Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

Abstract

Purpose: Liposomes have been proposed to be a means of selectively targeting cancer sites for diagnostic and therapeutic applications. The focus of this work was the evaluation of radiolabeled PEGylated liposomes derivatized with varying amounts of a cyclic arginyl-glycyl-aspartic acid (RGD) peptide. RGD peptides are known to bind to α v β 3 integrin receptors overexpressed during tumor-induced angiogenesis. Methods: Several liposomal nanoparticles carrying the RGD peptide targeting sequence (RLPs) were synthesized using a combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, cholesterol, diethylenetriaminepentaacetic acid-derivatized lipids for radiolabeling, a polyethylene glycol (PEG) building block, and a lipid-based RGD building block. Relative amounts of RGD and PEG building blocks were varied. In vitro binding affinities were determined using isolated α v β 3 integrin receptors incubated with different concentrations of RLPs in competition with iodine-125-labeled cyclo-(-RGDyV-). Binding of the indium-111-labeled RLPs was also evaluated. Biodistribution and micro single photon emission computed tomography/computed tomography imaging studies were performed in nude mice using different tumor xenograft models. Results: RLPs were labeled with indium-111 with high radiochemical yields. In vitro binding studies of RLPs with different RGD/PEG loading revealed good binding to isolated receptors, which was dependent on the extent of RGD and PEG loading. Binding increased with higher RGD loading, whereas reduced binding was found with higher PEG loading. Biodistribution showed increased circulating time for PEGylated RLPs, but no dependence on RGD loading. Both biodistribution and micro single photon emission computed tomography/computed tomography imaging studies revealed low, nonspecific tumor uptake values. Conclusion: In this study, RLPs for targeting angiogenesis were described. Even though good binding to α v β 3 integrin receptors was found in vitro, the balance between PEGylation and RGD loading clearly requires optimization to achieve targeting in vivo. These data form the basis for future development and provide a platform for the investigation of multimodal approaches.

Alendronate-coated long-circulating liposomes containing 99mtechnetium-ceftizoxime used to identify osteomyelitis

“…Several studies have been demonstrating the importance of the incorporation of PEGylated lipids onto the liposomal surface in order to increase the blood half-life and, consequently, uptake in the region of interest. 39,40 When considering the effect of alendronate-surface coating for both non-and long-circulating …”

Application of liposomes in drug development – focus on gastroenterological targets

“…61 Conjugating polyethylene glycol (PEG) to liposomes (ie, PEGylation) reduced phagocytic recognition, improved pharmacokinetics, and increased biological stability. 61 Pegylation of liposomal PTX drastically increased its in vivo stability, delivered significantly more PTX to tumor tissue, and improved PTX anticancer effects in C26 tumor bearing mice.…”

“…61 Conjugating polyethylene glycol (PEG) to liposomes (ie, PEGylation) reduced phagocytic recognition, improved pharmacokinetics, and increased biological stability. 61 Pegylation of liposomal PTX drastically increased its in vivo stability, delivered significantly more PTX to tumor tissue, and improved PTX anticancer effects in C26 tumor bearing mice. 62 Similarly, PEGylated liposomal formulated mitomycin C lipid based prodrug had a longer half-life, lower toxicity, and higher anticancer potency than conventional chemotherapy when treating gastric, colon, and pancreatic cancers.…”

Tumor targeting and imaging with dual-peptide conjugated multifunctional liposomal nanoparticles

“…13 We have recently developed radiolabeled LNPs carrying a cyclic RGD peptide showing more favorable binding characteristics than linear or multimeric RGD peptides. 14,15 Another interesting target is the G protein-coupled neurokinin-1 receptor interacting with the neuropeptide substance P (SP). This receptor, besides being overexpressed in several malignancies, including breast, ovarian, and prostate cancer as well as glioblastoma and melanoma, is also present on tumor cells infiltrating the intratumoral and peritumoral vasculature.…”

“…In this study, based on the promising results of our group with a single-targeted RLP, tumor targeting properties of single-targeted RLP and SP-LP were evaluated in a U-87 MG tumor xenograft mouse model. 14 The design of multifunctional molecular targeting and imaging probes is an attractive approach because many cancer types simultaneously express multiple receptor types. 28 Accordingly, we describe here for the first time the in vitro and in vivo evaluation of multifunctional LNPs derivatized with two targeting sequences (RGD and SP).…”