Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control

Shen, Yao; Shyu, Ing Luen; Lu, Maggie; He, Chun Lin; Hsu, Yen Mei; Liang, Hsiang Fa; Liu, Chih Peng; Liu, Ru‐Shi; Shen, Bo; Wei, Yau‐Huei; Chuang, Chi Mu

doi:10.2147/ijn.s78321

Cited by 5 publications

(1 citation statement)

References 48 publications

(37 reference statements)

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“…For instance, nanocarriers can enhance localized delivery of therapeutic agents by incorporating transport enhancing components, such as targeting ligands and sustained/triggered-release systems, and by taking advantage of transport phenomena that appear on the nanoscale, e.g. reduced renal clearance and the enhanced permeability and retention effect [1, 2]. Studies have demonstrated that nanodelivery can substantially increase the tumor accumulation of small molecules [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Contribution of Kupffer cells to liposome accumulation in the liver

Samuelsson

Shen

Blanco

et al. 2017

Colloids and Surfaces B: Biointerfaces

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The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ.

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Section: Introductionmentioning

confidence: 99%

Contribution of Kupffer cells to liposome accumulation in the liver

Samuelsson

Shen

Blanco

et al. 2017

Colloids and Surfaces B: Biointerfaces

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Decapeptide Modified Doxorubicin Loaded Solid Lipid Nanoparticles as Targeted Drug Delivery System against Prostate Cancer

Kyle

2021

Langmuir

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Growing instances of prostate cancer with poor prognosis have become a challenging task in cancer therapy. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in prostate cancer cells. Polyethylene glycol (PEG) conjugated lipids exhibit superiority in terms of retention/circulation in biological systems. PEGylated dipalmitoylphosphatedylethanolamine (DPPE-PEG), covalently linked with 6-hydrazinopyridine-3-carboxylic-acid, was conjugated with new LHRH-receptor positive peptide analog (DPPE-PEG-HYNIC-d-Glu-His-Trp-Ser-Tyr-d-Asn-Leu-d-Gln-Pro-Gly-NH2). Surface modified doxorubicin (DOX) loaded solid lipid nanoparticle (SLN) was prepared using soylecithin, stearic acid and Poloxamer-188 by solvent emulsification/evaporation method for targeted delivery of DOX into prostate cancer cells. SLN, DOX loaded SLN (DSLN) and surface modified DSLN (M-DSLN) were characterized by means of their size, zeta potential, morphology, storage time, drug payload, and subsequent release kinetics studies. Homogeneity of surface morphology, upon modification of SLN, was revealed from the dynamic light scattering, atomic force microscopy, and scanning electron microscopic studies. Homogeneous adsolubilization of DOX throughout the hydrophobic moiety of SLN was established by the differential scanning calorimetric studies. Release of DOX were sustained in DSLN and M-DSLN. Cellular uptake and in vitro activities of formulations against LHRH positive PC3/SKBR3 cancer cell lines revealed higher cellular internalization, cytotoxicity that followed the sequence DOX < DSLN < M-DSLN. Dye staining and flow cytometry studies revealed higher apoptosis in cancer cells. Such receptor specific drug delivery systems are considered to have substantial potential in prostate cancer therapy.

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Enhancing the Anticancer Activity and Selectivity of Goniothalamin Using pH-Sensitive Acetalated Dextran (Ac-Dex) Nanoparticles: A Promising Platform for Delivery of Natural Compounds

Braga

Kido

Lima

et al. 2020

ACS Biomater. Sci. Eng.

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Goniothalamin (GTN), a natural compound isolated from Goniothalamus species, has previously demonstrated cytotoxic activity against several cancer cell lines. However, similarly to many natural and synthetic anticancer compounds, GTN presents toxicity toward some healthy cells and low aqueous solubility, decreasing its bioavailability and precluding its application as an antineoplastic drug. In our efforts to improve the pharmacokinetic behavior and selectivity of GTN against cancer cells, we developed a polymeric nanosystem, in which rac-GTN was encapsulated in pH-responsive acetalated dextran (Ac-Dex) nanoparticles (NPs) with high loadings of the bioactive compound. Dynamic light scattering (DLS) analysis showed that the nanoparticles obtained presented a narrow size distribution of around 100 nm in diameter, whereas electron microscopy (EM) images showed nanoparticles with a regular spherical morphology in agreement with the size range obtained by DLS. Stability and release studies indicated that the GTN@Ac-Dex NPs presented high stability under physiological conditions (pH 7.4) and disassembled under slightly acidic conditions (pH 5.5), releasing the rac-GTN in a sustained manner. In vitro assays showed that GTN@Ac-Dex NPs significantly increased cytotoxicity and selectivity against cancer cells when compared with the empty Ac-Dex NPs and the free rac-GNT. Cellular uptake and morphology studies using MCF-7 cells demonstrated that GTN@Ac-Dex NPs are rapidly internalized into the cancer cells, causing cell death. In vivo investigation confirmed the efficient release of rac-GTN from GTN@Ac-Dex NPs, resulting in the delay of prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Furthermore, liver histopathology evaluation after treatment with GTN@Ac-Dex NPs showed no evidence of toxicity. Therefore, the in vitro and in vivo findings suggest that the Ac-Dex NPs are a promising nanosystem for the sustained delivery of rac-GTN into tumors.

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Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control

Cited by 5 publications

References 48 publications

Contribution of Kupffer cells to liposome accumulation in the liver

Contribution of Kupffer cells to liposome accumulation in the liver

Decapeptide Modified Doxorubicin Loaded Solid Lipid Nanoparticles as Targeted Drug Delivery System against Prostate Cancer

Enhancing the Anticancer Activity and Selectivity of Goniothalamin Using pH-Sensitive Acetalated Dextran (Ac-Dex) Nanoparticles: A Promising Platform for Delivery of Natural Compounds

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