pH-Promoted Release of a Novel Anti-Tumour Peptide by “Stealth” Liposomes: Effect of Nanocarriers on the Drug Activity in Cis-Platinum Resistant Cancer Cells

Sacchetti, Francesca; Marverti, Gaetano; D’Arca, Domenico; Severi, Leda; Maretti, Eleonora; Iannuccelli, Valentina; Pacifico, Salvatore; Ponterini, Glauco; Costi, Maria Paola; Leo, Eliana Grazia

doi:10.1007/s11095-018-2489-z

Cited by 14 publications

(14 citation statements)

References 38 publications

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“…The drug loading (DL) was 21.03 ± 1.66 µ g peptide/mg of lipid and the encapsulation efficiency approximately 40%. Consistently with the two-fold drug/lipid ratio used in the preparation, this formulation exhibited a DL twice that of the already reported homologue formulation [26]. The obtained loaded liposomes efficiently retained the peptide: after an 8 h incubation, only 30% of the initially encapsulated peptide was released and no further escape was observed in the next 16 h (Figure 7).…”

Section: Liposome Characterizationsupporting

confidence: 85%

“…The importance of these liposomes as vehicles for the peptide internalization into cells was confirmed by the inability of the free [D-Gln 4 ]LR peptide to interfere with the growth of all three cell lines [26]. The antiproliferative activity of the peptide encapsulated in these optimized liposomes (PpHL) was tested by the MTT assay on three OC cell lines, the cDDP-resistant C13* cells and their sensitive counterparts, the 2008, and the IGROV-1 cell lines, the latter sensitive to cDDP too.…”

Section: Cytotoxicity Of Peptide-loaded Liposomesmentioning

confidence: 93%

“…Despite being sensitive to cisplatin in vitro, they are resistant to Asta Z, and present an intermediate drug response to adriamycin. Finally, concerning the effect of drug loading, its doubling caused only a moderate increase in cytotoxicity on the C13* cells, with a 63% survival vs a 70% survival measured with the original preparation [26], a finding likely due to the saturation of the intracellular target enzyme, hTS.…”

Section: Cytotoxicity Of Peptide-loaded Liposomesmentioning

confidence: 94%

“…In fact, PEGylation represents a very useful method for achieving long circulation time for liposomes, hence allowing them more time for targeting tumours via the enhanced permeability and retention (EPR) effect [25]. The PEGylated pH-sensitive liposomes were characterized and compared favourably with non-PEGylated ones regarding surface hydrophilicity, stability in serum, interaction with macrophages, drug encapsulation efficiency and drug release [26]. Also, the well-characterized intracellular mechanism of action of the [D-Gln 4 ]LR peptide delivered using the SAINT-PhD delivery system was unaltered when the latter was replaced by these liposomes.…”

Section: Introductionmentioning

confidence: 99%

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A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

Marverti

Gozzi

Maretti

et al. 2020

IJMS

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There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.

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Section: Liposome Characterizationsupporting

confidence: 85%

Section: Cytotoxicity Of Peptide-loaded Liposomesmentioning

confidence: 93%

Section: Cytotoxicity Of Peptide-loaded Liposomesmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

Marverti

Gozzi

Maretti

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

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“…At low temperatures, the lipid bilayer exists in an ordered state and is non-permeable for hydrophilic payloads; the content of the internal cavity is trapped inside and protected from the outside environment [1]. Therefore, liposomes can be used as carriers for the encapsulation and controlled release of active substances including small-molecule drugs [2], biomolecules [3] and genes [4,5], or as building blocks for more complex drug delivery systems [6]. Beyond pharmaceutics, liposomes find applications in cosmetic [7] or nutraceutical [8] formulations.…”

Section: Introductionmentioning

confidence: 99%

In-silico screening of drug candidates for thermoresponsive liposome formulations

Balouch

Šrejber

Šoltys

et al. 2020

Preprint

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Highlights-New in silico methodology for predicting drug loading and thermal release from liposomes was developed and compared with experiments -Virtual lipid bilayers were constructed using molecular dynamics models and their interaction with penetrating solutes was studied by atomistic simulations -Rules for permeability (logPerm) and partition (logKlip/wat) coefficients were established to characterise drug compatibility with liposomes -Permeability and partition coefficients of 57 toxic compounds from DrugBank database were calculated, 5 suitable candidates identified and 1 demonstrated experimentally AbstractLiposomal formulations can be advantageous in a number of scenarios such as targeted delivery to reduce the systemic toxicity of highly potent Active Pharmaceutical Ingredients (APIs), to increase drug bioavailability by prolonging systemic circulation, to protect labile APIs from degradation in the gastrointestinal tract, or to improve skin permeation in dermal delivery. However, not all APIs are suitable for encapsulation in liposomes. Some of the issues are too high permeability of the API across the lipid bilayer, which may lead to premature leakage, too low permeability, which may hinder the drug release process, or too strong membrane affinity, which may reduce the overall efficacy of drug release from liposomes. Since the most reliable way to test API encapsulation and release from liposomes so far has been experimental, an in silico model capable of predicting API transport across the lipid bilayer might accelerate formulation development. In this work, we demonstrate a new in silico approach to compute the temperature dependent permeability of a set of compounds across the bilayer of virtual liposomes constructed by molecular dynamics simulation. To validate this approach, we have conducted a series of experiments confirming the model predictions using a homologous series of fluorescent dyes. Based on the performance of individual molecules, we have defined a set of selection criteria for identifying compatible APIs for stable encapsulation and thermally controlled release from liposomes. To further demonstrate the methodology, we have screened the DrugBank database, identified potent drugs suitable for liposome encapsulation and successfully carried out the loading and thermal release of one of them -an antimicrobial compound cycloserine.

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Strategies for the production of long-acting therapeutics and efficient drug delivery for cancer treatment

Al-Qahtani

O’Connor

Dömling

et al. 2019

Biomedicine & Pharmacotherapy

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pH-Promoted Release of a Novel Anti-Tumour Peptide by “Stealth” Liposomes: Effect of Nanocarriers on the Drug Activity in Cis-Platinum Resistant Cancer Cells

Abstract: PpHL can be considered as efficient delivery systems for the new promising anti-cancer peptide.

Cited by 14 publications

References 38 publications

A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

In-silico screening of drug candidates for thermoresponsive liposome formulations

Strategies for the production of long-acting therapeutics and efficient drug delivery for cancer treatment

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