Tumor-Targeted Delivery of the p53-Activating Peptide VIP116 with PEG-Stabilized Lipodisks

Lindström, Sara; Hernández, Víctor Agmo; Gedda, Lars; Sarén, Tina; Brown, Christopher J.; Lane, David P.; Edwards, Katarina; Nestor, Marika

doi:10.3390/nano10040783

Cited by 16 publications

(12 citation statements)

References 26 publications

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“…Similar findings have been recently reported in other PLA-PEGbased drug nanocarriers, demonstrating the potential of nanomedicine for cancer treatment. In particularly, PEG has been shown to enable site-specific delivery of drugs in various cancers (Xue et al, 2018;Duncan et al, 2019;Heshmati Aghda et al, 2020;Lundsten et al, 2020). Furthermore, no significant cytotoxicity of the blank PMs was observed in ALL cells in vitro, even when administered at maximum doses; and we didn't find obvious adverse reactions, such as gastrointestinal reactions, neurotoxicity, hepatoxicity and bone marrow suppression in the animals following DOX-PMs-NPMBP treatment.…”

Section: Discussionmentioning

confidence: 67%

Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

Gan

Chen

et al. 2021

Front. Pharmacol.

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Acute lymphoblastic leukemia (ALL) is an aggressive malignancy. Adults with ALL have more than 50% relapse rates. We have previously validated that overexpression of nucleophosmin (NPM) is involved in the multidrug resistance (MDR) development during ALL; and a synthetically engineered recombinant NPM binding protein (NPMBP) has been developed in our group; NPMBP and doxorubicin (DOX) can be conjugated in a nanoparticle-based drug delivery system named DOX-PMs-NPMBP to counteract MDR during ALL. Here, we evaluated the antileukemia potential of DOX-PMs-NPMBP in resistant ALL cells. This study demonstrates that DOX-PMs-NPMBP significantly enhances chemosensitivity to DOX in ALL cells. Despite at variable concentrations, both resistant and primary ALL cells from relapsed patients were sensitive to DOX-PMs-NPMBP. In detail, the half maximal inhibitory concentration (IC50) values of DOX-PMs-NPMBP were between 1.6- and 7.0-fold lower than those of DOX in cell lines and primary ALL cells, respectively; and apoptotic cells ratio was over 2-fold higher in DOX-PMs-NPMBP than DOX. Mechanistically, p53-driven apoptosis induction and cell cycle arrest played essential role in DOX-PMs-NPMBP-induced anti-leukemia effects. Moreover, DOX-PMs-NPMBP significantly inhibited tumor growth and prolonged mouse survival of ALL xenograft models; and no systemic toxicity occurrence was observed after treatment during follow-up. In conclusion, these data indicate that DOX-PMs-NPMBP may significantly exert growth inhibition and apoptosis induction, and markedly improve DOX antileukemia activity in resistant ALL cells. This novel drug delivery system may be valuable to develop as a new therapeutic strategy against multidrug resistant ALL.

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Section: Discussionmentioning

confidence: 67%

Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

Gan

Chen

et al. 2021

Front. Pharmacol.

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“…Incorporation of these residues into a vGFP variant designed to reduce deformation upon Mdm2 binding (vGFP3-M2) enhanced cellular activity ~ 2-fold. It will be interesting to see if this modi cation enhances Mdm2targeting stapled peptides being developed for clinical applications 18,37,38 .…”

Section: Discussionmentioning

confidence: 99%

Functional Display of Bioactive Peptides on the vGFP Scaffold.

Chee

Wongsantichon

Lau

et al. 2021

Preprint

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Grafting bioactive peptides into recipient protein scaffolds can often increase their activities by conferring enhanced stability and cellular longevity. Here, we describe use of vGFP as a novel scaffold to display peptides. vGFP comprises GFP fused to a bound high affinity Enhancer nanobody that potentiates its fluorescence. We show that peptides inserted into the linker region between GFP and the Enhancer are correctly displayed for on-target interaction, both in vitro and in live cells by pull-down, measurement of target inhibition and imaging analyses. This is further confirmed by structural studies highlighting the optimal display of a vGFP-displayed peptide bound to Mdm2, the key negative regulator of p53 that is often overexpressed in cancer. We also demonstrate a potential biosensing application of the vGFP scaffold by showing target-dependent modulation of intrinsic fluorescence. vGFP is relatively thermostable, well-expressed and inherently fluorescent. These properties make it a useful scaffold to add to the existing tool box for displaying peptides that can disrupt clinically relevant protein-protein interactions.

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“…Lipodisks consist of a disk-like structure where the phospholipids form a flat lipid surface, and the PEG-lipids are located at the highly curved rim (35)(36)(37). Many published results suggest that lipodisks are promising nanocarriers, and the rich contents of PEG may promote improved EE (38)(39)(40)(41). This is the first report adopting microfluidic methods to prepare lipodisk formulations to the best of our knowledge.…”

Section: Introductionmentioning

confidence: 92%

A Systematic Approach for Liposome and Lipodisk Preclinical Formulation Development by Microfluidic Technology

Levy¹,

Yu²,

Estevez³

et al. 2021

AAPS J

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Lipid nanoparticles have transformed the drug delivery field enhancing the therapeutic drug performance of small molecules and biologics with several approved drug products. However, in industry, these more complex drug delivery systems such as liposomes require more material and time to develop. Here, we report a liposome and lipodisk decision tree with model compounds of diverse physicochemical properties to understand how to resourcefully optimize encapsulation efficiency (EE) for these lipid-based drug delivery systems. We have identified trends with physicochemical properties such as Log P, where higher Log P compounds such as curcumin were able to efficiently load into the lipid bilayer resulting in high EE with altering the drug/lipid (D/L) ratio. Moderate Log P compounds such as cyclosporine A and dexamethasone had significantly higher encapsulation in lipodisks, which contain higher amounts of PEG lipid compared to liposomes. The EE of negative Log P compounds, like acyclovir, remained low regardless of altering the D/L ratio and PEG concentrations. In this study, microfluidic techniques were employed to fabricate liposomes and lipodisks formulations allowing for a reproducible strategy for formulation development. Both liposome and lipodisk of curcumin demonstrated enhanced in vivo performance compared with a conventional formulation in the rat pharmacokinetic study. This combination of approaches with multiple model compounds and lipid-based drug delivery systems provides a systematic guidance to effective strategies to generate higher EE with minimal drug waste and expedite the process for preclinical development when applied to industry compounds.

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Tumor-Targeted Delivery of the p53-Activating Peptide VIP116 with PEG-Stabilized Lipodisks

Cited by 16 publications

References 26 publications

Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

Functional Display of Bioactive Peptides on the vGFP Scaffold.

A Systematic Approach for Liposome and Lipodisk Preclinical Formulation Development by Microfluidic Technology

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