Mitochondria-Targeting and ROS-Responsive Nanocarriers via Amphiphilic TPP-PEG-TK-Ce6 for Nanoenabled Photodynamic Therapy

Abstract

Designing targeted-delivering and stimuli-responsive nanocarriers for photodynamic therapy (PDT) is an appealing method, especially, targeting delivery of photosensitizers to mitochondria as the most sensitive cellular organelles to reactive oxygen species (ROS) could significantly enhance the therapeutic efficacy of PDT. In this study, we synthesized triphenylphosphonium bonded PEG-NH2 (TPP-PEG-NH2) and bridged to chlorin e6 (Ce6) via thioketal (TK) linkage to obtain red light-triggered, amphiphilic copolymer (TPP-PEG-TK-Ce6), which could self-assemble into micelles with an average size of 160 nm and zeta potential of +20.1 mV. The in vitro release behavior of TPP-PEG-TK-Ce6 nanocarriers showed a light-activated way and was dependent on the H2O2 concentration. TPP-PEG-TK-Ce6 nanocarriers exhibited high cytotoxicity against C6 cells with illumination. Confocal laser scanning microscopy observation indicated that TPP-PEG-TK-Ce6 nanocarriers were efficiently internalized into the mitochondrion of C6 cells, released Ce6 via light activated. By contrast, in the case of TPP-PEG-NH2 directly bonded Ce6 (TPP-PEG-Ce6) nanocarriers, little Ce6 was found in the mitochondrion. The stronger fluorescence in the mitochondrion of TPP-PEG-TK-Ce6 nanocarriers originated from the mitochondrial-targeting capability of TPP and the cleavage of TK linkages activated by light irradiation, which greatly improved the cellular uptake of TPP-PEG-TK-Ce6 nanocarriers and released more Ce6 in the mitochondrion. This work provided a facile strategy to improve PDT efficacy.

Photodynamic Therapy Induced Mitochondrial Targeting Strategies for Cancer Treatment: Emerging Trends and Insights

“…The highest light-activated cytotoxicity was shown by TRM, indicating that the efficacy of PDT can be further ameliorated by ROS-stimulated release of chlorin e6 and mitochondrialtargetability of TPP in C6 tumor cells. 77 One of the major drawbacks of PDT is hypoxia, which hinders the therapeutic efficacy of this treatment. You and coworkers have reported a multifunctional nanoparticle that targets hypoxia and reduces hypoxia, made of gold−copper (AuCu) alloy conjugated with mitochondrial-targeting mercaptoethyl-TPP ligand and PS sulfhydryl chlorin e6 ligand.…”

“…In TRM and RM, upon light irradiation, the cell viability reduced to 22.5% and 36.3%, respectively. The highest light-activated cytotoxicity was shown by TRM, indicating that the efficacy of PDT can be further ameliorated by ROS-stimulated release of chlorin e6 and mitochondrial-targetability of TPP in C6 tumor cells …”

Combined Photosensitive Gene Therapy Effective Against Triple-Negative Breast Cancer in Mice Model

“… 25 Triphenylphosphine (TPP) has emerged as a common and extensively studied mitochondrial targeting group. 26 , 27 While single mitochondrial-targeted photodynamic therapy is insufficient to completely eradicate or prevent the formation and recurrence of metastatic tumors. 28 The concept of multifunctional nanomedicine has emerged as a way to integrate various treatment approaches and develop PDT-based combination therapies to address the limitations of PDT monotherapy.…”

Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression

“…Thus, the amount of CPT that accumulates in mitochondria is very limited due to the multiple intracellular barriers to reaching mitochondria and the extremely poor permeability of the mitochondrial inner membrane, which represent formidable hurdles [ 18 , 19 ]. Recently, various ligands have been reported to improve mitochondrial accumulation, such as triphenylphosphonium bromide, mitochondrial penetration peptide, and mitochondrial targeting sequence [ 20 , 21 , 22 ]. However, those lipophilic moieties might deteriorate the solubility of the highly hydrophobic CPT.…”