Targeting Colon Cancer Cells Using PEGylated Liposomes Modified With a Fibronectin-Mimetic Peptide

Abstract

Integrin α 5 β 1 is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. The ability to target the integrin α 5 β 1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth, reducing tumor metastasis, and decreasing deleterious side effects associated with different cancer therapies. Liposomes are nano-sized phospholipid bilayer vesicles that have been extensively studied as drug delivery carriers. The goal of this study is to design stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that will target colon cancer cells that express the integrin α 5 β 1 . The PEG provides a steric barrier allowing the liposomes to circulate in the blood and the functionalizing moiety, PR_b peptide, will specifically recognize and bind to α 5 β 1 expressing cells. PR_b is a novel peptide sequence that mimics the cell adhesion domain of fibronectin, and includes four building blocks, RGDSP (the primary recognition site for α 5 β 1 ), PHSRN (the synergy site for α 5 β 1 ), a (SG) 5 linker, and a KSS spacer. In this study we have demonstrated that by varying the amount of PEG (PEG750 or PEG2000) and PR_b on the liposomal interface we can engineer nano-vectors that bind to CT26.WT, HCT116, and RKOcolon cancer cells in a specific manner and are internalized through most likely α 5 β 1 -mediated endocytosis. GRGDSP-targeted stealth liposomes bind to colon cancer cells and internalize, but they have much lesser efficiency than PR_b-targeted stealth liposomes, and more importantly they are not as specific since many integrins bind to RGD peptides. PR_b-targeted stealth liposomes are as cytotoxic as free 5-Fluorouracil (5-FU) and exert the highest cytotoxicity on CT26.WT cells compared to GRGDSP-targeted stealth liposomes and non-targeted stealth liposomes. Thus, the proposed targeted delivery system has the great potential to deliver a therapeutic load directly to colon cancer cells, in an efficient and specific manner.

Lunasin induces apoptosis and modifies the expression of genes associated with extracellular matrix and cell adhesion in human metastatic colon cancer cells

“…In colon cancer, inhibition of the α 5 β 1 function resulted in the reduction of CRC liver metastasis and improved survival in mice 28. Also, targeting the α 5 β 1 integrin in colon cancer cells using a polyethylene glycolylated liposome RGD peptide PR_b resulted in its internalization via α 5 β 1 ‐mediated mechanism and improved cytotoxic effect of 5‐fluorouracil‐encapsulated stealth liposomes against CT26.WT CRC cells 29. Moreover, transfection of the α 5 integrin in HT‐29 colon cancer cells resulted in the suppression of apoptosis triggered by serum deprivation 30.…”

Zastosowanie nanocząsteczek w leczeniu i diagnostyce nowotworów

“…Możliwe jest także sprzężenie na powierzchni nanocząstek specyfi cznych przeciwciał, które kierują cały kompleks w docelowe miejsce. Przykładem są nanocząsteczki opłaszczone przeciwciałami, które rozpoznają receptor ludzkiego naskórkowego czynnika wzrostu 2 (human epidermal growth factor 2, HER-2), receptor dla transferyny lub receptor swoistego antygenu gruczołu krokowego (prostate specifi c antigen receptor) [74][75][76][77]. Innym białkiem, którego potencjał jest obecnie badany w celowanej terapii, jest urokinazowy aktywator plazminogenu (urokinase plasminogen activator, uPA), ligand dla receptora urokinazowego aktywatora plazminogeny (urokinase plasminogen activator receptor, uPAR) [78].…”

Self-Assembly of Fibronectin Mimetic Peptide-Amphiphile Nanofibers

“…The peptides can interact with the specific receptors and help ensure that the drug is delivered to the target tissue. 91 One of the most challenging issues in biomaterial design is modifying a surface to control the interactions of cells with the surface. 92 By controlling specific interactions between cells and the surface, the materialʼs biocompatibility can be improved and enhance the function and lifetime of the material.…”