Recent Progress of RGD Modified Liposomes as Multistage Rocket Against Cancer

Abstract

Cancer is a life-threatening disease, contributing approximately 9.4 million deaths worldwide. To address this challenge, scientific researchers have investigated molecules that could act as speed-breakers for cancer. As an abiotic drug delivery system, liposomes can hold both hydrophilic and lipophilic drugs, which promote a controlled release, accumulate in the tumor microenvironment, and achieve elongated half-life with an enhanced safety profile. To further improve the safety and impair the off-target effect, the surface of liposomes could be modified in a way that is easily identified by cancer cells, promotes uptake, and facilitates angiogenesis. Integrins are overexpressed on cancer cells, which upon activation promote downstream cell signaling and eventually activate specific pathways, promoting cell growth, proliferation, and migration. RGD peptides are easily recognized by integrin over expressed cells. Just like a multistage rocket, ligand anchored liposomes can be selectively recognized by target cells, accumulate at the specific site, and finally, release the drug in a specific and desired way. This review highlights the role of integrin in cancer development, so gain more insights into the phenomenon of tumor initiation and survival. Since RGD is recognized by the integrin family, the fate of RGD has been demonstrated after its binding with the acceptor's family. The role of RGD based liposomes in targeting various cancer cells is also highlighted in the paper.

Keywords: RGD peptide; cancer; integrin; liposome; nanomedicine; targeted therapy; toxicity.

FIGURE 1

The scope of liposomes in mediating anti-cancer therapy.

FIGURE 2

Bidirectional signalling by integrin family which is in virtue to confirmational state demonstrate its binding affinity towards extracellular matrix (ECM) and related protein. The bend or closed integrin epitomize the inactive form having low affinity towards ECM, while the straight-extended and upright integrin corresponds to the active form that show high affinity towards ECM, thereby promoting down-stream signalling eliciting cellular response following the ligand attachment. Following the integrin-ligand engagement also called as adhesion, and their clustering on plasma membrane, assembles the multimeric complexes to promote outside-in or downstream signalling. In consequence, phosphorylation of focal adhesion kinase (FAK) initiates, which further activate the steroid receptor coactivator or SRC. In association to this, other metabolic pathway-PI3K/AKT, MAPK/RAS also get activated to produce signal nodes. Talin bind to the β-integrin subunit tail which triggers the open structure. Moreover, integrin dependent signalling compounds and activated integrin in association with receptor tyrosine kinase and ECM encourages the “inside-in” signalling.

FIGURE 3

In vivo (A) and ex-vivo images (B) 4T1 bearing mice treated with (i) DID-Lip (ii) DID-FRU-Lip (iii) Did-RGD-Lip (iv) Did-RGD/FRU/Lip and (v) Did-RGD-FRU-Lip. Among the modified liposome (iv) showed strongest fluorescent intensity due to targeting effect. (https://doi.org/10.1016/j.ejmech.2019.111720).

FIGURE 4

(A) Schematic demonstration of different RGD modified nanocarrier towards the adjacent binding site of αvβ3 integrin. In first case, mo-RGD-L molecules, the RGD moiety were too distant to bind with two αvβ3 clustering elements, in second case with di-RGD-L, the two RGD motifs were very near to each other and thus conformationally unrelated to two αvβ3 clustering elements, while P-di-RGD-L were appropriate to bind efficiently to the two integrin cluster elements. (B) (i) Confocal laser microscopic images (CLSM) of melanoma cells (B16) incubated at 37°C, pre-incubated with respected preparations, (ii) In vivo fluorescent images of B16-tumor bearing C57BL/6 mice treated with Liposome, mo-RGD-L, di-RGD-L and P-di-RGD-L, each loaded with DID, confirming P-di-RGD-L exhibited maximum fluorescence at 12 h, which even encountered in following hours as well http://dx.doi.org/10.1016/j.biomaterials.2014.04.031.

FIGURE 5

Schematic illustration of pH dependent drug release from CaCO₃ nanoparticles containing BSA and PTX.

FIGURE 6

Schematic representation of preparation of RGD-decorated liposome loaded with galbanic acid against colon cancer.