Original Article
Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting

https://doi.org/10.1016/j.nano.2017.04.009Get rights and content

Abstract

Synthetic high-density lipoprotein nanoparticles (sHDL) are a valuable class of nanomedicines with established animal safety profile, clinical tolerability and therapeutic efficacy for cardiovascular applications. In this study we examined how the scavenger receptor B-I-mediated (SR-BI) tumor-targeting ability of sHDL, long plasma circulation half-life, and small particle size (9.6 ± 0.2 nm) impacted sHDL accumulation in SR-BI positive colorectal carcinoma cells, 3D tumor spheroids, and in vivo xenografts. We compared tumor accumulation of sHDL with that of liposomes (LIP, 130.7 ± 0.8 nm), pegylated liposomes (PEG-LIP, 101 ± 2 nm), and pegylated sHDL (12.1 ± 0.1 nm), all prepared with the same lipid components. sHDL penetrated deep (210 μm) into tumor spheroids and exhibited 12- and 3-fold higher in vivo solid tumor accumulation, compared with LIP (p < 0.01) and PEG-LIP (p < 0.05), respectively. These results suggest that sHDL with established human safety possess promising intrinsic tumor-targeted properties.

Graphical Abstract

The tumor tissue penetration of liposomes (LIP), pegylated liposomes (PEG-LIP), synthetic high density lipoproteins (sHDL) and pegylated sHDL (PEG-sHDL) were found to be very different when compared in vivo. The sHDL nanoparticles exhibit long in vivo residence time, extravasate through blood vessels, pass through inter-fibrillar openings (<40 nm) of interstitial collagens to penetrate deep into tumor tissues due to its ultra-small size (9.6 nm) and effective cellular uptake mediated by scavenger receptors B-I overexpressed on tumor cells. Tumor tissue penetration and cellular uptake appears to be most effective for sHDL followed by PEG-sHDL, PEG-LIP and LIP.

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Section snippets

Materials

ApoA-I mimetic peptide 22A (PVLDLFRELLNELLEALKQKLK) was synthesized by Genscript Inc. (Piscataway, NJ). Peptide purities were determined by reverse phase HPLC to be >95%. 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was generously donated by Nippon Oils and Fats (Osaka, Japan). Cholesterol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) were purchased from Avanti Polar Lipids, Inc. (Alabaster, Alabama). The fluorescent dyes 3,

Characterization of nanoparticles

Size distribution and purity of sHDL and liposomes were analyzed prior to their tests in vitro and in vivo. Dynamic light scattering (DLS) was used to characterize the average size and polydispersity (PDI) of nanoparticles. As shown in Figure 1, A, compared with the particle sizes of LIP (130.7 ± 0.8 nm) and PEG-LIP (100.9 ± 1.3 nm), sHDL and PEG-sHDL were much smaller, with average diameters of 9.6 ± 0.2 nm and 12.1 ± 0.1 nm, respectively. The size differences of nanoparticles were also observed in the

Discussion

In this study we examined the ability of sHDL 1) to be taken up into the cytosol of colon carcinoma in an SR-BI receptor-mediated manner; 2) to penetrate tumor spheroids in vitro, and 3) to accumulate in solid tumors in vivo. As a prelude to this effort, we previously showed that sHDL itself has cytotoxic affect and, at least in adrenal carcinoma cells, works in synergy with chemotherapeutic agents.12 We have also reported that the anticancer drug, 10-hydroxycamptothecin (10HCPT), can be

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    The authors declare no conflicts of interest.

    Funding: This work was supported in part by AHA grants (13SDG17230049, AS; 15PRE25090050, RK and 16POST27760002, WY), NIH (K22AI097291-01, R01EB022563, R01CA210273, JJM; R01GM113832, R21NS091555, AS), MTRAC for Life Sciences (AS, JJM), University of Michigan Comprehensive Cancer Center Forbes Institute for Cancer Discovery (AS, JJM), an Upjohn award (AS), and MCubed grant (JJM and AS). J.J.M. is a Young Investigator supported by the Melanoma Research Alliance (348774) and NSF CAREER Award (1553831).

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