skip to main content


Title: Mitochondrial Targeting Peptide-based Nanodelivery for Cancer Treatment
Abstract: Mitochondria are important intracellular organelles because of their key roles in cellular metabolism,proliferation, and programmed cell death. The differences in the structure and function of themitochondria of healthy and cancerous cells have made mitochondria an interesting target for drug delivery.Mitochondrial targeting is an emerging field as the targeted delivery of cytotoxic payloads andantioxidants to the mitochondrial DNA is capable of overcoming multidrug resistance. Mitochondrialtargeting is preferred over nuclear targeting because it can take advantage of the distorted metabolismin cancer. The negative membrane potential of the inner and outer mitochondrial membranes, as well astheir lipophilicity, are known to be the features that drive the entry of compatible targeting moiety,along with anticancer drug conjugates, towards mitochondria. The design of such drug nanocarrier conjugatesis challenging because they need not only to target the specific tumor/cancer site but have toovercome multiple barriers as well, such as the cell membrane and mitochondrial membrane. This reviewfocuses on the use of peptide-based nanocarriers (organic nanostructures such as liposomes, inorganic,carbon-based, and polymers) for mitochondrial targeting of the tumor/cancer. Both invitro and in vivo key results are reported.  more » « less
Award ID(s):
2129352 2032751 2129617 1940790
NSF-PAR ID:
10380164
Author(s) / Creator(s):
; ;
Date Published:
Journal Name:
Current Protein & Peptide Science
Volume:
23
Issue:
10
ISSN:
1389-2037
Page Range / eLocation ID:
657 to 671
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    Delivering magnetic nanoparticles (MNPs) into mitochondria provides a facile approach to manipulate cell life because mitochondria play essential roles in cell survival and death. Here we report the use of enzyme‐responsive peptide assemblies to deliver MNPs into mitochondria of live cells. The mitochondria‐targeting peptide (Mito‐Flag), as the substrate of enterokinase (ENTK), assembles with MNPs in solution. The MNPs that are encapsulated by Mito‐Flag peptides selectively accumulate to the mitochondria of cancer cells, rather than normal cells. The mitochondrial localization of MNPs reduces the viability of the cancer cells, but hardly affects the survival of the normal cell. This work demonstrates a new and facile strategy to specifically transport MNPs to the mitochondria in cancer cells for exploring the applications of MNPs as the targeted drug for biomedicine and cancer therapy.

     
    more » « less
  2. ABSTRACT  
    more » « less
  3. Abstract

    Chemoresistance is one of the major challenges for cancer treatment, more recently ascribed to defective mitochondrial outer membrane permeabilization (MOMP), significantly diminishing chemotherapeutic agent‐induced apoptosis. A boron‐dipyrromethene (BODIPY) chromophore‐based triarylsulfonium photoacid generator (BD‐PAG) was used to target mitochondria with the aim to regulate mitochondrial pH and further depolarize the mitochondrial membrane. Cell viability assays demonstrated the relative biocompatibility of BD‐PAG in the dark while live cell imaging suggested high accumulation in mitochondria. Specific assays indicated that BD‐PAG is capable of regulating mitochondrial pH with significant effects on mitochondrial membrane depolarization. Therapeutic tests using chlorambucil in combination with BD‐PAG revealed a new strategy in chemoresistance suppression.

     
    more » « less
  4. Mitochondrial inner NEET (MiNT) and the outer mitochondrial membrane (OMM) mitoNEET (mNT) proteins belong to the NEET protein family. This family plays a key role in mitochondrial labile iron and reactive oxygen species (ROS) homeostasis. NEET proteins contain labile [2Fe-2S] clusters which can be transferred to apo-acceptor proteins. In eukaryotes, the biogenesis of [2Fe-2S] clusters occurs within the mitochondria by the iron–sulfur cluster (ISC) system; the clusters are then transferred to [2Fe-2S] proteins within the mitochondria or exported to cytosolic proteins and the cytosolic iron–sulfur cluster assembly (CIA) system. The last step of export of the [2Fe-2S] is not yet fully characterized. Here we show that MiNT interacts with voltage-dependent anion channel 1 (VDAC1), a major OMM protein that connects the intermembrane space with the cytosol and participates in regulating the levels of different ions including mitochondrial labile iron (mLI). We further show that VDAC1 is mediating the interaction between MiNT and mNT, in which MiNT transfers its [2Fe-2S] clusters from inside the mitochondria to mNT that is facing the cytosol. This MiNT–VDAC1–mNT interaction is shown both experimentally and by computational calculations. Additionally, we show that modifying MiNT expression in breast cancer cells affects the dynamics of mitochondrial structure and morphology, mitochondrial function, and breast cancer tumor growth. Our findings reveal a pathway for the transfer of [2Fe-2S] clusters, which are assembled inside the mitochondria, to the cytosol. 
    more » « less
  5. Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are “nonlethal,” in that the inhibition of the enzymes’ activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).

     
    more » « less