Mitochondria and Nucleus Delivery of Active Form of 10-Hydroxycamptothecin with Dual Shell to Precisely Treat Colorectal Cancer

Abstract

Aim: The objective of this study was to deliver a ring-closed form of 10-hydroxycamptothecin (HCPT) to the mitochondria and nucleus to treat colorectal cancer. Materials & methods: HCPT-loaded nanoparticle HCPT@PLGA-PEG2k-triphenylphosphonium/PLGA-hyd-PEG4k-folic acid (PT/PHF) and HCPT@PT/PLGA-SS-PEG4k-folic acid (PSF) were prepared by using emulsion-solvent evaporation method. Results: In vitro experimental results indicated HCPT@PT/PHF and HCPT@PT/PSF maintained a large amount of HCPT in active form, and delivered more HCPT to the nucleus and mitochondria of the tumor cell, which resulted in the enhancement of cytotoxicity of HCPT. In vivo experimental results indicated that HCPT@PT/PHF and HCPT@PT/PSF delivered more ring-closed form of HCPT to tumor tissue, which led to strong antitumor activity. Conclusion: HCPT@PT/PHF and HCPT@PT/PSF could enhance therapeutic efficacy of HCPT to colorectal cancer.

Advances in Antitumor Nano-Drug Delivery Systems of 10-Hydroxycamptothecin

“… 90 Li et al showed that TPP-modified PLGA NPs could target mitochondria and nuclei, deliver more ring-closed form of HCPT to tumor tissues, and significantly enhance anti-tumor activity. 91 Furthermore, Ma et al demonstrated HCPT-loaded PLGA NPs with promising controlled release behavior, well stability and excellent tumor inhibition. 92 …”

Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges

“…Considering that mitochondrial membranes are rich in cardiolipids, researchers have synthesized liposomal and polymeric nanoparticles. Based on the strong negative potential of the TIM, researchers have synthesized mitochondria-targeting cationic compounds such as diquantinium chloride (DQA) and triphenylphosphine (TPP) derivatives to selectively target mitochondria [ 108 ]. The FDA-approved cationic lipid DQA can be used to create DQAsomes, a liposome-like structure that attaches to pDNA via electrostatic interactions, yet DQAsomes have a low efficiency of 5% at transfecting mitochondria.…”

Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy

“…Delocalized lipophilic cations, especially TPP, are widely applied as mitochondria-targeted ligands to deliver chemotherapeutic drugs into mitochondria [ 23 , 24 ]. Many recent studies have clearly demonstrated that TPP-modified nanoparticles can efficiently escape from lysosomes [ 25 , 26 , 27 ]. Dhar et al developed a mitochondria-targeting blended nanoparticle for the delivery of mitochondrial-acting drugs and clearly showed that conjugating TPP could effectively promote nanoparticles’ escape from lysosomes and further target and locate them in mitochondria [ 28 ].…”

“…Liu et al reported that drug-loaded micelles modified with TPP could deliver the drug to mitochondria and reduce the capture of lysosomes [ 29 ]. However, the reported mitochondria-targeting nano-drug delivery system in order to realize multi-functionalization usually requires laborious synthesis [ 30 ] or different blended polymers [ 26 , 28 ], which not only bring potential security risks but are also not conducive to large-scale production. Hence, it is essential to develop mitochondria-targeting multi-functional nano-drug delivery systems with high stability, biocompatibility, and facile synthesis.…”