2.4 Visualized drug delivery and controlled release
Due to the excellent water-solubility, biocompatibility and environmental friendliness of nonconventional polysiloxanes, they have gained increasing attention in biological applications, such as drug delivery and controlled release. Our group fabricated cell-targeting HBPSi-Apt by covalently linking the AS1411 aptamer with HBPSi and used it as a visual tracker for on-demand cell-targeting and intracellular drug release.[47] As can be seen in figure 10A, the AS1411 aptamer functionalized HBPSi selectively bound with nucleolin-overexpressed cancer cells than normal cells, confirming its on-demand drug delivery capability. When loaded with fluorescent DOX, intracellular drug accumulation and release was observed. The HBPSi-Apt@DOX incubated cells display uniformly distributed blue fluorescence in the cell cytoplasm and time-dependent red fluorescence in the cell nucleus, which is consist with the drug release process. With the numerous amine groups in HBPSi and the disulfide bond in HBPSi-Apt, HBPSi-Apt@DOX showed pH and GSH dual-responsive drug release behavior (Figure 10B). The acidic and alkaline conditions affected the charge of HBPSi-Apt@DOX and formed different electrostatic interactions, thus accelerated the DOX release at pH 5.0. The presence of GSH cleaved the disulfide bond in HBPSi-Apt and exposed the HBPSi core, leading to an enhance DOX release rate.[47]
The terminal modification gives HBPSi controlled drug release capability. The hydrophobic cavity inside β -CD is an excellent hydrophobic drug carrier, thus the modification of β -CD improved the drug loading capacity of HBPSi from 80.0 mg/g to 160.0 mg/mg with a pH responsive release behavior.[38] The connection with hydrophobic oleic acid also increases the ibuprofen loading capacity of HBPSi, which reaches 470 mg/g due to the hydrophobic core in the self-assembly structure.[45] The release rate of ibuprofen obviously accelerated in solution with a pH of 5.5 or 6.4 than that in solution at pH 7.4 (Figure 10D). The pH-controlled drug release behavior is caused by the electrostatic interactions between HBPSi derivatives and ibuprofen.[38] In acidic buffer, both HBPSi derivatives and ibuprofen are positively charged, thus the charge repulsion promotes the drug release. On the contrary, the surface charge of ibuprofen changes to negative at pH 7.4 and the charge attraction suppresses its release.
The abundant terminal groups also make HBPSi an excellent candidate for responsive prodrug. With the successive linking with 3,3′-dithiodipropionic acid anhydride and 10-hydroxycamptothecin, our group prepared a HBPSi prodrug (HBPSi-SS-HCPT) that displayed pH and redox dual-responsive drug release behavior.[39] The ester bond endows the HBPSi prodrug with pH responsiveness, and the disulfide bond in 3,3′-dithiodipropionic acid anhydride results in redox responsiveness. The pH and GSH works synergistically, thus makes HBPSi prodrug stable under physiological conditions, and burst drug release at intratumoral pH and GSH. In vivo antitumor experiments demonstrated efficient antitumor efficacy with a total tumor inhibition rate of 27% within 15 days (Figure 10F-10H). Moreover, the fluorescent nature of HBPSi also enables visualized drug delivery and releasein vivo .