Publications by authors named "Alexandre Lancelot"

9 Publications

  • Page 1 of 1

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Grupo de Terapia Génica y Celular, Instituto Aragonés de Ciencias de la Salud (IACS/IIS-Aragon), 50009 Zaragoza, Spain.

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.
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http://dx.doi.org/10.3390/ijms22105223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156097PMC
May 2021

Janus Dendrimers to Assess the Anti-HCV Activity of Molecules in Cell-Assays.

Pharmaceutics 2020 Nov 7;12(11). Epub 2020 Nov 7.

Instituto de Nanociencia y Materiales de Aragón (INMA), University of Zaragoza-CSIC, Pedro Cerbuna 12, 50009 Zaragoza, Spain.

The use of nanocarriers has been revealed as a valid strategy to facilitate drug bioavailability, and this allows for expanding the drug libraries for the treatment of certain diseases such as viral diseases. In the case of Hepatitis C, the compounds iopanoic acid and 3,3',5-triiodothyroacetic acid (or tiratricol) were identified in a primary screening as bioactive allosteric inhibitors of viral NS3 protease, but they did not exhibit accurate activity inhibiting viral replication in cell-based assays. In this work, dendritic nanocarriers are proposed due to their unique properties as drug delivery systems to rescue the bioactivity of these two drugs. Specifically, four different amphiphilic Janus dendrimers synthesized by combining 2,2'-(hydroxymethyl)propionic acid (-MPA) and 2,2'-(glyciloxy)propionic acid (-GMPA) functionalized with either hydrophilic or lipophilic moieties at their periphery were used to entrap iopanoic acid and tiratricol. Interestingly, differences were found in the loading efficiencies depending on the dendrimer design, which also led to morphological changes of the resulting dendrimer aggregates. The most remarkable results consist of the increased water solubility of the bioactive compounds within the dendrimers and the improved antiviral activity of some of the dendrimer/drug aggregates, considerably improving antiviral activity in comparison to the free drugs. Moreover, imaging studies have been developed in order to elucidate the mechanism of cellular internalization.
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http://dx.doi.org/10.3390/pharmaceutics12111062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695217PMC
November 2020

Promising nanomaterials in the fight against malaria.

J Mater Chem B 2020 10;8(41):9428-9448

Instituto de Nanociencia y Materiales de Aragón (INMA), Dep. Química Orgánica-Facultad de Ciencias, CSIC-Universidad de Zaragoza, 50009 Zaragoza, Spain.

For more than one hundred years, several treatments against malaria have been proposed but they have systematically failed, mainly due to the occurrence of drug resistance in part resulting from the exposure of the parasite to low drug doses. Several factors are behind this problem, including (i) the formidable barrier imposed by the Plasmodium life cycle with intracellular localization of parasites in hepatocytes and red blood cells, (ii) the adverse fluidic conditions encountered in the blood circulation that affect the interaction of molecular components with target cells, and (iii) the unfavorable physicochemical characteristics of most antimalarial drugs, which have an amphiphilic character and can be widely distributed into body tissues after administration and rapidly metabolized in the liver. To surpass these drawbacks, rather than focusing all efforts on discovering new drugs whose efficacy is quickly decreased by the parasite's evolution of resistance, the development of effective drug delivery carriers is a promising strategy. Nanomaterials have been investigated for their capacity to effectively deliver antimalarial drugs at local doses sufficiently high to kill the parasites and avoid drug resistance evolution, while maintaining a low overall dose to prevent undesirable toxic side effects. In recent years, several nanostructured systems such as liposomes, polymeric nanoparticles or dendrimers have been shown to be capable of improving the efficacy of antimalarial therapies. In this respect, nanomaterials are a promising drug delivery vehicle and can be used in therapeutic strategies designed to fight the parasite both in humans and in the mosquito vector of the disease. The chemical analyses of these nanomaterials are essential for the proposal and development of effective anti-malaria therapies. This review is intended to analyze the application of nanomaterials to improve the drug efficacy on different stages of the malaria parasites in both the human and mosquito hosts.
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http://dx.doi.org/10.1039/d0tb01398fDOI Listing
October 2020

Micelle carriers based on dendritic macromolecules containing bis-MPA and glycine for antimalarial drug delivery.

Biomater Sci 2019 Mar;7(4):1661-1674

Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain.

Biomaterials for antimalarial drug transport still need to be investigated in order to attain nanocarriers that can tackle essential issues related to malaria treatment, e.g. complying with size requirements and targeting specificity for their entry into Plasmodium-infected red blood cells (pRBCs), and limiting premature drug elimination or drug resistance evolution. Two types of dendritic macromolecule that can form vehicles suitable for antimalarial drug transport are herein explored. A new hybrid dendritic-linear-dendritic block copolymer based on Pluronic® F127 and amino terminated 2,2'-bis(glycyloxymethyl)propionic acid dendrons with a poly(ester amide) skeleton (HDLDBC-bGMPA) and an amino terminated dendronized hyperbranched polymer with a polyester skeleton derived from 2,2'-bis(hydroxymethyl)propionic acid (DHP-bMPA) have provided self-assembled and unimolecular micelles. Both types of micelle carrier are biocompatible and exhibit appropriate sizes to enter into pRBCs. Targeting studies have revealed different behaviors for each nanocarrier that may open new perspectives for antimalarial therapeutic approaches. Whereas DHP-bMPA exhibits a clear targeting specificity for pRBCs, HDLDBC-bGMPA is incorporated by all erythrocytes. It has also been observed that DHP-bMPA and HDLDBC-bGMPA incorporate into human umbilical vein endothelial cells with different subcellular localization, i.e. cytosolic and nuclear, respectively. Drug loading capacity and encapsulation efficiencies for the antimalarial compounds chloroquine, primaquine and quinacrine ranging from 30% to 60% have been determined for both carriers. The resulting drug-loaded nanocarriers have been tested for their capacity to inhibit Plasmodium growth in in vitro and in vivo assays.
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http://dx.doi.org/10.1039/c8bm01600cDOI Listing
March 2019

Self-Assembling Hybrid Linear-Dendritic Block Copolymers: The Design of Nano-Carriers for Lipophilic Antitumoral Drugs.

Nanomaterials (Basel) 2019 Jan 29;9(2). Epub 2019 Jan 29.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA), Facultad de Ciencias, CSIC, Universidad de Zaragoza, 50009 Zaragoza, Spain.

Two series of amphiphilic block copolymers with a hybrid linear-dendritic structure are presented. The compounds consisted of a hydrophilic poly (ethylene glycol) (PEG) block and a 2,2'-bis(hydroxymethyl)propionic acid (bis-MPA) dendron functionalized with stearic acid chains that impart a hydrophobic nature to the block. Different self-assembled nanostructures with a hydrophobic interior and a hydrophilic external part were obtained depending on the length of the PEG chain ( = 2000 and = 5000) and the generation of the bis-MPA dendron. The materials were characterized by transmission electron microscopy (TEM). The shapes of the aggregates ranged from spherical or cylindrical micelles to flexible bilayers. The hydrophobic core enabled these nanostructures to encapsulate the water-insoluble drug plitidepsin. The efficacy of these new plitidepsin-containing carriers was evaluated in four cancer cell-lines and they showed similar anticancer activity to the current standard drug formulation.
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http://dx.doi.org/10.3390/nano9020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409548PMC
January 2019

Cationic poly(ester amide) dendrimers: alluring materials for biomedical applications.

J Mater Chem B 2018 Jun 31;6(23):3956-3968. Epub 2018 May 31.

Instituto de Nanociencia de Aragón (INA), Universidad de Zaragoza, Spain.

Novel cationic poly(ester amide) dendrimers have been synthesized by copper(i) azide-alkyne cycloaddition (CuAAC) of a tripropargylamine core and azide-terminated dendrons, in turn prepared by iterative amide coupling of the new monomer 2,2'-bis(glycyloxymethyl)propionic acid (bis-GMPA). The alternation of ester and amide groups provided a dendritic scaffold that was totally biocompatible and degradable in aqueous media at physiological and acidic pH. The tripodal dendrimers naturally formed rounded aggregates with a drug that exhibited low water solubility, camptothecin, thus improving its cell viability and anti-Hepatitis C virus (anti-HCV) activity. The presence of numerous peripheral cationic groups enabled these dendrimers to form dendriplexes with both pDNA and siRNA and they showed effective in vitro siRNA transfection in tumoral and non-tumoral cell lines.
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http://dx.doi.org/10.1039/c8tb00639cDOI Listing
June 2018

DNA Transfection to Mesenchymal Stem Cells Using a Novel Type of Pseudodendrimer Based on 2,2-Bis(hydroxymethyl)propionic Acid.

Bioconjug Chem 2017 04 13;28(4):1135-1150. Epub 2017 Mar 13.

Departamento de Quı́mica Orgánica, Facultad de Ciencias, Instituto de Nanociencia de Aragón, Universidad de Zaragoza , Zaragoza 50009, Spain.

In the search for effective vehicles to carry genetic material into cells, we present here new pseudodendrimers that consist of a hyperbranched polyester core surrounded by amino-terminated 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) dendrons. The pseudodendrimers are readily synthesized from commercial hyperbranched bis-MPA polyesters of the second, third, and fourth generations and third-generation bis-MPA dendrons, bearing eight peripheral glycine moieties, coupled by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). This approach provides globular macromolecular structures bearing 128, 256, and 512 terminal amino groups, and these can complex pDNA. The toxicity of the three pseudodendrimers was studied on two cell lines, mesenchymal stem cells, and HeLa, and it was demonstrated that these compounds do not affect negatively cell viability up to 72 h. The complexation with DNA was investigated in terms of N-to-P ratio and dendriplex stability. The three generations were found to promote internalizing of pDNA into mesenchymal stem cells (MSCs), and their transfection capacity was compared with two nonviral commercial transfection agents, Lipofectamine and TransIT-X2. The highest generations were able to transfect these cells at levels comparable to both commercial reagents.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00037DOI Listing
April 2017

Shell Cross-Linked Polymeric Micelles as Camptothecin Nanocarriers for Anti-HCV Therapy.

Macromol Biosci 2015 Oct 5;15(10):1381-91. Epub 2015 Jun 5.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón (ICMA) - Universidad de Zaragoza-CSIC, 50009, Zaragoza, Spain.

A suitable carrier for camptothecin to act as therapy against the hepatitis C virus is presented. The carrier relies on an amphiphilic hybrid dendritic-linear-dendritic block copolymer, derived from pluronic F127 and bis-MPA dendrons, that forms micelles in aqueous solution. The dendrons admit the incorporation of multiple photoreactive groups that allow the clean and effective preparation of covalently cross-linked polymeric micelles (CLPM), susceptible of loading hydrophilic and lipophilic molecules. Cell-uptake experiments using a newly designed fluorophore, derived from rhodamine B, demonstrate that the carrier favors the accumulation of its cargo within the cell. Furthermore, loaded with camptothecin, it is efficient in fighting against the hepatitis C virus while shows lower cytotoxicity than the free drug.
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http://dx.doi.org/10.1002/mabi.201500094DOI Listing
October 2015

Nanostructured liquid-crystalline particles for drug delivery.

Expert Opin Drug Deliv 2014 Apr 3;11(4):547-64. Epub 2014 Feb 3.

Universidad de Zaragoza, Instituto de Nanociencia de Aragón , Zaragoza , Spain.

Introduction: Nanostructured lyotropic liquid crystal particles (LLC NPs) have proven to be extremely useful tools for applications in drug delivery. These structured nanoparticles are formed by amphiphilic molecules and contain internal water channels, which are not in contact with external water, and where polar drugs can situate; on the other hand, apolar drugs can be loaded in the lipophilic part of the structure and the amphiphilic drugs can locate at the polar/apolar interfaces.

Areas Covered: A revision of the most relevant results published in the field of LLC NPs has been made. The first section discusses the most common compounds used in these nanoparticles and their preparation and characterization. A summary of recent and relevant results including the composition and type of nanoparticles used, the illness treated, the administration via and some special features in each case have been summarized in a table.

Expert Opinion: LLC NPs are highly versatile drug delivery systems, which can be applied by topical, oral and intravenous treatments. Especially relevant is their use for the release of anticancer drugs, biomolecules and vaccines. Nevertheless a number of critical points need to be solved in order to attain practical applications.
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http://dx.doi.org/10.1517/17425247.2014.884556DOI Listing
April 2014
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