Development of Novel Peptides for Mitochondrial Drug Delivery: Amino Acids Featuring Delocalized Lipophilic Cations

Kelley, Shana O.; Stewart, Kelly M.; Mourtada, Rida

doi:10.1007/s11095-011-0530-6

Cited by 41 publications

(32 citation statements)

References 32 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell-penetrating peptides (also called protein transduction domains) are highly versatile, nontoxic sequences (as compared with liposomes and polymers) for intracellular delivery [143]. CPPs generally come in two flavors, either as short amino acid sequences that are mainly composed of arginine, lysine and histidine (cationic character mediates the interaction of the peptide with anionic/acidic motifs on the plasma membrane in a receptor-independent fashion), or as amphipathic peptides (lipophilic and hydrophilic tails) that mediate peptide translocation across the plasma membranes.…”

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

“…CPPs generally come in two flavors, either as short amino acid sequences that are mainly composed of arginine, lysine and histidine (cationic character mediates the interaction of the peptide with anionic/acidic motifs on the plasma membrane in a receptor-independent fashion), or as amphipathic peptides (lipophilic and hydrophilic tails) that mediate peptide translocation across the plasma membranes. However, the exact mechanism of uptake is controversial for this type of CPP [143]. Recently, a new class of CPPs with delocalized lipophilic cations incorporated into the peptide sequence have been created to specifically facilitate drug delivery to the mitochondria [144].…”

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

“…Recently, a new class of CPPs with delocalized lipophilic cations incorporated into the peptide sequence have been created to specifically facilitate drug delivery to the mitochondria [144]. Finally, CPPs have been widely used in animal models and can achieve systemic delivery in vivo (therefore deliverable to any type of cancer) [143]. However, optimization testing is required for every modification because the orientation of peptide, cargo and linkages can have a significant impact on therapeutic peptide efficacy [64,143].…”

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

“…Finally, CPPs have been widely used in animal models and can achieve systemic delivery in vivo (therefore deliverable to any type of cancer) [143]. However, optimization testing is required for every modification because the orientation of peptide, cargo and linkages can have a significant impact on therapeutic peptide efficacy [64,143]. …”

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

“…Risk of immunogenic response (especially non-human peptides, such as enfuvirtide) can be mitigated by re-engineering to reduce the size and/or elimination of MHC-II epitopes [147] through standard humanization techniques. Standard strategies for increasing half-life can also reduce immunogenicity, such as PEGylation or the introduction of non-natural amino acids [143]. …”

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

See 4 more Smart Citations

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

View full text Add to dashboard Cite

The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein-protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.The mitochondrion holds importance among cellular organelles in consideration of selective anticancer therapy because it is the nexus for propagating malignant transformation and controls cell death. The mitochondrion is a universal target in all cancer cells, and new information about functional and structural differences between healthy and malignant cells continues to emerge [1]. Peptides that specifically target malignant mitochondria offer advantages of low toxicity, high specificity and generally increase the range of interactions that are difficult to target with small molecules (e.g., protein-protein, protein-lipid and protein-DNA) [2]. However, the benefits of peptides are offset by difficulties in delivery, such as degradation by proteases and rapid clearance. As such, the delivery of peptide/ protein therapeutics is almost exclusively by the parenteral route, but the status quo is actively being challenged by broad efforts (e.g., liposomes, microparticles, nanoparticles, 'smart' polymers, hydrogels and chemical modifications to the peptide/protein) to achieve more convenient routes of administration (i.e., oral, nasal and transdermal) and improved pharmacokinetics [3][4][5]. However, peptides, in many cases, are far from passive in the delivery process and through the maze that is drug delivery (from route of administration to perhaps a target residing within a specific organelle), peptides are employed as the vehicle, homing motif and trans-/intra-cellular passport [6].There is an emerging view in cancer therapy that the way in which a cancer cell dies (i.e., immunogenic cell death) is important for a durable response [7]. However, traditional chemo therapy and immune response are in conflict because chemotherapy (e.g., DNA-© 2012 Future Science Ltd * Author for correspondence: Tel.: +1 801 581 7120 Fax: +1 801 585 3614 carol.lim@pharm.utah.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript....

show abstract

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

Section: Peptides Are Uniquely Suited To Target Malignant Mitochondriamentioning

confidence: 99%

See 3 more Smart Citations

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

View full text Add to dashboard Cite

show abstract

Mitochondria‐Targeted Cancer Therapy Using a Light‐Up Probe with Aggregation‐Induced‐Emission Characteristics

Gao

Feng

et al. 2014

Angewandte Chemie

View full text Add to dashboard Cite

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondriatargeting probe (AIE-mito-TPP) by conjugating a triphenylphosphine (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). Owing to the more negative mitochondrial membrane potential of cancer cells than normal cells, the AIE-mito-TPP probe can selectively accumulate in cancer-cell mitochondria and light up its fluorescence. More importantly, the probe exhibits selective cytotoxicity for studied cancer cells over normal cells. The high potency of AIE-mito-TPP correlates with its strong ability to aggregate in mitochondria, which can efficiently decrease the mitochondria membrane potential and increase the level of intracellular reactive oxygen species (ROS) in cancer cells. The mitochondrial light-up probe provides a unique strategy for potential image-guided therapy of cancer cells.

show abstract

Mitochondria‐Targeted Cancer Therapy Using a Light‐Up Probe with Aggregation‐Induced‐Emission Characteristics

et al. 2014

View full text Add to dashboard Cite

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria-targeting probe (AIE-mito-TPP) by conjugating a triphenylphosphine (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). Owing to the more negative mitochondrial membrane potential of cancer cells than normal cells, the AIE-mito-TPP probe can selectively accumulate in cancer-cell mitochondria and light up its fluorescence. More importantly, the probe exhibits selective cytotoxicity for studied cancer cells over normal cells. The high potency of AIE-mito-TPP correlates with its strong ability to aggregate in mitochondria, which can efficiently decrease the mitochondria membrane potential and increase the level of intracellular reactive oxygen species (ROS) in cancer cells. The mitochondrial light-up probe provides a unique strategy for potential image-guided therapy of cancer cells.

show abstract

Development of Novel Peptides for Mitochondrial Drug Delivery: Amino Acids Featuring Delocalized Lipophilic Cations

Abstract: DLCs can be incorporated into synthetic peptides and facilitate mitochondrial drug delivery. Lipophilicity and charge distribution must be carefully balanced to ensure localization within mitochondria.

Cited by 41 publications

References 32 publications

Targeting Malignant Mitochondria With Therapeutic Peptides

Targeting Malignant Mitochondria With Therapeutic Peptides

Mitochondria‐Targeted Cancer Therapy Using a Light‐Up Probe with Aggregation‐Induced‐Emission Characteristics

Mitochondria‐Targeted Cancer Therapy Using a Light‐Up Probe with Aggregation‐Induced‐Emission Characteristics

Contact Info

Product

Resources

About