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Updated: Jul 1, 2025
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder
Da-Yong Hou1,2, Ni-Yuan Zhang3, Lu Wang1,2
1NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin Medical University, Harbin 150001, China.
Abstract:
Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.
Insights
This study introduces an Intracellular ATP Sequestration (IAS) system using self-assembling nanomaterials to deplete tumor cell energy. This novel approach effectively suppresses bladder cancer by inducing mitochondriopathy-like damage.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Nanomedicine
Background:
- Mitochondriopathy-inspired adenosine triphosphate (ATP) depletion is a strategy for controlling tumor growth.
- Selective ATP sequestration in biological environments presents significant challenges.
Purpose of the Study:
- To design an Intracellular ATP Sequestration (IAS) system for tumor nuclei.
- To induce mitochondriopathy-like damage for bladder cancer suppression.
Main Methods:
- Development of a transformable nucleopeptide (NLS-FF-T) for self-assembly into nuclear-targeted nanoparticles.
- In vivo self-assembly into nanofibrous ATP trappers on tumor nuclei via KPNA2 interaction.
- Evaluation of efficacy in bladder cancer cell lines (T24, EJ, RT-112) and T24 xenograft mouse models.
Main Results:
- NLS-FF-T formed nanofibrous nanostructures on tumor nuclei, binding and sequestering ATP.
- Reduced half-maximal inhibitory concentration (IC50) of NLS-FF-T by approximately 4-fold compared to NLS-T.
- Demonstrated dose-dependent accumulation in tumor sites and significant antitumor efficacy in vivo, prolonging survival.
Conclusions:
- The IAS system effectively suppresses bladder cancer by inducing mitochondriopathy-like damage through intracellular ATP sequestration.
- Self-assembled nanofibrous nanostructures offer a promising therapeutic strategy for malignancies.
- This approach highlights the potential of targeting cellular energy metabolism for cancer treatment.
