Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA

Abstract

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.

Nanomedicine: a new paradigm to overcome drug incompatibilities

“…[60][61][62][63][64][65] Nanocarriers could increase drug solubility and impart protection for several drugs from the surrounding biological environment and have been also utilized in drug detoxification. [66][67][68][69] In addition, nanocarriers provided targeted delivery of therapeutics to the site of the disease to allow for enhanced therapeutic efficacy, imaging contrast and accuracy, and to reduce the dose, cost and the side effects of medications. [64,70,71] Despite their numerous biomedical applications, nanocarriers have not been sufficiently explored for their ability to circumvent physical and chemical interactions that occur between incompatible drugs.…”

“…In these studies, it was evident that the effect of freeze-drying on particle size and PDI varied depending on the type of nanoparticles, and type and concentration of the cryoprotectant used. [67,68,93]…”

Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery

“…1−6 Intracellular delivery of nucleic acid drugs, such as DNA and siRNA (short interfering RNA), can either trigger or knockdown the expression of specific proteins that are linked to several diseases. However, the poor cellular uptake of genetic material, due to its overall negative charge and rapid degradation of DNA/RNA by nucleases in biological media, still represent major challenges toward their successful cellular delivery.…”

“…These cationic complexes can then undergo endocytosis and ultimately release the genetic materials in the cytosol. 2−6,10−14 …”

Hydrophilic polyphosphoester-conjugated fluorinated chlorin as an entirely biodegradable nano-photosensitizer for reliable and efficient photodynamic therapy

“…PPEs present great potential as a stealth material due to their biocompatibility and biodegradability. 22 The backbone of PPEs is similar to biomacromolecules, such as DNA, RNA and teichoic acids and phosphorus is a fundamental element of bone making up 1% of the total human body mass. 23,24 Therefore, the final degradation products of PPEs, phosphate or phosphonate, exist in or are well tolerated by the human body.…”