Dual Drug Conjugated Nanoparticle for Simultaneous Targeting of Mitochondria and Nucleus in Cancer Cells

Abstract

Effective targeting of mitochondria has emerged as an alternative strategy in cancer chemotherapy. However, considering mitochondria's crucial role in cellular energetics, metabolism and signaling, targeting mitochondria with small molecules would lead to severe side effects in cancer patients. Moreover, mitochondrial functions are highly dependent on other cellular organelles like nucleus. Hence, simultaneous targeting of mitochondria and nucleus could lead to more effective anticancer strategy. To achieve this goal, we have developed sub 200 nm particles from dual drug conjugates derived from direct tethering of mitochondria damaging drug (α- tocopheryl succinate) and nucleus damaging drugs (cisplatin, doxorubicin and paclitaxel). These dual drug conjugated nanoparticles were internalized into the acidic lysosomal compartments of the HeLa cervical cancer cells through endocytosis and induced apoptosis through cell cycle arrest. These nanoparticles damaged mitochondrial morphology and triggered the release of cytochrome c. Furthermore, these nanoparticles target nucleus to induce DNA damage, fragment the nuclear morphology and damage the cytoskeletal protein tubulin. Therefore, these dual drug conjugated nanoparticles can be successfully used as a platform technology for simultaneous targeting of multiple subcellular organelles in cancer cells to improve the therapeutic efficacy of the free drugs.

Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release

“…A solution containing doxorubicin (1 ml, 2 mg) was added to the mixture and the reaction was stirred for 48 h at room temperature protected from the surrounding light [38]. The final solution was again then dialyzed using a dialysis membrane (MWCO 30 kDa) to remove the free DOX and stored at 4°C.…”

Novel platinum–palladium bimetallic nanoparticles synthesized by Dioscorea bulbifera: anticancer and antioxidant activities

“…FITC-AV binding is highly specific to early stages of apoptosis, which is marked by transposition of phosphatidylserine from the internal to the outer surface of cell membrane. 19,40 Pt-PdNPs exhibited superior triggered translocation of phosphatidylserine as compared to individual PtNPs and PdNPs indicating extensive damage to cell membrane leading to apoptotic effects rather than necrosis. Antioxidants are considered to be one of the most promising cancer chemopreventive agent that can reverse, suppress, or prevent carcinogenic progression.…”

Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer

“…This compound has been found to inhibit the proliferation of various cancer cells in vitro and in vivo, [20][21][22][23][24][25][26] including cervical cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, and so on. TOS, a mitochondria-targeting drug, has the synergic effect on nuclear DNA-damaging drugs such as CDDP.…”

“…TOS, a mitochondria-targeting drug, has the synergic effect on nuclear DNA-damaging drugs such as CDDP. 25 The dual drug conjugates (TOS-CDDP) were anticipated to improve the lipophilic property, enable easy encapsulation into lipid NPs, and improve their in vivo stability.…”