Fit-for-purpose lipids can speed up RNA-LNP drug development

The drug delivery foundation for RNA-lipid nanoparticle (LNP) drugs is only as strong as the lipid formulation. Lipids are functional excipients that play a significant role in tailoring the lipid nanoparticles for drug delivery. The lipid component of an LNP can be optimized for structural properties and additional functionalities such as targeting and immunomodulation and is essential for clinical translation. They promote key LNP features and influence nucleic acid protection, formulation stability, and drug release.

As drug development is lengthy and costly, developing new formulations including novel lipids, at the discovery stage is required. Rapid validation of lipids drives growth in the genomic medicine toolbox to encapsulate varied payloads, target different cell types and tissues, and manufacture products at various scales. Access to quality lipids and optimization services can provide a competitive advantage and accelerate development and manufacturing by reducing the number of lipid formulation steps, simplifying the process, and reducing costs.

In a study, it was observed that Doxil iteratively improved formulation design and lipids with additional functionalities to ensure robust manufacturing methods, higher encapsulation efficiencies, better drug accumulation at the target site, and fewer dose-limiting toxicities [1]. In another study, Anderson and colleagues demonstrated that an alkyne ionizable lipid (A6) could significantly increase membrane fusion and facilitate albumin-mediated mRNA delivery when incorporated into benchmark LNP (e.g., MC3) [2]. These examples indicate that rational design and lipids screening are necessary for potent RNA delivery. Therefore, the following considerations can accelerate the delivery of commercial nanomedicines.

Develop fit-for-purpose lipids

LNP formulations are not one-size-fits-all. Several studies have highlighted that LNP formulations optimized for siRNA delivery are unsuitable for other payloads like mRNA and DNA [2]. However, the formulations can be optimized at the earliest stages so that it is fit-for-purpose. Optimization can be labor-intensive, but with access to a lipid library, the developers can reach the full potential of nucleic acid therapeutics across applications. Many biotechs have started working on experimental formulations, notably, Replicate Bioscience entered a licensing agreement with Cytiva to access the full lipid nanoparticle solution, including the proprietary lipid library. Accessing the lipid library will allow Replicate Bioscience to develop novel drug candidates fit for the company's lead programs and de-risk and accelerate drug program development.

Lipid validation data and performance criteria

Therapeutically relevant application-based screening can identify lipids and LNP compositions for specific applications. Developing the right analytics from the discovery stage saves significant time for validation and lowers the risk of developing a desired lipid nanoparticle formulation, accelerating preclinical programs. Procuring lipids with proven validation data and a lipid nanoparticle portfolio comprising more than 100 lipids with diverse pKa and biodegradability for different applications can help achieve the program goals.

Lipids safety and tolerability

To avoid unexpected setbacks, consider checking the lipids' safety and toxicity at earlier stages. In a study, a class of multi-tail ionizable phospholipids was developed; the best-performing 9A1P9 aided in membrane instability and cargo release, considerably improving LNP-mediated tissue-selective mRNA delivery and gene editing [3]. However, because lead multi-tail ionizable lipids often have stable backbones and limited degradability, their toxicity and immunogenicity should always be considered, and validating lipid safety data at the earliest stages is crucial.

Scalable lipids

Clinical ionizable lipids are all synthesized in multiple steps trying countless variations on various lipid combinations, posing scalability challenges. Thus, considerations such as scalability, the economy of scale, and batch size while selecting lipids early in drug development can help achieve the end goal of commercialization. It is important to invest in lipids that enable the clinical use of lead formulation.

Lipid licensing

Achieving optimal formulation is a complex task but once optimized for one target organ, the mRNA payload can be changed with minimal optimization, and the nanoparticle can be used repeatedly for similar targeted applications. Cytiva helps accelerate customers' genomic medicine programs to investigational new drug (IND) submission through unique and easy-to-use LNP RUO kits and proprietary lipids owned by the company and offered under affordable licensing to be used for clinical/commercial applications.

Access to quality lipids and continuous synthesis and screening of functionalized lipids by chemically optimizing their molecular structures can promote the development of more versatile, highly efficient, and biocompatible delivery vehicles. However, the formulation medium influences the self-assembly process and encapsulation efficiency, and the formulation method influences the lipid nanoparticles' properties, quality, and efficacy. Thus, nanoparticle delivery technologies are also central to developing genomic medicines. Cytiva has strong experience in continuous flow microfluidic mixing technologies, instruments, lipid reagents, and clinical nanoparticle development that provides an end-to-end solution to accelerate genomic medicine development. The research-use-only RUO, GLP, and GMP lipids are accessible through off-the-shelf kits allowing early access to lipids that can scale.

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