Delivering Clinical Breakthroughs by Lipid Nanoparticles

March 29 13:19 2021
Liposomes, Lipid Nanoparticles (LNPs), and other lipid-based formulations have been clinically proven to improve the therapeutic index of a wide variety of active pharmaceutical ingredients (API). Lipids are an amphipathic class of biological molecules that exhibit ideal safety and pharmacokinetic profiles when incorporated into pharmaceutical drug products. LNPs have gained attention due to their incorporation into mRNA-based vaccine formulations aimed at preventing the spread of the COVID-19.

Liposomes have long been established as an effective drug delivery vehicle for API with poor pharmacokinetics, limited bioavailability or solubility, and high toxicity. Discovered in the 1960s by Alec D. Bangham, liposomes were originally utilized as an artificial bilayer to study membranes’ biophysical properties. The liposome morphology can be described as an aqueous core surrounded by one or many lipid bilayers, a lipid phase preferred by cylindrical space-filling lipid molecules. The amphiphilic bilayer, typically comprised of phospholipids and sterols, resembles biological cell membranes and facilitates cellular endocytosis and subsequent cellular uptake. Led by the efforts of Gregory Gregoriadis in the 1970s, liposomes would be revealed as ideal DDS solutions for pharmaceutical applications. This research would provide the first knowledge of the complex relationship between the physical properties of nanomedicines and the biological milieu in vivo. By 1995, a liposomal formulation of doxorubicin (Doxil®) would become the first FDA-approved nano DDS.


CORE ISSUE: SOLID LIPID NANOPARTICLES AND NANOSTRUCTURED LIPID CARRIERS

Solid lipid nanoparticles (SLN) are lipid-based nanocarriers made with high phase transition lipids that are solid at body temperature and stabilized by emulsifiers. The SLN has a different morphology from liposomes in that it contains a solid lipid interior that appears as an electrondense core in electron micrographs. SLN can be manufactured in the nanoscale size range and have good long-term stability with nonpolar API. Unfortunately, SLN shows poor drug loading efficiency and exhibits difficult-to-control drug release characteristics. Recently, advanced methods to produce nanostructured lipid carriers (NLC) with solid and liquid phase lipid components were designed to overcome the limitations of SLN. NLCs show improved drug loading capacity in the lipid matrix core and demonstrate ideal and predictable drug release profiles. 

GENE THERAPY AND MRNA VACCINES: THE DELIVERY SOLUTION FOR GENETIC PAYLOADS

The ability to treat rare and previously undruggable diseases by expressing therapeutic or mutated proteins, silencing pathological genes, or editing the native genome of patients has become a clinical reality. Current examples of nucleic acid therapeutics that have been approved or are in late-stage clinical trials include antisense oligonucleotides (ASO), small interfering RNA (siRNA), messenger RNA (mRNA), and plasmid DNA (pDNA). The emergence of mRNA vaccines, whereby viral antigens are expressed by host cell machinery before immunization, has allowed researchers to develop solutions to the COVID-19 pandemic with unprecedented speed. This is largely due to the 20+ years of proven clinical and commercial success of LNPs as an effective and safe delivery agent for genetic payloads like mRNA and DNA. Considering any gene in the human genome is druggable, gene therapeutics is poised to become the future of modern medicine and allow researchers to conquer rare, incorrigible ailments. Alas, nucleic acids are volatile and require a delivery vehicle to protect the genetic cargo and facilitate entry into the target cells in vivo. Initial efforts to encapsulate and deliver DNA and RNA with lipid-based formulations involved passive encapsulation strategies with neutral, zwitterionic lipid formulations. To improve the loading efficiency of often expensive nucleic acid payloads, cationic lipids (e.g., DOTAP, DOTMA) were incorporated into liposomal formulations to boost encapsulation through electrostatic lipid/DNA lipoplexes. Lipoplex-mediated delivery of gene therapy has shown considerable utility for in vitro transfection experiments (e.g., Lipofectamine®). However, the complexation process parameters are spontaneous and difficult to control, resulting in particles characterized by wide size distributions ranging from the nanoscale up to several microns. According to FDA guidance for GMP Drug Manufacturers, control over particle size and particle distribution are important for any lipid-based drug delivery system. As manufacturing methods for lipid-based solutions in nanomedicine have advanced, the focus has moved toward LNP morphology for the delivery of nucleic acids in the pharmaceutical industry.

LIPID NANOPARTICLES:

The development of mRNA vaccines in the fight against COVID-19 is one of the most important medical discoveries of the 21st century. Predictably, LNP formulations are quickly becoming the gold standard for nucleic acid delivery. Initial investigations with LNP formulations began with the spontaneous assembly of lipid-nucleic acid complexes internalized and stabilized in a lipid core, analogous to NLC morphology discussed herein. LIPID NANOPARTICLES: SOLID LIPID NANOPARTICLES (SLN) AND NANOSTRUCTURE LIPID CARRIERS (NLC) www.ttscientific.com 06 Figure 3. Comparison of lipoplex and LNP morphology with encapsulated nucleic acid cargo T&T Scientific is home to the world’s most advanced and cutting-edge lipid nanoparticle technologies and services. T&T Scientific offers pharmaceutical technologies to manufacture lipid nanoparticles for pharmaceutical vaccines, therapeutics, and diagnostics and has customers in over 60 countries. T&T also provides contract research and manufacturing services in its 15,000 sq. ft. stateof-the-art FDA-registered facility. Their technologies include NanoSizer MINI, AUTO, FLOW, ProFECT protected with over 10 US and international patents. These platforms represent the most advanced pharmaceutical lipid nanoparticle technologies. T&T Scientific Services T&T Scientific Products Formulation and Discovery at T&T’s CRO Pharmaceutical Development at Our CDMO Pharmaceutical cGMP Manufacturing at Our CDMO NanoSizer AUTO Extrusion Technology NanoSizer FLOW Solvent Injection Technology ProFECT : Proprietary & Patent Protected Licensable Lipid Nanoparticle Technology TM TM TM The first LNP formulations employed a detergent dialysis method for production, often employed to encapsulate hydrophilic API in hybrid NLC formulations. The introduction of ionizable cationic lipids combined with ethanol injection and microfluidic techniques has provided a scalable manufacturing method to achieve high loading efficiencies of nucleic acids in monodisperse LNP less than 100 nm in diameter. These LNP systems exhibit low surface charge, which helps overcome noted toxicity and pharmacokinetic issues in vivo.

About T&T Scientific 

T&T Scientific is home to the world’s most advanced and cutting-edge lipid nanoparticle technologies and services. T&T Scientific offers pharmaceutical technologies to manufacture lipid nanoparticles for pharmaceutical vaccines, therapeutics, and diagnostics and has customers in over 60 countries. T&T also provides contract research and manufacturing services in its 15,000 sq. ft. stateof-the-art FDA-registered facility. Their technologies include NanoSizer MINI, AUTO, FLOW, ProFECT protected with over 10 US and international patents. These platforms represent the most advanced pharmaceutical lipid nanoparticle technologies.

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