Figure 5 The hydrodynamic diameters of beta-CD (a), aldehyde
group functionalized beta-CD (b), crosslinked beta-CD nanocage (c) and
crosslinked beta-CD nanocage loaded with DOX (d).
3.2 Self-regulate drug release of beta-CD nanocage in mimic tumor
microenvironment
In this beta-CD nanocage, cystamine was used as a crosslinker in a
simple manner to assemble this nanostructure, benefiting from its
disulfide bond and amino groups at the two ends. This property makes it
convenient to react with the aldehyde group-functionalized beta-CD. The
new covalent framework with imine and disulfide bonds has been
established, but its acidity/reduction-sensitive performance remained
unclear. Therefore, understanding the acidity/reduction-responsive
release of drugs is crucial for determining their impact on enhancing
anti-tumor efficiency. To investigate the acidity/reduction-responsive
drug release, pH 4.5 PBS solution and 5 mM GSH solution were used to
mimic the acidic and highly reductive tumor microenvironments,
respectively. In the acidic-mimic environment, the beta-CD nanocage
exhibited a rapid drug release rate (over 60% drug release in
conjugation of imine contributed to bond fission in an acidic
environment. This led to the disassembly of the beta-CD nanocage and the
release of DOX from the enclosed nanocage. In the GSH-mimic environment,
the DOX release rate from the beta-CD nanocage increased (over 60% drug
release in ~25 h) but was weaker compared to the
acidic-mimic environment, suggesting that the controllable breakage of
disulfide bonds was mediated by GSH. More importantly, the beta-CD
nanocage exhibited weak release even after 50 h in a normal
physiological environment. This contrasted markedly with its
controllable drug release under acidic/GSH stimuli. Additionally, the
hydrodynamic diameters of the DOX-loaded beta-CD nanocage treated with
acidic and reductive agents, as well as neutral solutions, were measured
(Figure S3). The change in hydrodynamic diameters was more pronounced
when the DOX-loaded beta-CD nanocage was treated with acidic and
reductive agents, indicating easier disintegration of the beta-CD
nanocage structure in acidic and reductive environments. Therefore, the
stimuli-responsive properties of the beta-CD nanocage were ultimately
attributed to the covalent imine and disulfide bonds.