title: 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.
authors: †Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Pune, 411021, Maharashtra India.
authors: Abhik
authors: A
authors: Mallick
authors: †Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Pune, 411021, Maharashtra India.|§Institute of Bioinformatics and Biotechnology (IBB), University of Pune, Pune, 411007, Maharashtra India.
authors: Piyush
authors: P
authors: More
authors: §Institute of Bioinformatics and Biotechnology (IBB), University of Pune, Pune, 411007, Maharashtra India.
authors: Sougata
authors: S
authors: Ghosh
authors: §Institute of Bioinformatics and Biotechnology (IBB), University of Pune, Pune, 411007, Maharashtra India.|ΦDepartment of Biology, Indian Institute of Science Education and Research (IISER)-Pune, Pune, 411021, Maharashtra India.
authors: Rohan
authors: R
authors: Chippalkatti
authors: ⊥Department of Microbiology, Savitribai Phule Pune University, Pune, 411007, Maharashtra India.
authors: Balu A
authors: BA
authors: Chopade
authors: ΦDepartment of Biology, Indian Institute of Science Education and Research (IISER)-Pune, Pune, 411021, Maharashtra India.
authors: Mayurika
authors: M
authors: Lahiri
authors: †Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Pune, 411021, Maharashtra India.
authors: Sudipta
authors: S
authors: Basu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D002467:Cell Nucleus / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D053769:Nanocapsules; D058726:Nanoconjugates; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin
keywords: cancer; cisplatin; doxorubicin; dual drug conjugated nanoparticle; mitochondria; nucleus; paclitaxel; tocopheryl succinate