Comment on Shaniv et al. Neonatal Drug Formularies-A Global Scope. Children 2023, 10, 848.

We read the article by Shaniv D. et al. entitled "Neonatal Drug Formularies-A Global Scope" [...].

Biomedical applications of bisphosphonates.

Since their discovery over 100 years ago, bisphosphonates have been used industrially as corrosion inhibitors and complexing agents. With the discovery of their pharmacological activity in the late 1960s, implicating their high affinity for hydroxyapatite, bisphosphonates have been employed in the treatment of bone diseases and as targeting agents for colloids and drugs. They have notably been investigated for the treatment of Paget's disease, osteoporosis, bone metastases, malignancy-associated hypercalcemia, and pediatric bone diseases. Currently, they are first-line medications for several of these diseases and are taken by millions of patients worldwide, mostly postmenopausal women. A major problem associated with their use is their low oral bioavailability. Several delivery systems have been proposed to improve their absorption and to direct them to sites other than bone tissues. Beyond their important pharmacological role, the medical applications of bisphosphonates are numerous. In addition, their metal-chelating properties have been exploited to coat and stabilize implants, nanoparticulates, and contrast agents. In this contribution, we review the pharmacological and clinical uses of bisphosphonates and highlight their novel applications in the pharmaceutical and biomedical fields.

siRNA transfection with calcium phosphate nanoparticles stabilized with PEGylated chelators.

Despite the enormous therapeutic potential of siRNAs, their delivery is still problematic due to unfavorable biodistribution profiles and poor intracellular bioavailability. Calcium phosphate co-precipitate has been used for nearly 40 years for in vitro transfection due to its non-toxic nature and simplicity of preparation. However, rapid particle growth has largely prevented the translation of this method for in vivo purposes. It has recently been shown that bisphosphonate derivatives can physically stabilize calcium phosphate nanoparticles while still allowing for efficient cell transfection with plasmid DNA. Herein, two novel PEGylated chelating agents (PEG-alendronate and PEG-inositolpentakisphosphate) with enhanced stabilizing properties are introduced, and it is demonstrated that the bisphosphonate-stabilized nanoparticles can efficiently deliver siRNA in vitro. The nanoparticles are mainly taken up by clathrin-dependent endocytosis, and acidification of the endosomal compartment is required to release the entrapped siRNA into the cytosol. Furthermore, particle uptake enhances the inhibition of the mevalonate pathway by the bisphosphonate in macrophages.

Gene delivery with bisphosphonate-stabilized calcium phosphate nanoparticles.

Nucleic acid drugs are promising new therapeutics, due to their possible applications in a wide variety of diseases and their strong targeting potential and associated lower off-target effects compared to conventional pharmaceuticals. However, their poor intracellular bioavailability and rapid degradation hinder their development as drugs. Therefore, efficient delivery is a major challenge. Various systems have been developed to overcome this problem. The entrapment of genetic material into nanoparticles constitutes a promising approach to increase the in vitro and in vivo transfection activity. Calcium phosphate-DNA co-precipitates have been used for gene delivery for more than 35 years and have the advantage of being nontoxic, easy to produce, and having the ability to complex nucleic acids leading to efficient transfection. Conventional synthetic methods yield particles that are only stable for a short period of time. Herein is proposed a versatile, surfactant-free method to stabilize calcium phosphate-DNA nanoparticles based on the use of poly(ethylene glycol)-functionalized bisphosphonate. The strength of the interaction between the bisphosphonate and the calcium phosphate enabled the formation of stable, but bioresorbable particles of around 200 nm, which exhibited physical stability over several days. Additionally, the nanoparticles revealed good and sustained ability to transfect cells while displaying low toxicity.

Aminated linear and star-shape poly(glycerol methacrylate)s: synthesis and self-assembling properties.

Over the past 10 years, polyglycerols and their structurally related analogs have received considerable attention in the biomedical field. Poly(glycidyl methacrylate) (PGMA) is a versatile polymer because its pendant epoxide groups can be opened with different functional groups to generate poly(glycerol methacrylate)s (PGOHMA) derivatives. In this work, linear and star-shape PGMAs were synthesized by atom transfer radical polymerization and then functionalized with four different amines by ring-opening addition. This resulted in the formation of polyglycerol-like polymers having both hydroxyl and amine moieties and different water-solubility. The water-insoluble polymers could form pH-sensitive nanoassemblies, while the soluble derivatives efficiently complexed a short strand polynucleotide. The aminated polyglycerol interacted more avidly with the oligonucleotide than the control poly(ethyleneimine), and high transfection efficacy could be obtained with the linear derivative. Such polymers could find practical applications for the delivery of drugs and nucleic acids.