Peptide-drug co-assembling: A potent armament against cancer

Abstract

Cancer is still one of the major problems threatening human health and the therapeutical efficacies of available treatment choices are often rather low. Due to their favorable biocompatibility, simplicity of modification, and improved therapeutic efficacy, peptide-based self-assembled delivery systems have undergone significant evolution. Physical encapsulation and covalent conjugation are two common approaches to load drugs for peptide assembly-based delivery, which are always associated with drug leaks in the blood circulation system or changed pharmacological activities, respectively. To overcome these difficulties, a more elegant peptide-based assembly strategy is desired. Notably, peptide-mediated co-assembly with drug molecules provides a new method for constructing nanomaterials with improved versatility and structural stability. The co-assembly strategy can be used to design various nanostructures for cancer therapy, such as nanotubes, nanofibrils, hydrogels, and nanovesicles. Recently, these co-assembled nanostructures have gained tremendous attention for their unique superiorities in tumor therapy. This article describes the classification of assembled peptides, driving forces for co-assembly, and specifically, the design methodologies for various drug molecules in co-assembly. It also highlights recent research on peptide-mediated co-assembled delivery systems for cancer therapy. Finally, it summarizes the pros and cons of co-assembly in cancer therapy and offers some suggestions for conquering the challenges in this field.

Keywords: cancer therapy; co-assembly; drug delivery; nanostructures; peptide.

Figure 1

Three types of peptide-based assembly delivery system: (I) Drug-peptide conjugates; (II) Peptide mediated co-assembly; (III) Physical encapsulation.

Figure 2

Schematic illustration of co-assembled peptide-drug nanomaterials in various cancer therapeutics.

Figure 3

Structure diagram of various building blocks of assembled peptides. (A) Structure diagram of FF-based peptide derivative. (B) Three types of peptide amphiphiles: Amphiphilic peptides, lipidated peptide amphiphiles, and supramolecular PAs. (C) Chemical structures of ionic-complementary peptide RADA16. (D) Assembly process of cyclic peptide.

Figure 4

(A) Driving forces involved in peptide-based co-assembly: Aromatic interactions, hydrogen bond, hydrophobic interactions, electrostatic interactions and Van der Waals force. (B) Commonly used amino acids and molecules in peptide-based co-assembly.

Figure 5

Chemotherapeutic agents-peptide co-assembly for combined chemotherapy. (A) Schematic illustration of the co-assembly of CDDP/Pept-AlgNP/IRN nanocomposite hydrogel loaded with dual drug cisplatin (CDDP) and irinotecan (IRN) for combination therapy. Adapted with permission from , copyright 2020, Elsevier Ltd. (B) Schematic illustration of supramolecular nanostructures for nuclear delivery of 10-hydroxycamptothecine (HCPT) and cisplatin (CDDP) against cancer cells. Adapted with permission from , copyright 2017, American Chemical Society.

Figure 6

Peptide-based co-assembly for sensitized radiotherapy. (A) Chemical structure of FFRGD peptide. (B) Chemical structure of H₂S Donor (CL3). (C) Schematic illustration of FFRGD peptide co-assembled with H₂S into nanocarriers. (D) Schematic illustration of the co-assembled nanocarriers for cancer therapy. (E) Schematic illustration of representative xenografts were extracted from 2-Gy radiation (IR) or co-assembled nanocarriers+IR treated groups of nude mice. (F) Time curve of average tumor volume after nude mice were received with 2-Gy radiation (IR) or co-assembled nanocarriers+IR. Adapted with permission from , copyright 2022, American Chemical Society.

Figure 7

Gene therapeutic agents-peptide co-assembly for cancer therapy. (A) Schematic illustration of the co-assembled pDNA@TR4 nanofibers by using a short peptide derivative (TR4) and plasmid DNA (pDNA) for traceable gene delivery. (B) TEM image of pDNA@TR4 complexes, bar: 2 μm. Adapted with permission from , copyright 2017, American Chemical Society. (C) Schematic illustration of Co-CHL NPs, by the assembly of CHL (Chol-HHHHHHH-AKRGARSTA), siRNA of programmed cell death ligand 1 (siPD-L1) and 1-methyl-DL-tryptophan (1MT) and the mechanism of Co-CHL NPs for cancer treatment. (D) The size distribution characteristic of Co-CHL NPs. (E) Zeta potential of Co-CHL NPs. (F) In vivo images of 4T1 tumor-bearing mice after receiving tail vein injection of free DiR or DiR-loaded Co-CHL NPs in different times. Adapted with permission from , copyright 2019, American Chemical Society.

Figure 8

Photothermal conversion agents-peptide co-assembly for photothermal therapy. (A) Phosphatase-instructed in situ co-assembly of NapFFKYp (2) and indocyanine green (ICG, 1) to form nanofibers (5) for photothermal therapy (PTT). (B) Calcein AM/PI staining of HeLa cells after incubating with indocyanine green (ICG)-doped nanofibers with laser irradiation (808 nm, 1 W/cm², 5 min). Adapted with permission from , copyright 2015, American Chemical Society. (C) Schematic illustration of the Fmoc-L-L/Mn²⁺/Ce6 nanoparticles (FMCNPs) which were formed by co-assembling of peptide derivative Fmoc-L-L, MRI contrast agent Mn²⁺ and photosensitizer Ce6 via the cooperation of multiple non-covalent interactions for MRI-guided PDT. (D) Time curve of average tumor volume of MCF7-tumor-bearing mice after receiving various groups treatments. Adapted with permission from , copyright 2018, American Chemical Society. (E) Schematic illustration of the supramolecular nanofibers, assembled by LND-peptide conjugate (LND-K) and photosensitizer TPPS₄ for the efficient delivery of lonidamine (LND) and synergistic photodynamic therapy. (F) CLSM images of LND-K/TPPS4-treated cells with JC-10 for indicating mitochondrial membrane potential. Red, JC-10 aggregates; Green, JC-10 monomer. Adapted with permission from , copyright 2023, Elsevier Ltd.

Figure 9

Immunotherapeutic agents-peptide co-assembly for immunotherapy and combined immunotherapy. (A) Schematic illustration of the preparation of OVA-induced co-assembled hydrogel vaccine. (B) Chemical structure of Comp.1. (C) Optical images of co-assembled hydrogel vaccine after addition OVA into Comp.1 solution. Adapted with permission from , copyright 2020, Ivyspring International. (D) Schematic illustration of multicomponent Fmoc-FF/PLL-SH hydrogel nanoparticles, formed by co-assembling Fmoc-FF and PLL-SH to regulate immunosuppressive tumor microenvironment. Adapted with permission from , copyright 2017, American Chemical Society. (E) Schematic illustration of the co-assembled peptide-based treatment integrated by peptide DEAP-^DPPA-1 and NLG919 for inhibiting Trp metabolism and blocking PD-L1against cancer cells. Adapted with permission from , copyright 2018, American Chemical Society.