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

Abstract

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.

Studies of cell-penetrating peptides by biophysical methods

“…Micelles have a hydrophobic interior and are usually used to deliver non-polar molecules, many times cytostatic. An example is the delivery of the cytostatic paclitaxel (PTX) into model breast cancer cells or organisms (Shuai et al ., 2020). Many times, CPP molecules polymerize or form larger spherical structures by non-covalent bonding when they are mixed with cargo molecules, particularly fragments of nucleic acids.…”

Fluorinated PEG-PEI Coated Magnetic Nanoparticles for siRNA Delivery and CXCR4 Knockdown

“…Using cleavable chemical bonds, such as hydrazide-hydrazone bonds [ 35 ], Schiff base bonds [ 36 ], thioketal bonds [ 37 ], and matrix metalloproteinase substrates [ 38 ] to connect PEG and carriers would be effective strategies to overcome this dilemma. In addition, the nanoparticles can also be modified with peptides (e.g., RGD peptide [ 39 , 40 ], TAT peptide [ 41 ]) to improve the efficiency of cellular uptake.…”

Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers

“…To enhance the cellular internalization of therapeutic drugs, various attempts have been made to conjugate CPPs with PMs. CPPs including TAT or TME sensitive CPPs have been modified with polyethylene glycol-polylactic acid (PEG-PLA) to enhance drug delivery in tumor models [ 76 , 77 ]. CPP-modified micelles are also proven excellent non-viral gene delivery systems.…”