Lipid-based nanoparticle formulations for small molecules and RNA drugs

ABSTRACT

Introduction: Liposomes and lipid-based nanoparticles (LNPs) effectively deliver cargo molecules to specific tissues, cells, and cellular compartments. Patients benefit from these nanoparticle formulations by altered pharmacokinetic properties, higher efficacy, or reduced side effects. While liposomes are an established delivery option for small molecules, Onpattro® (Sanofi Genzyme, Cambridge, MA) is the first commercially available LNP formulation of a small interfering ribonucleic acid (siRNA).

Areas covered: This review article summarizes key features of liposomal formulations for small molecule drugs and LNP formulations for RNA therapeutics. We describe liposomal formulations that are commercially available or in late-stage clinical development and the most promising LNP formulations for ASOs, siRNAs, saRNA, and mRNA therapeutics.

Expert opinion: Similar to liposomes, LNPs for RNA therapeutics have matured but still possess a niche application status. RNA therapeutics, however, bear an immense hope for difficult to treat diseases and fuel the imagination for further applications of RNA drugs. LNPs face similar challenges as liposomes including limitations in biodistribution, the risk to provoke immune responses, and other toxicities. However, since properties of RNA molecules within the same group are very similar, the entire class of therapeutic molecules would benefit from improvements in a few key parameters of the delivery technology.

KEYWORDS:

• Drug delivery system
• DDS
• Lipid nanoparticle formulation
• LNP
• liposome
• RNA drug

Article highlights

• Commercial liposomal formulations are briefly reviewed for, in total, 11 small molecule drugs, i.e. doxorubicin, daunorubicin, cytarabine (in combination with daunorubicin), amphotericin B, bupivacaine, vincristine, mifamurtide, irinotecan, verteporfin, paclitaxel, and amikacin, as well as cisplatin (in late-stage clinical trials).

• The most advanced and most potent delivery systems for RNA drugs are concisely reviewed, i.e. siRNA, small activating RNAs (saRNA), anti-miRNA, and messenger RNA (mRNA) with a focus on the ionizable lipids, which are chiefly responsible for efficient RNA encapsulation as well as efficient RNA cytosolic release.

• The siRNA formulation of Onpattro is discussed, which contains the cationic lipid DLinMC3-DMA for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis.

• The active targeting approach for RNA using N-acetylgalactosamine (GalNAc) as the targeting moiety is described as the most promising alternative approach to direct RNA to a specific cell type, i.e. hepatocytes.

• We conclude that despite recent progress, an increased understanding of the molecular and cellular mechanisms of how the body interacts with nanoparticles and how the nanoparticles interact with the body is needed to rationally design even more efficacious delivery systems with fewer side effects.

This box summarizes the key points contained in the article.

Declaration of interest

L Ickenstein has a financial interest in Vyxeos (Jazz Pharmaceuticals, Dublin, Ireland). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.