Lipid Nanoparticles for Small Molecule Delivery

Lipid nanoparticles (LNPs) are a multifunctional drug delivery system that has demonstrated significant advantages in small molecule drug delivery and are widely used in the pharmaceutical and biomedical fields. These nanoparticles are primarily composed of lipids, enabling them to effectively encapsulate hydrophobic or amphipathic drug molecules, protecting them from degradation and enhancing bioavailability. LNPs provide a highly customizable platform that can achieve controlled drug release and enhance targeted delivery to specific tissues or cells. This characteristic is particularly important in the field of drug delivery, especially concerning the encapsulation and release of small molecule drugs, which directly impacts therapeutic outcomes.

What are Small Molecule Drugs?

Small molecule drugs are a class of chemical compounds with a low molecular weight (typically less than 500 Da) that can cross cell membranes and interact with intracellular molecular targets to regulate biological processes. These drugs are typically synthesized through chemical methods and, compared to macromolecular drugs (such as proteins and antibodies), are characterized by low molecular weight, simple structures, and high chemical stability. Small molecule drugs are widely used to treat various diseases, including cancer, infectious diseases, metabolic disorders, and cardiovascular diseases. Due to their ability to bind directly to molecular targets such as enzymes, receptors, ion channels, and nucleic acids, small molecule drugs exhibit significant biological activity within organisms. Compared to biologics, small molecules still hold notable advantages in several areas:

• Oral Bioavailability: Most small molecule drugs can be administered orally, providing convenience for patients.
• Wide Tissue Penetration: Because small molecule drugs can pass through cell membranes, they can target a wide range of intracellular sites.
• Lower Production Costs: The chemical synthesis of small molecule drugs is less expensive than biologics, and their manufacturing processes are more easily scalable.

Types of Small Molecule Drugs

As an essential component of traditional medicine, small molecule drugs are widely used in the treatment of various diseases. These drugs operate through different mechanisms and have high potential for drug development and market demand. Based on their mechanisms of action, targets, and pharmacological properties, small molecule drugs can be classified into several categories. The following table summarizes common classifications of small molecule drugs and their specific applications.

Small Molecule Drugs vs Biologics

Biological drugs refer to substances produced from biological sources using techniques such as genetic engineering, antibody engineering, or cell engineering, which are used for in vivo diagnosis, treatment, or prevention. Specifically, biological drugs include hormones, enzymes, growth factors, vaccines, monoclonal antibodies, antisense oligonucleotides or nucleic acids, cell therapies, and tissue engineering products. Generally, small molecule drugs refer to compounds with a molecular weight of less than 1000 Da, and most small molecule drugs have a molecular weight of less than 500 Da. For example, the active ingredient in aspirin, acetylsalicylic acid (ASA), has a molecular weight of approximately 180 g/mol or 180 Da. In contrast, biological drugs are several hundred to even a thousand times larger in molecular weight, with monoclonal antibody drugs reaching molecular weights of up to 150,000 Da. The difference between these two types of drugs lies not only in their molecular size but, more importantly, in the complexity of their molecular structure. For example, protein drugs have primary structures (amino acid sequences), secondary structures (such as α-helices, β-sheets), and complex tertiary structures (further folding based on secondary structure). Some biological drugs' protein subunits form quaternary structures after binding via hydrophobic interactions, hydrogen bonds, and ionic bonds.

Small Molecule Drug Delivery

Small molecule drug delivery plays a crucial role in pharmacotherapy, ensuring drugs can effectively reach target tissues and exert therapeutic effects. Traditional delivery methods for small molecule drugs include oral, injection, transdermal, and inhalation routes. Oral delivery is the most common due to its convenience and higher patient compliance, especially for long-term treatments. However, oral drugs often face challenges from the gastrointestinal environment and first-pass metabolism, requiring good gastrointestinal absorption and metabolic stability. Injection delivery is commonly used for drugs that need to act quickly or are unsuitable for oral administration, such as anticancer drugs and vaccines. Transdermal and inhalation deliveries are suitable for local treatments and respiratory drugs, reducing systemic side effects. Despite some success in practical applications, these traditional delivery methods still face limitations in drug targeting, stability, and controlling side effects.

Fig. 1. Types of lipid nanoparticles (Adv. NanoBiomed Res. 2022, 2: 2100109).

In recent years, the use of LNPs in small molecule drug delivery has become a research hotspot. LNPs can effectively encapsulate drug molecules, protecting them from degradation, and enhancing their bioavailability and targeting. LNPs possess good biocompatibility and controllable drug release properties, allowing for precise drug delivery through adjustments in particle size and surface modifications. Especially in cancer therapy and vaccine delivery, LNPs have shown enormous potential. Through lipid nanoparticles, small molecule drugs can better penetrate cell membranes, target tumor cells, and improve therapeutic effects, while reducing side effects. Therefore, lipid nanoparticles are becoming an important tool in small molecule drug delivery, driving the development of modern drug therapy.

What are Lipid Nanoparticles?

Lipid nanoparticles (LNPs) are nanoscale particles primarily composed of lipids, typically consisting of four components: (i) Ionizable lipids: These enable the self-assembly of nanoparticles, improve drug encapsulation efficiency, and facilitate intracellular escape; (ii) Stabilizers: Used to enhance the stability of the nanoparticle structure and its ability to fuse with cell membranes, commonly including cholesterol or cholesterol analogs; (iii) Phospholipids: Used to increase the stability of the lipid structure of the nanoparticles; and (iv) PEG-lipids: By reducing non-specific binding with proteins and evading non-specific phagocytosis by the reticuloendothelial system (RES), these extend the half-life and circulation time in the body. These components improve the rigidity and dynamic stability of lipid nanoparticles, allowing them to effectively deliver small molecule drugs and also serve as efficient delivery vehicles for nucleic acid drugs (DNA and RNA).

Lipid Nanoparticle Formulation

BOC Sciences' lipid nanoparticle synthesis materials include various phospholipids, fatty acids, cholesterol derivatives, and other functional lipids, all with good biocompatibility and tunable physicochemical properties. These materials can be used to encapsulate a range of drugs, such as small molecule drugs, RNA, and DNA molecules, ensuring the stability, solubility, and targeted delivery of the drugs. We have extensive experience and expertise in lipid nanoparticle synthesis, and are capable of providing customized LNP preparation services to meet different drug delivery needs.

Lipid Nanoparticles in Small Molecule Delivery

Traditionally, LNPs have been referred to as liposomes, lipid polymers, solid lipid nanoparticles, nanostructured lipid nanoparticles, microemulsions, and nanoemulsions, primarily used for the release of small molecules and peptides. Recently, LNPs have become a drug delivery system for biopharmaceuticals, particularly for COVID-19 mRNA vaccines, where LNPs play a crucial role in transporting mRNA into target cells. Due to the unique properties and excellent biocompatibility of lipid materials, LNPs are suitable for nanodrugs, vaccines, nutritional supplements, and diagnostics through various routes of administration such as oral, topical, pulmonary, and parenteral injection.

Liquid Lipid Nanoparticles

Microemulsions and nanoemulsions are liquid lipid nanoparticles primarily composed of lipid carriers, cosolvents, surfactants, and cosurfactants. Depending on the amount of surfactant, microemulsions are thermodynamically stable lipid concentrates, while nanoemulsions are kinetically stable systems formed through high-energy input. In oral administration, lipid nanoparticles exist in the form of microemulsions, which form nanoparticles when diluted by gastrointestinal fluids, thereby increasing the solubility and bioavailability of poorly soluble drugs. Lipid nanoparticles enhance oral bioavailability by dissolving drugs, inhibiting efflux transporters, and bypassing first-pass metabolism. Common lipid concentrates include SEDDS and SMEDDS, which are suitable for the release of insoluble drugs. Nanoemulsions consist of nanoscale droplets and can be water-in-oil or oil-in-water types. Nanoemulsions possess small droplet sizes, a larger surface area, and lower surface tension, which solve issues related to drug solubility and permeability. Compared to microemulsions, nanoemulsions are more susceptible to Ostwald ripening, but with careful formulation, they can maintain physicochemical stability. Nanoemulsions have advantages in reducing injection pain, targeted delivery, and reducing drug toxicity. In recent years, lipid-based nanoemulsion drugs have been widely used, such as fat emulsion infusions and propofol emulsions, and have also been applied in vaccine adjuvants.

Solid Lipid Nanoparticles and Structured Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) were developed as alternative systems to existing emulsion formulations, where liquid lipids (i.e., oils) are replaced with solid lipids. SLNs not only retain the excellent biocompatibility, high bioavailability, nano-size, and large surface area of emulsions, but they also maintain high drug loading capacity and sustained release of drugs from their matrix. Structured lipid nanoparticles (NLCs) are introduced by adding a small amount of liquid lipids into solid lipids to overcome the potential issues of SLNs, such as drug crystallization or solid lipid transformation during storage. NLCs can be created by combining solid lipids with small amounts of liquid lipids or by introducing special lipids (such as stearic acid hydroxide and isopropyl myristate) into solid lipids to form non-crystalline structures. Like traditional emulsion formulations, SLNs/NLCs are composed of solid and/or liquid lipids, emulsifiers, and water. The lipids used can include triglycerides, partial glycerides, fatty acids, cholesterol, and waxes.

Liposomes and Lipid Complexes

Liposomes are nanoparticles composed of one or more lipid bilayers, ranging in size from 20 nm to 1000 nm. Liposomes can encapsulate both hydrophilic and hydrophobic drugs and are classified into multilamellar vesicles (MLV) and unilamellar vesicles (SUV and LUV). Their surface charge is determined by the lipid headgroups, and stability depends on the zeta potential. Unilamellar liposomes improve drug efficacy and reduce toxicity by altering the pharmacokinetics and biodistribution of the drugs. Successful liposome drugs include Doxil® for cancer treatment, Epaxal® for vaccines, Onpattro® for siRNA, and Comirnaty® for mRNA. Liposomes are typically composed of phospholipids (such as phosphatidylcholine and phosphatidylethanolamine) and auxiliary lipids (such as cholesterol). When designing liposomes, attention must be paid to phase transition temperatures, which affect liposome stability and drug release. RNA liposomes typically contain cationic lipids and auxiliary lipids, which enhance RNA encapsulation efficiency and reduce degradation. Ionizable cationic lipids are positively charged at low pH, aiding RNA encapsulation, and reduce RNA degradation at neutral pH. By adjusting the pH, RNA liposomes can enhance cellular uptake and RNA release. The mRNA vaccine lipid nanoparticles from Pfizer/BioNTech and Moderna have similar components, including ionizable lipids, PEGylated lipids, and phosphatidyl-dipalmitoylphosphatidylcholine.

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Reference

1. Xu, L. et al. Lipid Nanoparticles for Drug Delivery. Adv. NanoBiomed Res. 2022, 2: 2100109.