Construction Of Supramolecular Nanocarriers Via Host-guest Interactions: From Pre-assembly To Intracellular Assembly

Nanocarriers could be potentially used as drug delivery systems. However, how to deliver drug to the lesion location efficiently is still a great challenge for the current stage of drug delivery. Regarding to two key processes during drug delivery:① How to keep nanoplatforms stable during circulation, but quickly release the drug once reach the tumor site? ② How to achieve accumulation in tumor site, meanwhile diffuse from outside to inside of tumor site quickly? A series of tumor microenvironment related stimulus responsive supramoleuclar nanoplatforms based on host-guest interactions were developed in this dissertation. In general, assembled behaviors, stimulus induced changes and effect on inhibition of cancer cells were studied. The details are given as follows,1. Supramoleuclar prodrug based on cyclodextrin for drug deliveryTowards contradiction between keeping nanoplatforms stable during circulation and releasing the drug quickly once reaching the tumor site, pH sensitive doxorubicin modified a-CD (a-CD-hydrazone-DOX·HCl) was synthesized. Taking advantage of host-guest interactions beween a-CD-hydrazone-DOX·HCl and double hydrophilic block copolymers poly(ethylene glycol)-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PEG-b-PMPC), pH sensitive pseudopolyrotaxane prodrug micelles with high drug content were prepared. In vitro drug release experiment implied that drug release behavior of prodrug micelles highly depended on pH. Cell experiments showed that this kind of prodrug micelles could be internalized into cancer cells quickly and then inhibit proliferation of cancer cells. Meanwhile, due to the dynamically tunable property of host-guest interactions, multifunctional supramoleuclar prodrug micelles could be obtained by introducing different kinds of functional groups. This study demonstrated that this facile way could enrich and simplify the preparation of multifunctional nanocarriers.2. Supramoleuclar prodrug based on water-soluble pillar[5] arene for drug deliveryTowards contradiction between keeping nanoplatforms stable during circulation and releasing the drug quickly once reaching the tumor site, pH sensitive methyl viologen functioned doxorubicin (MV-DOX) was synthesized. According to the fact that pillar[5]arene could form inclusion with methyl viologen at the mole ratio of 1:1. Dual pH sensitive supramolecular prodrug micelles were prepared from the ammonium carboxylate groups decorated pillar[5]arene and MV-DOX. Results showed that prodrug micelles could aggregate upon extracellular pH of tumor site. However, they could be still internalized into cancer cells by endocytosis, then drug could be released at endo-/lysosomal pH and inhibit the proliferation of cancer cells. More important, pH induced aggregation could lead to retention of nanocarriers in cancer cells. This study demonstrated that ideal nanocarriers could be prepared by implementing of functional groups on rim of pillar[5]arene, which could be used to meet some of key requirements for drug delivery.3. Intracellular assembly of gold nanoparticles in cancer cells triggered by GSHTowards contradiction between penetration and retention of nanocarriers in tumor site, mono-6-thio-β-cyclodextrin (β-CD-SH) and mercapto capped poly(ethylene glycol) (PEG-SH) simultaneously modified gold nanoparticles (GNPs) and ferrocenium cation capped PEG (Fc+-PEG-Fc+) were synthesized. It has been proved that ferrocenium cation could be reduced to ferrocene at the aid of reducing agents. After GNPs and Fc+-PEG-Fc+ are internalized into cancer cells, aggregates of gold nanoparticles (GNPs) could be obtained at the aid of GSH. Results have shown that GNPs could maintain their penetration capability while be retained in cancer cells after formation of the aggregates. Moreover, the assembly of GNPs makes them potent for photothermal therapy, but also being capable of inducing the apoptosis of cancer cells. This study demonstrated that shift from small to large could be used to address the contradiction between penetration and retention of nanocarriers in tumor site by intracellular signaling molecules.