Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles

Abstract

Aminoglycosides are a class of naturally occurring and semi synthetic antibiotics that have been used for a long time in fighting bacterial infections. Due to acquired antibiotic resistance and inherent toxicity, aminoglycosides have experienced a decrease in interest over time. However, in the last decade, we are seeing a renaissance of aminoglycosides thanks to a better understanding of their chemistry and mode of action, which had led to new trends of application. The purpose of this comprehensive review is to highlight one of these new fields of application: the use of aminoglycosides as building blocks for the development of liposomal and polymeric vectors for gene delivery. The design, synthetic strategies, ability to condensate the genetic material, the efficiency in transfection, and cytotoxicity as well as when available, the antibacterial activity of aminoglycoside-based cationic lipids and polymers are covered and critically analyzed.

Aminoglycoside‐Based Biomaterials: From Material Design to Antibacterial and Gene Delivery Applications

“…Owing to these features, aminoglycosides were conjugated with lipophilic segments such as saturated or unsaturated alkyl chains and cholesterol derivatives for gene delivery. [ 120 ]…”

“…The first aminoglycoside‐derived giant lipid was synthesized through a precise site‐selective conjugation of cholesterol at the 6'‐NH 2 of kanamycin. [ 120,121 ] As kanamycin possesses multiple cationic charges on the headgroup, the self‐assembled vesicular nanostructure could efficiently condense nuclei acids into nanoparticles. The Kana–Chol conjugate was found to be highly efficient for the delivery of genes into various mammalian cells either alone or co‐formulated with dioleoylphosphatidylethanolamine (DOPE).…”

Amphiphilic Aminoglycosides as Medicinal Agents

“…AG conjugates to an efflux pump inhibitor or to an antibiotic drug of another class (antibiotic hybrids) can promote, as adjuvants, the uptake of antibiotics through the OM of Gram-negative bacteria via the self-promoted uptake mechanism by displacement of the divalent cations (Ca 2+ or Mg 2+ ), which stabilize LPS [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. The high affinity of strongly lipophilic AAGs of the first and second types for nucleic acids was used to develop efficient non-antibacterial vehicles for nucleic acid uptake in mammalian cells [129][130][131][132][133][134][135]. AAGs have also been employed for drug delivery [158,159] and their cationic characters should be exploited to deliver anionic drugs.…”

“…AAGs have also received interest in relation to different medicinal applications, especially for intracellular delivery of active agents, for example, nucleic acids or analogues, non-covalently or covalently bound to AAGs or AGs. The synthesis and development of gene delivery vehicles was recently reviewed [129]. Here, we mainly illustrate the precursor works of J.M.…”

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

“…The full potential of polymer-based delivery systems has yet to be realized. In 2020, aminoglycosides, a class of naturally occurring and semi-synthetic antibiotics, have been investigated as new cationic polymeric vectors to facilitate the transfer of genes into cells ( 29 ).…”