Novel PEGylated Nanoassemblies Made of Self‐Assembled Squalenoyl Nucleoside Analogues

Abstract

This study describes a new simple method to obtain high loading of anticancer or antiviral nucleoside analogues into “stealth” poly(ethylene glycol) (PEG)‐coated nanoassemblies. These nanodevices are obtained by co‐nanoprecipitation in water of (i) squalenoyl prodrugs obtained by the bioconjugation of the natural lipid squalene with either the anticancer drug gemcitabine (Gem‐Sq) or the antiviral drug deoxycytidine (ddC‐Sq) with (ii) a PEG derivative of either cholesterol (Chol‐PEG) or squalene (Sq‐PEG). It was found that both PEG derivatives (Chol‐PEG or Sq‐PEG) were efficiently incorporated in the resulting composite nanoassemblies (CNAs), as shown by radioactivity studies, Zeta potential determination, and size measurements. Optimal compositions were defined for each PEG derivative to ensure the best stability in water and in buffer solutions. X‐ray diffraction and electron microscopy investigations revealed that depending on the structure of the squalenoyl nucleoside analogue used (Gem‐Sq or ddC‐Sq), these nanoassemblies might be toroids or cubosomes. Following PEGylation, the Gem‐Sq nanoassemblies displayed superior in vitro anticancer activity on gemcitabine‐resistant leukemia L1210 10K cells than either their non‐PEGylated counterparts or gemcitabine alone.

Ruthenium polypyridyl squalene derivative: A novel self-assembling lipophilic probe for cellular imaging

“…In previous work, the squalenoylation platform developed by our group was employed to design self-assembling nanomedicines derived from hydrophilic therapeutic agents, namely Gem, 2 ,3 -dideoxycytidine, and 2 ,3 -dideoxyinosine (Bekkara-Aounallah et al, 2008;Couvreur et al, 2006).…”

Self-assembly drug conjugates for anticancer treatment

“…The cytotoxic activity of the drug-drug conjugate was demonstrated to be strongly dependent on its concentration -if the concentration is lower than the CAC value the cytotoxic activity is worse than the mixture of the two drugs but if the concentration is higher than the CAC value NPs showed a much better activity than the free drug mixture. This result suggested that the Our research group studied the formation of hetero-NPs by co-self-assembly of two squalene-based conjugates with the drugs paclitaxel (7) and cyclopamine (18) [42]. …”

Anti-HIV-1 nanotherapeutics: promises and challenges for the future

“…[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] Table 2 lists the commonly used nanomaterials in biomedical applications. The current review focuses predominantly on nanoparticles used in HIV-1 therapeutics.…”

“…the responsiveness of these nanostructures to specific stimuli through remote activation. 34,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] Inorganic particles are much smaller, typically less than 20 nm, and circulate easily in the bloodstream and are easily cleared via renal excretion. [42][43][44][45][46] Silica-based nanoparticles such as organically modified silica are known for their low toxicity and biocompatibility for targeted imaging and therapy.…”

“…98,99 Dendrimers, PLGA nanoparticles, and cholesterol-conjugated siRNA have been evaluated for delivery of microbicides against HIV and although in vivo studies in mice suggest proximal and distal site topical delivery of the microbicides, issues of deep penetration into the epithelial barrier and issues with degradation in the mucus physiological environment remain to be resolved. 13,30,31,[36][37][38][39][40][41][100][101][102][103][104][105][106][107][108][109] HIV-1 nanotherapy: an emerging technology, its promise, and limitations Nanotechnology can impact HIV therapy at several levels. (1) Nanoparticles by themselves have therapeutic effects since they can penetrate and neutralize the virus, by structural interference with viral assembly and thereby inhibit viral replication.…”