Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression

Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase slightly after loading with siRNA and DOX. Notably, it can be internalized by cancer cells mainly through electronic interactions and PD-L1-mediated endocytosis. Compared with poly-l-lysine and polyethyleneimine, it has a much higher efficiency (about four times) of gene transduction while lowering toxicity. In the treatment of cancer, it causes apoptosis (21%) and inhibits the expression of SURVIVIN protein in vitro. In vivo, it shows good biocompatibility as there are no changes in mice’s body weight. When administering peptide-siRNA-DOX, tumor growth is inhibited the most (about three times). These results above prove the sequence to be a good candidate for gene therapy and drug delivery.

Download Full-text

Cell-Penetrating Peptide Modified PEG-PLA Micelles for Efficient PTX Delivery

International Journal of Molecular Sciences ◽

10.3390/ijms21051856 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1856

Author(s):

Qi Shuai ◽

Yue Cai ◽

Guangkuo Zhao ◽

Xuanrong Sun

Keyword(s):

Cell Penetrating Peptides ◽

Mice Model ◽

Block Polymer ◽

Chemotherapy Drugs ◽

Tumor Tissues ◽

Cell Penetrating ◽

20 Nm ◽

Targeting Effect

On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7) in vitro. But when further used in vivo, TAT-NP-PTX showed an acceleration of the drug’s plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide’s positive charges may be a hot topic to overcome the present dilemma.

Download Full-text

The anticancer efficacy of paclitaxel liposomes modified with low-toxicity hydrophobic cell-penetrating peptides in breast cancer: an in vitro and in vivo evaluation

RSC Advances ◽

10.1039/c8ra03607a ◽

2018 ◽

Vol 8 (43) ◽

pp. 24084-24093 ◽

Cited By ~ 8

Author(s):

Qi Zhang ◽

Jing Wang ◽

Hao Zhang ◽

Dan Liu ◽

Linlin Ming ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Delivery ◽

Cell Penetrating Peptides ◽

Cell Penetrating Peptide ◽

In Vivo Evaluation ◽

Anticancer Efficacy ◽

Cell Penetrating ◽

Low Toxicity

Hydrophobic cell penetrating peptide PFVYLI-modified liposomes have been developed for the targeted delivery of PTX into tumors.

Download Full-text

In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides

Peptides ◽

10.1016/j.peptides.2016.11.011 ◽

2017 ◽

Vol 87 ◽

pp. 50-63 ◽

Cited By ~ 88

Author(s):

Azam Bolhassani ◽

Behnaz Sadat Jafarzade ◽

Golnaz Mardani

Keyword(s):

Therapeutic Proteins ◽

Cell Penetrating Peptides ◽

Cell Penetrating ◽

In Vivo Delivery

Download Full-text

Applications of cell-penetrating peptides in regulation of gene expression

Biochemical Society Transactions ◽

10.1042/bst0350770 ◽

2007 ◽

Vol 35 (4) ◽

pp. 770-774 ◽

Cited By ~ 30

Author(s):

P. Järver ◽

K. Langel ◽

S. El-Andaloussi ◽

Ü. Langel

Keyword(s):

Gene Expression ◽

Lipid Bilayers ◽

Regulation Of Gene Expression ◽

Cell Penetrating Peptides ◽

Remarkable Feature ◽

Cell Penetrating ◽

Plasmid Delivery ◽

Interfering Rna

CPPs (cell-penetrating peptides) can be defined as short peptides that are able to efficiently penetrate cellular lipid bilayers. Because of this remarkable feature, they are excellent candidates regarding alterations in gene expression. CPPs have been utilized in in vivo and in vitro experiments as delivery vectors for different bioactive cargoes. This review focuses on the experiments performed in recent years where CPPs have been used as vectors for multiple effectors of gene expression such as oligonucleotides for antisense, siRNA (small interfering RNA) and decoy dsDNA (double-stranded DNA) applications, and as transfection agents for plasmid delivery.

Download Full-text

Delivery of Nucleic Acids and Nanomaterials by Cell-Penetrating Peptides: Opportunities and Challenges

BioMed Research International ◽

10.1155/2015/834079 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 13

Author(s):

Yue-Wern Huang ◽

Han-Jung Lee ◽

Larry M. Tolliver ◽

Robert S. Aronstam

Keyword(s):

Nucleic Acids ◽

Biomedical Applications ◽

Cell Penetrating Peptides ◽

Biologically Active ◽

The Past ◽

Cell Penetrating ◽

Cellular Entry

Many viral and nonviral systems have been developed to aid delivery of biologically active molecules into cells. Among these, cell-penetrating peptides (CPPs) have received increasing attention in the past two decades for biomedical applications. In this review, we focus on opportunities and challenges associated with CPP delivery of nucleic acids and nanomaterials. We first describe the nature of versatile CPPs and their interactions with various types of cargoes. We then discussin vivoandin vitrodelivery of nucleic acids and nanomaterials by CPPs. Studies on the mechanisms of cellular entry and limitations in the methods used are detailed.

Download Full-text

Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: a comparative study

Biochemical Journal ◽

10.1042/bj20070507 ◽

2007 ◽

Vol 407 (2) ◽

pp. 285-292 ◽

Cited By ~ 151

Author(s):

Samir El-Andaloussi ◽

Peter Järver ◽

Henrik J. Johansson ◽

Ülo Langel

Keyword(s):

Membrane Integrity ◽

Cell Penetrating Peptides ◽

Bioactive Molecules ◽

Cargo Delivery ◽

Wide Range ◽

Cell Penetrating ◽

Coupling Strategy ◽

Transactivator Of Transcription

The use of CPPs (cell-penetrating peptides) as delivery vectors for bioactive molecules has been an emerging field since 1994 when the first CPP, penetratin, was discovered. Since then, several CPPs, including the widely used Tat (transactivator of transcription) peptide, have been developed and utilized to translocate a wide range of compounds across the plasma membrane of cells both in vivo and in vitro. Although the field has emerged as a possible future candidate for drug delivery, little attention has been given to the potential toxic side effects that these peptides might exhibit in cargo delivery. Also, no comprehensive study has been performed to evaluate the relative efficacy of single CPPs to convey different cargos. Therefore we selected three of the major CPPs, penetratin, Tat and transportan 10, and evaluated their ability to deliver commonly used cargos, including fluoresceinyl moiety, double-stranded DNA and proteins (i.e. avidin and streptavidin), and studied their effect on membrane integrity and cell viability. Our results demonstrate the unfeasibility to use the translocation efficacy of fluorescein moiety as a gauge for CPP efficiency, since the delivery properties are dependent on the cargo used. Furthermore, and no less importantly, the toxicity of CPPs depends heavily on peptide concentration, cargo molecule and coupling strategy.

Download Full-text

Cell-Penetrating Peptides: Possibilities and Challenges for Drug Delivery in Vitro and in Vivo

Molecules ◽

10.3390/molecules200713313 ◽

2015 ◽

Vol 20 (7) ◽

pp. 13313-13323 ◽

Cited By ~ 28

Author(s):

Tore Skotland ◽

Tore Iversen ◽

Maria Torgersen ◽

Kirsten Sandvig

Keyword(s):

Drug Delivery ◽

Cell Penetrating Peptides ◽

Cell Penetrating

Download Full-text

Cell-penetrating-peptide-mediated siRNA lung delivery

Biochemical Society Transactions ◽

10.1042/bst0350807 ◽

2007 ◽

Vol 35 (4) ◽

pp. 807-810 ◽

Cited By ~ 34

Author(s):

S.A. Moschos ◽

A.E. Williams ◽

M.A. Lindsay

Keyword(s):

Protein Function ◽

Cell Penetrating Peptides ◽

Mitogen Activated Protein Kinase ◽

Mouse Lung ◽

Immunological Responses ◽

Cell Penetrating ◽

Mitogen Activated Protein ◽

Interfering Rna

The therapeutic application of siRNA (short interfering RNA) shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. A potential approach to solving this problem is the chemical conjugation of siRNA to the cationic CPPs (cell-penetrating peptides), Tat-(48–60) (transactivator of transcription) and penetratin, which have been shown previously to mediate protein and peptide delivery in a host of animal models. In this transaction, we review recent studies on the utility of siRNA for the investigation of protein function in the airways/lung. We show that, despite previous studies showing the utility of cationic CPPs in vitro, conjugation of siRNA to Tat-(48–60) and penetratin failed to increase residual siRNA-mediated knockdown of p38 MAPK (mitogen-activated protein kinase) (MAPK14) mRNA in mouse lung in vivo. Significantly, we will also discuss potential non-specific actions and the induction of immunological responses by CPPs and their conjugates and how this might limit their application for siRNA-mediated delivery in vivo.

Download Full-text

Novel Lung Targeting Cell Penetrating Peptides as Vectors for Delivery of Therapeutics

10.21203/rs.3.rs-1056707/v1 ◽

2021 ◽

Author(s):

Maliha Zahid ◽

Kayla McCandless ◽

Sanjay Mishra ◽

Jeffrey Stiltner ◽

Kyle Feldman ◽

...

Keyword(s):

Amino Acid ◽

Lung Tissue ◽

Cell Penetrating Peptides ◽

Mouse Lung ◽

Specific Cell ◽

Lung Targeting ◽

Biodistribution Studies ◽

Cell Penetrating

Abstract Cell penetrating peptides are unique, 5-30 amino acid long peptides that are able to breach cell membrane barriers and carry cargoes intracellularly in a functional form. Our prior work identified a synthetic, non-naturally occurring 12-amino acid long peptide that we termed cardiac targeting peptide (CTP: APWHLSSQYSRT) due to its ability to transduce cardiomyocytes in vivo. Studies looking into its mechanism of transduction identified two lung targeting peptides (LTPs), S7A (APWHLSAQYSRT) and R11A (APWHLSSQYSAT). These peptides robustly transduced human bronchial epithelial cell lines in vitro and mouse lung tissue in vivo. This uptake occurred independently of clathrin mediated endocytosis. Biodistribution studies of R11A showed peak uptake at 15 minutes with uptake in liver but not kidneys, indicating primarily a hepatobiliary mode of excretion. Cyclic version of both peptides was ~100-fold more efficient in permeating cells than their linear counterparts. As proof of principle, we conjugated anti-spike and anti-envelope SARS-CoV-2 siRNAs to cyclized R11A and demonstrate anti-viral efficacy in vitro. Our work presented here identifies two novel lung-specific cell penetrating peptides that could potentially deliver myriad therapeutic cargoes to lung tissue.

Download Full-text