Transformable “tubulin traps” interfere with mitochondrial autophagy and promote the elimination of glioblastoma
Based on the important role of protective autophagy
in tumor drug resistance of glioblastoma, our research group developed a
deformable nano drug delivery system with biomimetic neurofilament functional
structure and proposed a combined therapy based on apoptosis autophagy
cytoskeleton crosstalk. Relevant achievements were published in the
internationally renowned journal Advanced Functional Materials (IF=19.9) under
the title: Transformable "tubulin traps" interchange with
mitochondrial autophagy and promote the elimination of glioblastoma.
Effective treatment of GBM with high mortality has
always been a challenging topic. Most patients cannot obtain long-term survival
benefits from current clinical treatments, including surgery, radiotherapy, or
chemotherapy. A large number of studies have proved that the anti-stress
ability of GBM is closely related to poor prognosis. Mitochondrial protective
autophagy of tumor cells plays a crucial role in maintaining the stability of
the intracellular environment against tumor therapy.
Previous studies have shown that inhibition of
autophagy is an important lever to reverse GBM-related drug resistance.
However, the existing therapeutic strategies, such as chloroquine, which can
promote tumor cell apoptosis by inhibiting autophagy, can only target the
downstream process of autophagy, and its limited scope of action is reflected
in the limitation of therapeutic effect. This means that there is an urgent
need for new strategies that can comprehensively regulate autophagy.
The internal regulation process of biology is
naturally strict, effective, and accurate. The regulation strategy that
imitates the inherent structure of life has significant advantages in tumor
treatment. The highly active tubulin system is involved in the initiation and
subsequent core process of mitochondrial autophagy, which means that
interference with tubulin polymerization can induce persistent defects in tumor
cells based on autophagy resistance in multiple directions. Neurofilament is
regarded as the intrinsic and primary skeleton structure of neurons, which can
regulate tubulin polymerization. It was reported that the derived NFL-TBS 40-63
peptide (NFL Pep) showed the ability to capture free tubulin and inhibit
microtubule formation in vitro, indicating its potential to prevent protective
autophagy.
Inspired by the natural fiber structure of
neurofilament, we designed a supramolecular sequence platform, which can form
spherical nanoparticles (NP) in the whole body circulation to ensure that they
pass through BBB and accumulate in GBM, and then transform into short fibers
after entering GBM cells. The sequence mainly includes three functional
regions: 1) Palmitic acid (PA) as the core hydrophobic block provides the
self-assembly ability of nanoparticles and the space for loading hydrophobic
drugs; 2) The multi amino acid sequence that can form hydrogen bonds provides
the possibility of transforming the sphere into short fiber; 3) Hydrophilic
functional blocks, which can be designed as PEG fragments or therapeutic
peptides, such as NFL Pep. In addition, ceramide is encapsulated in hydrophobic
nuclei as a key drug to induce GBM apoptosis. Ceramide is an indispensable
second messenger molecule in tumor cells. It acts as a key endogenous signal
molecule of apoptosis during the treatment process. It can promote tumor cell
apoptosis by inducing mitochondrial damage while protecting autophagy. The nano
platform showed effective inhibition of protective autophagy, promotion of
apoptosis, and anti-tumor effects in the in situ models of glioblastoma, and
also showed a remarkable ability to activate anti-tumor immunity.
Zhang Yiwen, a doctoral student of the research
group, is the first author of the paper, Professor Jiang Chen is the
corresponding author of the paper, and Associate Professor Sun Tao is the
co-corresponding author of the paper. The research was supported by the
National Natural Science Foundation of China and the Shanghai Academic Research
Leader Program.
Link: https://doi.org/10.1002/adfm.202209216
