Khalid Oumzil

Nucleoside-lipid-based nanoparticles for cisplatin delivery.

The use of delivery vehicles to selectively transport anticancer agents to tumors is very attractive to address both toxicity and efficacy issues. We report a novel approach based on hybrid nucleoside-lipids allowing the efficient encapsulation and delivery of cisplatin. We demonstrate that the nucleoside polar heads guide the self-assembly of the aggregates into highly loaded and stable nanoparticles. The nanoparticles, which are efficient vehicles for the delivery of cisplatin into different sensitive and resistant cancer cell lines, can overcome the disadvantages and limitations of drug delivery systems previously reported.

Cation Tuning of Supramolecular Gel Properties: A New Paradigm for Sustained Drug Delivery.

Hydrogels formed by the self-assembly of low-molecular-weight gelators (LMWGs) are promising scaffolds for drug-delivery applications. A new biocompatible hydrogel, resulting from the self-assembly of nucleotide-lipid salts can be safely injected in vivo. The resulting hydrogel provides sustained-release of protein for more than a week.

Solid Lipid Nanoparticles for Image-Guided Therapy of Atherosclerosis

Although the application of nanotechnologies to atherosclerosis remains a young field, novel strategies are needed to address this public health issue. In this context, the magnetic resonance imaging (MRI) approach has been gradually investigated in order to enable image-guided treatments. In this contribution, we report a new approach based on nucleoside-lipids allowing the synthesis of solid lipid nanoparticles (SLN) loaded with iron oxide particles and therapeutic agents. The insertion of nucleoside-lipids allows the formation of stable SLNs loaded with prostacycline (PGI2) able to inhibit platelet aggregation. The new SLNs feature better relaxivity properties in comparison to the clinically used contrast agent Feridex, indicating that SLNs are suitable for image-guided therapy.

Efficient delivery of therapeutic small nucleic acids to prostate cancer cells using ketal nucleoside lipid nanoparticles

A novel nucleoside lipid derived from dioleyl ketal was synthesized from uridine in three steps starting from dioleyl ketone. Electronic microscopy studies show that Ketals Nucleoside Lipids (KNL) self-assemble to form liposome-like structures in aqueous solutions. KNL is able to bind siRNA as demonstrated by electrophoresis experiment and standard ethidium bromide fluorescence displacement assay. Transfection assays of stable hepatic cell lines HupIRF, carrying a luciferase reporter gene demonstrate that KNL is able to transfect siRNA and exhibits protein knockdown more efficiently than its diester analog (DOTAU) and lipofectamine. Herein, we also report that KNLs are suitable transfecting reagents for the development of novel therapeutic approaches involving either siRNA or antisense oligonucleotide against human prostate cancer PC-3 cells resistant to chemotherapy.

A hybrid lipid oligonucleotide: a versatile tool for supramolecular chemistry

Lipid oligonucleotides (LONs) are emerging as promising supramolecular tools for biomedical and technological applications. In this contribution we highlight recent advances in the area of LONs with an emphasis on their supramolecular properties and applications. In the first section we focus on the design, self-assembly and applications of LONs. In the last section, we describe recent biomedical applications thereof.

Nucleolipids as building blocks for the synthesis of 99mTc-labeled nanoparticles functionalized with folic acid

The development of drug delivery nanocarriers is emerging as a promising therapeutic tool to transport anti-cancer agents to tumors. In this contribution, preparation of nanoparticles (NPs) highly loaded with cisplatin using the bio-inspired hybrid nucleoside-lipids has been reported. The construction of these NPs using a “layer-by-layer’’ approach allows surface functionalization with polyethylene glycol and targeting moieties. Uridine moieties were pegylated for folic acid (FA) functionalisation to render specificity for active targeting. The uridine moieties at the surface of the nanoparticle act as ligands for 99mTc radiolabeling, whereas the lipid chains maintain the structure of the nanoparticle. In vitro, these hybrid NPs are stable and actively internalize in two different cell lines overexpressing the folic acid receptor. In vivo scintigraphy shows that nucleolipid functionalized NPs notably improved the pharmacokinetic profile of cisplatin (enhanced blood circulation time) and accumulated in the tumor xenografted mice model.

Lipid-oligonucleotide conjugates improve cellular uptake and efficiency of TCTP-antisense in castration-resistant prostate cancer

ABSTRACT Translationally controlled tumor protein (TCTP) has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. Therefore, TCTP is now recognized as a potential therapeutic target in several cancers including prostate, breast and lung cancers. We previously showed that TCTP is overexpressed in castration‐resistant prostate cancer (CRPC), and it has been implicated resistance to treatment. Recently, we developed TCTP antisense oligonucleotides (ASOs) to inhibit TCTP expression. However, the intracellular delivery and silencing activity of these oligonucleotides remains a challenge, and depend on the use of transfection agents and delivery systems. Here we show that lipid‐modified ASO (LASOs) has improved penetration and efficiency in inhibiting TCTP expression in the absence of additional transfection agents, both in vitro and in vivo. Transfection with TCTP‐LASO led to rapid and prolonged internalization via macropinocytosis, TCTP downregulation and significant decreased cell viability. We also show that lipid‐modification led to delayed tumor progression in CRPC xenografts models, with no significant toxic effects observed.