Peptide functionalized liposomes for receptor targeted cancer therapy

Abstract

Most clinically approved cancer therapies are potent and toxic small molecules that are limited by severe off-target toxicities and poor tumor-specific localization. Over the past few decades, attempts have been made to load chemotherapies into liposomes, which act to deliver the therapeutic agent directly to the tumor. Although liposomal encapsulation has been shown to decrease toxicity in human patients, reliance on passive targeting via the enhanced permeability and retention (EPR) effect has left some of these issues unresolved. Recently, investigations into modifying the surface of liposomes via covalent and/or electrostatic functionalization have offered mechanisms for tumor homing and subsequently controlled chemotherapeutic delivery. A wide variety of biomolecules can be utilized to functionalize liposomes such as proteins, carbohydrates, and nucleic acids, which enable multiple directions for cancer cell localization. Importantly, when nanoparticles are modified with such molecules, care must be taken as not to inactivate or denature the ligand. Peptides, which are small proteins with <30 amino acids, have demonstrated the exceptional ability to act as ligands for transmembrane protein receptors overexpressed in many tumor phenotypes. Exploring this strategy offers a method in tumor targeting for cancers such as glioblastoma multiforme, pancreatic, lung, and breast based on the manifold of receptors overexpressed on various tumor cell populations. In this review, we offer a comprehensive summary of peptide-functionalized liposomes for receptor-targeted cancer therapy.

FIG. 1.

Schematic illustration of liposome-encapsulated therapies. (Left) FDA-approved therapies for chemotherapeutic-encapsulated liposomes (top left) without PEGylation and (bottom left) with PEGylation. (Right) Peptide-functionalized liposomes for receptor-targeted chemotherapeutic delivery.

FIG. 2.

Intratumoral distribution of liposomes encapsulated with DiD in HepG2 xenograft tumors. (Red) DiD-encapsulated liposome. (Blue) DAPI-cell nuclei. (Green) anti-CD34-blood vessels. Scale bar = 40 μm. Reprinted with permission from Tang et al., “A stabilized retro-inverso peptide ligand of transferrin receptor for enhanced liposome-based hepatocellular carcinoma-targeted drug delivery,” Acta Biomater. 83, 379–389 (2019). Copyright 2019 Elsevier.

FIG. 3.

Schematic illustration of STP-decorated, doxorubicin-loaded liposomes in response to pH changes for targeting the tumor microenvironment. Confocal micrographs of HUVEC cells with stained nuclei (blue) and doxorubicin (red) treated with (a) STP-LS-DOX at pH 7.4, (b) LS-DOX at pH 5.8, and (c) STP-LS-DOX at pH 5.8. Adapted with permission from Han et al., ACS Appl. Mater. Interfaces 8(29), 18658–18663 (2016). Copyright 2016 American Chemical Society.

FIG. 4.

(a) Transmission electron microscopy (TEM) was conducted on c(RGDfK)/Pep-22-DOX-LP, indicating the uniform size and morphology of dually modified liposomes. (b) Kaplan–Meier survival curve of glioma-bearing mice when treated with unmodified liposomes LP, liposomes functionalized with the peptide c(RGDfk)-LP or Pep-22-LP, and co-functionalized liposomes with both c(RGDfk)/Pep-22-LP showing that the combination imparts a lower intensity of localization to the liver as well as a greater intensity of localization to the tumor. Ex vivo excised (c) organs and (d) brains in mice with glioma after 24 h post-injection. Adapted with permission from Chen et al., ACS Appl. Mater. Interfaces 9(7), 5864–5873 (2017). Copyright 2017 American Chemical Society.

FIG. 5.

(a) Structural design of Cilengitide-loaded Pep-1-conjugated liposomes. (b) Confocal micrographs of human glioma cells treated with liposomes before (left) and after (right) Pep-1 conjugation. Coumarin-6 (green) was used as a tracking agent. Scale bar = 20 μm. (c) Ki67 immunohistochemical analysis of sectioned tumors from mice. Control-untreated; blank NL-blank liposome; CLG-free cilengitide; CNL-cilengitide loaded liposome; and PeCNL-Pep-1-conjugated cilengitide-loaded liposome. Reprinted with permission from Jiao et al., “Pep-1 peptide-functionalized liposome to enhance the anticancer efficacy of cilengitide in glioma treatment,” Colloids Surf., B 158, 68–75 (2017). Copyright 2017 Elsevier.