Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma

Zuccari, Guendalina; Milelli, Andrea; Pastorino, Fabio; Loi, Monica; Petretto, Andrea; Parise, Amelia; Marchetti, Chiara; Minarini, Anna; Cilli, Michele; Emionite, Laura; Paolo, Daniela Di; Brignole, Chiara; Piaggio, Francesca; Perri, Patrizia; Tumiatti, Vincenzo; Pistoia, Vito; Pagnan, Gabriella; Ponzoni, Mirco

doi:10.1016/j.jconrel.2015.05.286

Cited by 49 publications

(29 citation statements)

References 43 publications

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“…This also indicates that peripheral side effects may decrease, which is in line with other studies on liposomal formulations. [25][26][27] Thus, there is a 3-fold distribution advantage to the brain compared to the pharmacologically active concentrations in the periphery. This was possible to be studied by utilizing microdialysis in both plasma and brain, allowing separation of encapsulated vs released MTX in plasma, as well as direct measurement of the active form of MTX in the brain.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study

Rip²,

Gaillard

et al. 2017

Journal of Pharmaceutical Sciences

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The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis. Total MTX concentrations in plasma were determined using regular blood sampling. The administration of both high- and low-dose EYPC liposomes resulted in 10 times higher extent of MTX release in plasma compared to that obtained from HSPC liposomes (p < 0.05). MTX itself possessed limited brain uptake with steady-state unbound brain-to-plasma concentration ratio (K) of 0.10 ± 0.06. Encapsulation in HSPC liposomes did not affect MTX brain uptake (K 0.11 ± 0.05). In contrast, EYPC liposomes significantly improved MTX brain delivery with a 3-fold increase of K (0.28 ± 0.14 and 0.32 ± 0.13 for high- and low-dose EYPC liposomal MTX, respectively, p < 0.05). These results provide unique quantitative evidence that liposomal formulations based on different phospholipids can result in very different brain delivery of MTX.

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Section: Discussionmentioning

confidence: 99%

The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study

Rip²,

Gaillard

et al. 2017

Journal of Pharmaceutical Sciences

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“…Moreover, the clinical translation of BTZ is also impaired by a poor bioavailability and also, in case of treatment of pediatric tumors, by a difficult administration to children. To overcome these limitations, a novel method to stably encapsulate BTZ into sterically stabilized liposomes has been developed . The new BTZ‐entrapped liposomal formulation is targeted to tumor vasculature, thanks to the surface modification with NGR‐containing peptides.…”

Section: Liposomal Bortezomibmentioning

confidence: 99%

Overcoming Biological Barriers in Neuroblastoma Therapy: The Vascular Targeting Approach with Liposomal Drug Nanocarriers

Pastorino

Brignole

Paolo

et al. 2019

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Neuroblastoma is a rare pediatric cancer characterized by a wide clinical behavior and adverse outcome despite aggressive therapies. New approaches based on targeted drug delivery may improve efficacy and decrease toxicity of cancer therapy. Furthermore, nanotechnology offers additional potential developments for cancer imaging, diagnosis, and treatment. Following these lines, in the past years, innovative therapies based on the use of liposomes loaded with anticancer agents and functionalized with peptides capable of recognizing neuroblastoma cells and/or tumor‐associated endothelial cells have been developed. Studies performed in experimental orthotopic models of human neuroblastoma have shown that targeted nanocarriers can be exploited for not only decreasing the systemic toxicity of the encapsulated anticancer drugs, but also increasing their tumor homing properties, enhancing tumor vascular permeability and perfusion (and, consequently, drug penetration), inducing tumor apoptosis, inhibiting angiogenesis, and reducing tumor glucose consumption. Furthermore, peptide‐tagged liposomal formulations are proved to be more efficacious in inhibiting tumor growth and metastatic spreading of neuroblastoma than nontargeted liposomes. These findings, herein reviewed, pave the way for the design of novel targeted liposomal nanocarriers useful for multitargeting treatment of neuroblastoma.

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“…Recently, peptides containing the asparagine-glycine-arginine (Asn-Gly-Arg, NGR) motif [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] and their deamidation products containing the iso DGR motif [38,41,46,48,56,59,74,76,77,78,79,80,81...…”

Section: Introductionmentioning

confidence: 99%

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

Kirikoshi

Manabe

Takahashi

2017

IJMS

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The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH2CO-NGRC]-NH2, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H2PO4− ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H2PO4− ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH2 group on the five-membered ring, was shown to easily undergo NH3 elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation.

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Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma

Cited by 49 publications

References 43 publications

The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study

The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study

Overcoming Biological Barriers in Neuroblastoma Therapy: The Vascular Targeting Approach with Liposomal Drug Nanocarriers

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

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