ABSTRACT
Abstract ..................................................................................................311 3.1 Introduction .................................................................................. 312 3.2 Cell-Penetrating Peptides ............................................................. 314 3.3 Delivery of Cpps into Cells .......................................................... 318 3.3.1 CPPs: Clinical Development ............................................ 320 3.3.2 CPPs Drug Delivery in Vivo:
Problems and Limitations ................................................ 321 3.3.3 Cationic CPPs: Toxicity ................................................... 323 3.3.4 Local CPP-Mediated Delivery ......................................... 325 3.3.5 Strategies to Home CPPs ................................................. 325 3.3.5.1 Utilizing Matrix Metalloproteases .................... 326 3.3.5.2 Utilizing Peritumoral Acidic pH ....................... 326 3.3.5.3 Utilizing Biological State of Targeted Cells ...... 328 3.3.6 Local Release of CPP-Loaded Devices ............................ 329 3.3.6.1 Role of Thermal Sensitive Polymers ................. 329 3.3.6.2 Role of Ultrasound Sensitive Particles .............. 330 3.4 Types of CPPs .............................................................................. 331 3.4.1 Protein-Derived Cell-Penetrating Peptides ...................... 332 3.4.1.1 Penetratins: Homeodomain-Derived
Peptides ............................................................. 332 3.4.1.2 Tat-Derived Peptides ......................................... 332 3.4.1.3 Signal-Sequence-Based Peptides ...................... 333
3.4.2 Chimeric or Synthetic Cell-Penetrating Peptides ........... 334 3.4.2.1 Role of Transportan ......................................... 334 3.4.2.2 Protein-Derived Cell-Penetrating Peptides ..... 334 3.4.2.3 Chimeric and/or Synthetic
Cell-Penetrating Peptides ................................ 335 3.4.2.4 Model Amphipathic Peptides .......................... 336 3.4.2.5 Herpes Simplex Virus Type 1 (HSV-1)
Protein VP22 ................................................... 336 3.4.2.6 Trans-Activating Transcriptional
Activator (TAT) ............................................... 337 3.4.2.7 Homeodomain of Antennapedia (Antp) .......... 338 3.5 CPPs Penetration: in Vitro and in Vivo ........................................ 338 3.5.1 Mechanism of Internalization of CPP ............................ 339 3.6 Cellular Uptake of Cpps ............................................................... 340 3.6.1 Delivery of Proteins ....................................................... 342 3.6.2 Delivery of DNA ............................................................ 342 3.6.3 Delivery of Antibodies ................................................... 343 3.6.4 Delivery of Imaging Agents ........................................... 344 3.7 Applications of Cell-Penetrating Peptides ................................... 344 3.7.1 Intracellular Delivery ..................................................... 344 3.7.2 Delivery of Oligonucleotides ......................................... 345 3.7.3 Delivery of Large Particles and DNA ............................ 345 3.7.4 Cargo .............................................................................. 346 3.7.5 Quantum DOTS: Delivering Across the
Blood-Brain Barrier ....................................................... 347 3.7.6 CPPs Mediated Intracellular Delivery of Antibodies ..... 347 3.7.7 Visualization of Real-Time Viral
Infection of Living Cells with CPPs .............................. 347 3.7.8 CPPs to Deliver Biosensors ........................................... 348 3.7.9 Cellular Trojan Horses ................................................... 348 3.7.10 Small Molecule Delivery ............................................... 349 3.7.11 CPPs for Delivery of Peptides,
Peptides and Proteins...................................................... 349
3.7.12 Delivery of Nucleic Acids and siRNA ........................... 350 3.7.13 CPPs: Harnessed to Improve Absorption ....................... 351 3.7.14 CPPs in Cancer Therapy ................................................ 352 3.7.15 Application in Vaccine Delivery .................................... 352 3.8 Cell-Targeting Peptides (CTPs) ................................................... 353 3.8.1 Identification of CTPs .................................................... 353 3.8.1.1 Structure-Activity Relationship of Ligands .... 354 3.8.1.2 Phage Display .................................................. 354 3.8.1.3 Chemical Strategies ......................................... 355 3.8.2 Improving CTPS ............................................................ 356 3.8.2.1 The RGD Peptide ............................................ 356 3.8.2.2 Cyclization ...................................................... 357 3.8.2.3 Multimerization ............................................... 357 Keywords .............................................................................................. 358 References ............................................................................................. 359
ABSTRACT
Current exploration of novel potential therapeutics that doesn’t enter the clinic owing to poor delivery and low bioavailability has made their foundation in therapeutic development. Various technologies have been employed to improve cellular uptake of these therapeutic molecules, including cell-penetrating peptides (CPPs). These potential therapeutic molecules were discovered 20 years ago. Their discovery was based on the potency of several proteins to enter cells. Till now several CPPs have been investigated which can be categorized into two major classes (those require chemical linkage with the drug for cellular internalization and second includes formation of stable, non-covalent complexes with cargos). Current research explored the potential of CPPs in non-invasive cellular import of cargos. CPPs are very capable in delivering various molecules into cells. In addition they have been successfully employed for ex vivo and in vivo delivery of therapeutic molecules. Nevertheless, apart from some particular cases, their lack of cell specificity remains the major limitation for their clinical development. During this time several peptides
with precise binding activity for a known cell line (cell-targeting peptides) have also been demonstrated in the literature. One of the primary objective of peptide mediated drug delivery based research is to optimize the tissue and cell delivery of therapeutic molecules by means of peptides which unite both targeting and internalization benefits.
