The in vivo toxicological profile of cationic solid lipid nanoparticles

Mendonça, Monique Culturato Padilha; Radaic, Allan; Garcia-Fóssa, Fernanda; Cruz‐Höfling, Maria Alice da; Vinolo, Marco Aurélio Ramirez; Jesus, Marcelo Bispo de

doi:10.1007/s13346-019-00657-8

Cited by 19 publications

(7 citation statements)

References 38 publications

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“…In addition, due to the cationic lipid DOTAP, they are positively charged (zeta potential >+30 mV) and exhibit high homogeneity (PDI < 0.2). These results (supporting information table S1) agree with those obtained by previous studies (de Jesus et al 2014, Radaic et al 2014, Mendonça et al 2019. The detailed characterization of SLN loading builds upon prior studies (de Jesus et al 2014).…”

Section: Resultssupporting

confidence: 90%

Exploring the interplay between the TGF-β pathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells

Moraes-Lacerda,

Garcia-Fossa,

de Jesus

2024

Nanotechnology

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Solid lipid nanoparticles (SLN) are widely recognized for their biocompatibility, scalability, and long-term stability, making them versatile formulations for drug and gene delivery. Cellular interactions, governed by complex endocytic and signaling pathways, are pivotal for the successful application of SLN as therapeutic agents. This study aims to enhance our understanding of the intricate interplay between SLN and cells by investigating the influence of specific endocytic and cell signaling pathways, with a focus on the impact of the TGF-β pathway on SLN-mediated cell transfection in both cancerous and non-cancerous prostate cells. Here we conducted a systematic exploration of the intricate mechanisms governing the interactions between solid lipid nanoparticles and cells. By selectively manipulating endocytic and signaling pathways, we analyzed alterations in SLNplex internalization, intracellular traffic, and cell transfection dynamics. Our findings highlight the significant role of macropinocytosis in the internalization and transfection processes of SLNplex in both cancer and non-cancer prostate cells. Moreover, we discovered that the TGF-β pathway is an important factor influencing endosomal release, potentially impacting gene expression and modulating cell transfection efficiency. This study provides novel insights into the dynamic mechanisms governing the interaction between cells and SLN, emphasizing the pivotal role of TGF-β signaling in SLN-mediated transfection. With this, we shed new light on the mechanisms governing the interaction between cells and SLN and highlight the important role of TGF-β signaling in SLN-mediated transfection, affecting internalization, intracellular transport, and release of the genetic cargo. These findings contribute valuable knowledge for the optimization of SLN-based therapeutic strategies in prostate-related applications.

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Section: Resultssupporting

confidence: 90%

Exploring the interplay between the TGF-β pathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells

Moraes-Lacerda,

Garcia-Fossa,

de Jesus

2024

Nanotechnology

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“…These results agree with the modification of the morphology observed in both organs (Figure 6). Similar findings have been found after the acute administration of cationic nanoparticles [18,36]. Increased DNA damage in both lung and spleen after a single administration of cationic liposomes was observed in a previous study [18].…”

Section: Histopathological Examinationsupporting

confidence: 87%

Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study

et al. 2022

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Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.

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“…However, these can be toxic, are not selective for tumor cells, and are preferentially sequestered by the reticuloendothelial system. 24 , 25 , 26 Similarly, while cholesterol-siRNA conjugates have demonstrated good potency, they are taken up by numerous cell/tissue types, resulting in lower tumor accumulation. 27 , 28 Previously reported tumor-targeting strategies also include aptamer-siRNA conjugates.…”

Section: Discussionmentioning

confidence: 99%

Centyrin ligands for extrahepatic delivery of siRNA

et al. 2021

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RNA interference (RNAi) offers the potential to treat disease at the earliest onset by selectively turning off the expression of target genes, such as intracellular oncogenes that drive cancer growth. However, the development of RNAi therapeutics as anti-cancer drugs has been limited by both a lack of efficient and target cell-specific delivery systems and the necessity to overcome numerous intracellular barriers, including serum/ lysosomal instability, cell membrane impermeability, and limited endosomal escape. Here, we combine two technologies to achieve posttranscriptional gene silencing in tumor cells: Centyrins, alternative scaffold proteins binding plasma membrane receptors for targeted delivery, and small interfering RNAs (siRNAs), chemically modified for high metabolic stability and potency. An EGFR Centyrin known to internalize in EGFR-positive tumor cells was site-specifically conjugated to a beta-catenin (CTNNb1) siRNA and found to drive potent and specific target knockdown by free uptake in cell culture and in mice inoculated with A431 tumor xenografts (EGFR amplified). The generalizability of this approach was further demonstrated with Centyrins targeting multiple receptors (e.g., BCMA, PSMA, and EpCAM) and siRNAs targeting multiple genes (e.g., CD68, KLKb1, and SSB1). Moreover, by installing multiple conjugation handles, two different siRNAs were fused to a single Centyrin, and the conjugate was shown to simultaneously silence two different targets. Finally, by specifically pairing EpCAM-binding Centyrins that exhibited optimized internalization profiles, we present data showing that an EpCAM Centyrin CTNNb1 siRNA conjugate suppressed tumor cell growth of a colorectal cancer cell line containing an APC mutation but not cells with normal CTNNb1 signaling. Overall, these data demonstrate the potential of Centyrin-siRNA conjugates to target cancer cells and silence oncogenes, paving the way to a new class of anticancer drugs.

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The in vivo toxicological profile of cationic solid lipid nanoparticles

Cited by 19 publications

References 38 publications

Exploring the interplay between the TGF-β pathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells

Exploring the interplay between the TGF-β pathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells

Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study

Centyrin ligands for extrahepatic delivery of siRNA

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