Lipid Nanoparticle Development and Formulation Services

Overview

Liposomes, which were discovered in 1960, have become increasingly recognized as a viable and effective drug delivery system. Aside from therapeutics, liposomes and lipid nanoparticles (LNPs) have been studied in a variety of fields, including but not limited to medical imaging, cosmetics, and agriculture.

LNPs, which are very small lipophilic substances that have been extensively researched and clinically proven to be capable of safely and effectively delivering nucleic acid therapeutics, present themselves as a promising delivery system capable of improving drug selectivity and biodistribution. It has successfully entered clinical use for the delivery of mRNA; specifically, LNP–mRNA vaccines are now being used to combat coronavirus disease 2019. (COVID-19).

At Esco Aster, we can help develop your LNP formulations with our expert team of formulation scientists and provide contract manufacturing service with our fill-and-finish systems in an advanced facility to produce your product at large-scale quantities for clinical trials. We have the speed, reliability and expertise to collaborate with you through a turnkey solution from development to manufacturing .

Main Applications

Our lipid nanoparticle development and formulation services are applied in the following areas:

In Vitro and In Vivo Diagnostics

Medical Imaging

Nanotherapeutics

Vaccines

Regenerative Medicine

Nanomedicine and mRNA Vaccines

Nanomedicine is ideally placed to upend current standards in disease diagnosis, prevention, and treatment. It is a versatile technology that uses nanoparticle encapsulation of a wide range of substances to achieve a variety of clinical outcomes.

In the area of prevention, nanomedicine has proven to be a useful platform for the delivery of new vaccine modalities. Notably, two of the most widely used COVID-19 vaccines contain mRNA encapsulated in lipid nanoparticles (LNPs). This delivery system improves the stability, shelf life, and efficiency of mRNA delivery within the body.

Nanomedicine and mRNA Vaccines

Nanomedicine in Diagnostics and
Medical Imaging

Nanomedicine has diagnostic applications as well. Various imaging modalities can be delivered using various nanoparticle types. Nanoparticles, for example, have been used to deliver and localize fluorescence markers in fluorescence imaging. The nanoparticles could be further modified to target specific cell types or organs.

Nanomedicine in Diagnostics and Medical Imaging

Nanomedicine in Peptide and
Nucleic Acid-based Therapeutics

Nanomedicine has the most diverse range of applications in disease treatment.

Encapsulating small molecule drugs, especially those with poor permeability and solubility, within nanoparticles enables their application by overcoming their pharmacokinetic limitations. Larger molecules, such as natural product analogs or their derivatives, can also be successfully delivered with nanoparticles.

Perhaps the most significant benefit of nanoparticle technology would be the ability to develop peptide and nucleic acid-based therapeutics. Because of their poor stability and susceptibility to degradation, peptide and nucleic acid therapeutics have been used sparingly in the past. Liposome encapsulation not only protects the contents from degradation, but in some cases, such as LNPs, it also facilitates cellular delivery of the payloads.

In addition, derivatization of the nanoparticles is another tool that is used to improve the delivery to the target sites, particularly for radioactive or chemotherapeutic agents.

Nanomedicine in Peptide and Nucleic Acid-based Therapeutics

Nanomedicine In Drug Delivery

The promise of nanomedicines can be expanded to include early cancer detection as well as combination therapies that can begin treating tumors earlier and more effectively. Below is a diagram depicting an overview of the nanomedicines currently being studied in clinical trials for cancer treatment.

Recent Advancements in
RNA Therapeutics and Nanomedicine

Advances in RNA manufacturing and lipid-based delivery platforms have permitted the development of RNA-based therapeutics for a wide range of applications, including previously untreatable illnesses. The FDA's approval of mRNA-based vaccinations against SARS-CoV-2 has accelerated the RNA-based therapy revolution.

Aptamers, anti-sense oligonucleotides (ASO), short-interfering RNA (siRNA), micro-RNA (miRNA), messenger RNA (mRNA), self-amplifying RNA (saRNA), and a closed loop or circular RNA are among the types of RNA molecules now being developed.  RNA-based therapeutics are used as protein replacement therapies, vaccinations, or to prevent or change protein production. mRNA is also used in several cell-based therapeutics in clinical trials.

In addition, the lipid nanoparticle (LNP) platform for RNA administration has addressed some of RNA's intrinsic limitations as a therapeutic agent. LNPs with a cationic lipid, structural lipid, cholesterol, and a PEG lipid can encapsulate anionic RNA, preserve it from degradation, prolong its circulation, and facilitate cellular delivery.

RNA therapeutics is a rapidly emerging field with the promise to treat and cure diseases that were previously thought to be incurable. When combined with a flexible and adaptive LNP delivery platform, the possibilities for RNA therapeutics are nearly endless.

Recent Advancements in RNA Therapeutics and Nanomedicine

Our Contract Development Services

At Esco Aster, our team of scientists can support you through formulation development, scale-up, clinical and commercial manufacturing, as well as analytical development and testing of final products. We collaborate and guide our clients throughout each stage of product development.

Ideation Phase

First, we come together during this phase to understand your product objectives and develop a Target Product Profile. It could be the encapsulation of a commercially available material with a client-supplied payload, or custom synthesis of a wide range of substances. We also create a preliminary encapsulation formulation at this stage.

In order to optimize the formulation, a systematic design of experiments (DOE) study might be used, as requested by the client. This step will involve technology transfer to our facility if you currently have an optimal formulation. Our analytical team will be working on developing or porting existing methods to our site at the same time.

Clients will have to ensure they have the freedom to operate for their payloads, lipids and mixing systems.

A variety of payloads can be encapsulated into the LNP depending on your application. These include aptamers, anti-sense oligonucleotides (ASOs), mRNA, siRNA, saRNA and circular RNA. These payloads can either be provided by the client, or Esco Aster will work with our qualified partner to manufacture the payload required.

  • Aptamers: Short, single-stranded nucleic acids that bind to macromolecules such as peptides, proteins, carbohydrates, etc. to elicit their therapeutic effects.1
  • ASO: Short, single-stranded nucleic acids that are complimentary to a region of their target RNA. Binding of ASO to the RNA either inhibits or alters translation of the protein of interest.
  • mRNA: messenger RNA sequence, encoding certain peptides/proteins that can be expressed in the cytoplasm.
  • siRNA: short interfering RNA able to regulate expression of genes by recognizing and binding to complementary sequences in RNA and alter their processing, such as inhibition of genes in different genetic diseases2
  • miRNA: micro-RNA are small non-coding RNA molecules that regulate expression of multiple mRNAs by blocking translation or promoting degradation of target mRNA.
  • saRNA: self-amplifying RNA allows enhanced antigen expression at lower doses compared to conventional mRNA. saRNA is derived from self-replicating single-stranded RNA viruses, which contain a replicase gene coding for RNA-dependent RNA polymerase (RdRP) that can amplify the RNA of interest3.
  • Emerging RNA technologies such as an engineered closed loop RNA that is naturally stable and able to translate into protein endlessly4.
Ideation Phase

Procurement Phase

On this phase, Esco Aster works with its trusted network of suppliers to secure raw materials of the highest quality and right grade. We may also look into custom synthesis for small molecules or peptide-based active compounds with our in-house organic chemists.

Working with us gives you access to a dependable, cost-effective network of suppliers in the region, which is critical for eventual commercialization.

Procurement Phase

Formulation Phase

Esco Aster’s formulation scientists construct and optimize the formulation to achieve the goal attributes specified in the Target Product Profile, such as nanoparticle size, release behavior, and other factors.

Analytical Development works in tandem with the prototype development to help with the development of specialized analytical methods.

Formulation Phase

Analytical Development

To ensure quality compliance and product safety, specific analytical methods and tools are used. Esco Aster’s analytical development team can create and choose robust test methods for testing product specifications. We can validate testing procedures and develop protocols to ensure that tests are accurate and meet global standards.

Esco Aster can also work with existing test methods and evaluate equipment suitability based on the formulation characteristics.

Analytical Development

Iterative Improvement

Esco Aster will now proceed through development in an iterative manner, always collaborating closely with you to gather timely feedback and improve the prototype. We are well equipped with cutting edge technologies for LNP production, including,

  • T-mixer or impingement jet mixer (client to ensure freedom to operate)
  • Microfluidic mixing (may need licensing)
  • Esco Aster can also provide custom designed single- or multiple-use mixing skids

Additionally, our downstream processing capabilities for LNP purification take into account the fragility of LNPs, using technologies such as tangential flow filtration. Concurrently, we may also conduct optimization experiments to determine the design space of the process, providing crucial insight on the parameters of the production process.

Iterative Improvement

Prototype Scale-Up

At Esco Aster, we are able to support your progress to Contract Manufacturing seamlessly with the provision of scaling up services. At this time, selected formulations could be subjected to stability tests amongst others. The eventual goal is to offer a prototype with a clear path towards large scale manufacturing for eventual commercialization.

Prototype Scale-Up

Our Contract Manufacturing Services

Esco Aster offers high-quality, GMP-compliant products that are suitable for clinical development or commercial delivery.
Our facility is equipped with both clinical and commercial manufacturing equipment for your needs.

References:

  1. Damase TR, Sukhovershin R, Boada C, Taraballi F, Pettigrew RI and Cooke JP (2021) The Limitless Future of RNA Therapeutics. Front. Bioeng. Biotechnol. 9:628137. doi: 10.3389/fbioe.2021.628137
  2. Dana H, Chalbatani GM, Mahmoodzadeh H, et al. Molecular Mechanisms and Biological Functions of siRNA. Int J Biomed Sci. 2017;13(2):48-57.
  3. Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther 28, 117–129 (2021). https://doi.org/10.1038/s41434-020-00204-y
  4. Infinitty Capital. (2022, May 19). Is self-amplifying or endless RNA the future of mrna vaccines? Infinitty Capital. Retrieved May 31, 2022, from https://www.infinittycapital.com/fa-quick-look-at-2-companies-innovating-to-overcome-the-short-half-life-of-mrna-is-self-amplifying-or-endless-rna-the-future-of-mrna-vaccines/amp/