A graphene oxide based smart drug delivery system for tumor mitochondria-targeting photodynamic therapy

Abstract

Subcellular organelles play critical roles in cell survival. In this work, a novel photodynamic therapy (PDT) drug delivery and phototoxicity on/off nano-system based on graphene oxide (NGO) as the carrier is developed to implement subcellular targeting and attacking. To construct the nanodrug (PPa-NGO-mAb), NGO is modified with the integrin αvβ3 monoclonal antibody (mAb) for tumor targeting. Pyropheophorbide-a (PPa) conjugated with polyethylene-glycol is used to cover the surface of the NGO to induce phototoxicity. Polyethylene-glycol phospholipid is loaded to enhance water solubility. The results show that the phototoxicity of PPa on NGO can be switched on and off in organic and aqueous environments, respectively. The PPa-NGO-mAb assembly is able to effectively target the αvβ3-positive tumor cells with surface ligand and receptor recognition; once endocytosized by the cells, they are observed escaping from lysosomes and subsequently transferring to the mitochondria. In the mitochondria, the 'on' state PPa-NGO-mAb performs its effective phototoxicity to kill cells. The biological and physical dual selections and on/off control of PPa-NGO-mAb significantly enhance mitochondria-mediated apoptosis of PDT. This smart system offers a potential alternative to drug delivery systems for cancer therapy.

Mitochondria-selective photodynamic tumor therapy using globular PEG nanoparticles

“…Recently, there have been several efforts to engineer mitochondria-targeting drug carrier systems. 5,[15][16][17] However, even in the case of sophisticatedly designed drug carrier systems, drug delivery efficiency and tumor ablation efficiency has been a major concern.…”

“…19 Mitochondrial damage can lead to extensive cell death mechanisms, including bioenergetic dysfunctions and the cytosolic release of proapoptotic proteins. 5,[15][16][17][18][19] Therefore, pursuing the versatile design of mitochondria-targeting nano-sized drug carriers may be crucial for advanceing PDT. Recently, there have been several efforts to engineer mitochondria-targeting drug carrier systems.…”

“…[5][6][7][8][9][10][11][12][13][14] In particular, a broad range of drug carrier design methods for efficient photodynamic tumor therapy have been investigated based on the structural, chemical, and biological aspects of tumor cells. [15][16][17][18] For example, mitochondria targeting is one of the current challenges for highly efficient PDT. 5,[15][16][17] It is known that mitochondria regulate vital and lethal functions of cells such as ATP synthesis, reactive oxygen species (ROS) production, programmed cell death (apoptosis), and oxidative phosphorylation.…”

“…[15][16][17][18] For example, mitochondria targeting is one of the current challenges for highly efficient PDT. 5,[15][16][17] It is known that mitochondria regulate vital and lethal functions of cells such as ATP synthesis, reactive oxygen species (ROS) production, programmed cell death (apoptosis), and oxidative phosphorylation. 19 Mitochondrial damage can lead to extensive cell death mechanisms, including bioenergetic dysfunctions and the cytosolic release of proapoptotic proteins.…”

Lymphatic targeting drug delivery system and tumor treatment

“…The conventional treatment methods are based on radical surgery combined with radiotherapy and chemotherapy [1][2][3][4][5], which can prolong the patients' life to a certain extent but can lead to patients' more adverse reactions and lower living quality [6]. Some studies have pointed out that the application of the lymphatic targeting drug delivery system in the treatment of malignant tumors has achieved favorable results [7][8].…”