Two birds, one stone: dual targeting of the cancer cell surface and subcellular mitochondria by the galectin-3-binding peptide G3-C12

Abstract

Active tumor-targeting approaches using specific ligands have drawn considerable attention over the years. However, a single ligand often fails to simultaneously target the cancer cell surface and subcellular organelles, which limits the maximum therapeutic efficacy of delivered drugs. We describe a polymeric delivery system modified with the G3-C12 peptide for sequential dual targeting. In this study, galectin-3-targeted G3-C12 peptide was conjugated onto the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer for the delivery of D(KLAKLAK)2 (KLA) peptide. G3-C12-HPMA-KLA exhibited increased receptor-mediated internalization into galectin-3-overexpressing PC-3 cells. Furthermore, G3-C12 peptide also directed HPMA-KLA conjugates to mitochondria. This occurred because the apoptosis signal triggered the accumulation of galectin-3 in mitochondria, and the G3-C12 peptide that specifically bound to galectin-3 was trafficked along with its receptor intracellularly. As a result, G3-C12-HPMA-KLA disrupted the mitochondrial membrane, increased the generation of reactive oxygen species (ROS) and induced cytochrome c release, which ultimately resulted in enhanced cytotoxicity. An in vivo study revealed that the G3-C12 peptide significantly enhanced the tumor accumulation of the KLA conjugate. In addition, G3-C12-HPMA-KLA exhibited the best therapeutic efficacy and greatly improved the animal survival rate. Our work demonstrates that G3-C12 is a promising ligand with dual-targeting functionality.

Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1–hexokinase-II complex

“…[1][2][3] They currently underlie new drug developments, which will complement the existing therapies for cancer cells killing and cancer elimination. [4][5][6][7][8][9][10][11][12] The mitochondrial-targeting anti-cancer mechanisms include the activation of mitochondria-mediated apoptotic pathways via voltagedependent-anion-channel (VDAC) targeting agents or electron transport/respiratory chain blockers, [13][14][15] the increased induction of reactive oxygen species (ROS), 16,17 the inhibition of the Bcl-2 anti-apoptotic family of proteins, 18 the activation of the mitochondrial membrane permeability transition pore protein subunits, 19,20 the mtDNA targeting in cancer cells, 19 and treatments involving mitochondrial destabilization, mitochondrial membrane permeabilization, 21 mitochondrial fission and massive mitochondrial fragmentation using lipophilic cations targeting the inner membrane. [22][23][24][25][26][27][28] Hexokinase-II (HK-II) is increasingly regarded as an attractive therapeutic target for cancer therapy based on its key role in glycolysis as a part of the cell energy metabolism.…”

Membrane Trafficking and Subcellular Drug Targeting Pathways

“…The multivalent functionalization platforms perform various functions like enhancing the cellular uptake, more transfection efficiencies, and precise and effective targeting of subcellular organelles etc. (Chen et al, 2017;Peng et al, 2017;Sun et al, 2017). Sometimes the nanoparticulate platforms are used for minimization of the reaction distances between different reactants such that the reaction efficiencies can be maximized.…”

“…This approach provides multiple advantages such as enhanced mitochondrial membrane disruption, significantly more ROS generation, and much better cytotoxic effects. It also resulted in better tumor accumulation of the delivery system and the best therapeutic efficiencies were achieved with a better animal survival rate (Sun et al, 2017). Another similar approach for particles decorated with two targeting moieties involves one of these binding to folate membrane cell surface receptors and the second (triphenylphosphine, TPP) targeting the mitochondrial membrane.…”

Mitochondrial-Targeting Anticancer Agent Conjugates and Nanocarrier Systems for Cancer Treatment

“…The advantages of polymeric nanoparticles can be biocompatibility, a small size, high drug loading capacity, good water solubility, low toxicity, and easy modification ( Kedar et al, 2010 ; Oerlemans et al, 2010 ; Yokoyama, 2010 ; El-Say and El-Sawy, 2017 ). Some examples of polymeric nanoparticles for mitochondria-targeted drug delivery are poly(ethylene glycol) ( Khatun et al, 2017 ), poly(𝜀-caprolactone) (PCL) ( Cho et al, 2015 ; Choi et al, 2017 ), polysaccharides (e.g., chitosan, hyaluronic acid, and dextran) ( Kim et al, 2016 ; Hou et al, 2017 ; Liu et al, 2018 ; Tan et al, 2018 ), poly[(2-hydroxypropyl)-methacrylic acid] (pHPMA) ( Sun et al, 2017 ), poly(lactic-co-glycolic acid) ( Marrache and Dhar, 2012 ; Marrache et al, 2013 ), and micelles formed from small amphiphilic molecules ( He et al, 2018 ; Lee et al, 2018 ; Young et al, 2018 ).…”