Fa-PEG)antennas by electrostatic interactions capable of active targeting at tumor lesions,in a controlled,highly integrated fashion for achieving multi-stimuli responsive drug release,and synergistic chemo-photothermal therapy of tumor.In this integrated system,HMSN-Py ensured efficient loading of anticancer drug doxorubicin(DOX);CP5-CuS nanovalves not only guaranteed the controllable drug release under quadruple stimuli including temperature,pH,competitive binding,and NIR light,reducing the side effects caused by drug burst release,but also achieved photothermal conversion efficiency under 808 nm laserirradiation,serving as photothermal agents;Fa-m PEG endowed the hybrid nanosystem with enhanced biocompatibility and active targeting,improving cellular internalization of Fa-overexpressed tumor cells to supramolecular nanocarriers.Both in vitro and in vivo experimental results further demonstrated that the as-prepared supramolecular drug delivery system had good tumor treatment ability through synergistic chemo-photothermal therapy.This novel supramolecular nanoplatform exhibits great potential in controlled drug delivery and enhanced tumor cellular internalization for synergistic chemo-photothermal therapy,which provides a promising approach for synergistic cancer treatment based on macrocycle-functionalized multifunctional supramolecular nanomaterial drug delivery system.(3)By combining the superiorities of supramolecular macrocycles and metal-organic frameworks(MOFs),a smart supramolecular plant hormone delivery system based on MOFs and supramolecular nanovalves,namely gibberellin(GA)-CLT6@PCN-Q,was designed and prepared for plant growth regulation.The surface of MOF was modified with quaternary ammonium Q by coordination interaction to fabricate PCN-Q,followed by the encapsulation of Rh B/GA.Subsequently,through the host-guest interaction between the quaternary ammonium Q and the supramolecular macrocycle CLT6,CLT6 was decorated on the surface of GA-PCN-Q to achieve supramolecular drug delivery system Rh B/GA-CLT6@PCN-Q with efficient drug loading and controlled drug release.Experimental results showed that Rh B-CLT6@PCN-Q exhibited controllable cargo release behaviors under various stimuli of pH,temperature,and competitive agent SPM.Plant growth regulation experimental results demonstrated that GA-CLT6@PCN-Q could effectively promote seed germination,plant growth,and organic matter accumulation of dicotyledonous Chinese cabbage and monocotyledonous wheat.This intelligent supramolecular drug delivery system based on MOFs and supramolecular macrocycles provides an effective method for the controllable delivery of plant hormones and other agrochemicals to regulate plant growth and increase crop yields,which is of great significance for ensuring the sustainable development of modern agriculture.