Lipid-Drug Conjugates (LDCs) for Nanoparticle Drug Delivery

Some drugs have the disadvantages of poor oral absorption, low efficacy, side effects and first-pass effects. Lipid-drug conjugates (LDCs) obtained by covalent bonding of lipid materials (fatty acids, glycerides, phospholipids, cholesterol, etc.) with drugs can increase the lipophilicity of the drug, promote its integration with the biofilm, make it easy to penetrate the biological barrier, promote absorption, and then improve the biological activity of the original drug. In addition, from the perspective of preparing nanocarriers, LDC significantly increases the ability of drugs to be encapsulated by lipid carriers. Some LDCs can self-assemble into lipid nanoparticles, which reduces the use of preparation excipients and is easy for industrial production.

Fig. 1. Lipid-drug conjugate for enhancing drug delivery (Mol Pharm. 2017, 14(5): 1325-1338).

What are Lipid Conjugated Nanoparticles?

The nanocarrier drug delivery system has smaller particle size and greater dispersion, which is beneficial to keeping the drug in a dissolved and dispersed state, and can increase the contact area between the drug and the gastrointestinal tract to promote drug dissolution. Currently, common drug-lipid conjugate nanocarrier preparations include: biodegradable nanoparticles (lipid nanoparticles and polymer nanoparticles), liposomes and micelles, etc. Because the materials of solid lipid nanoparticles (SLNs) and liposomes are mostly glycerides and phospholipids, they have good biocompatibility with LDC, especially SLNs are more likely to achieve the goal of high drug loading and high encapsulation efficiency, so they are commonly used dosage forms of LDC nanocarriers.

Advantages of Lipid-Drug Conjugates

LDCs have been successfully used to enhance the delivery of a variety of drugs, including small and large molecules. Conjugation of lipids significantly increases lipophilicity and changes the properties of the drug. These changes in drug properties may facilitate drug delivery to the lymphatic system, improve oral bioavailability, enhance tumor targeting, etc. Some LDCs can form self-assembling nanoparticles on their own and can be administered without any delivery vehicle. Currently, the advantages of lipid-drug conjugates include:

• Improving the performance of oral medications
• Improving anticancer drug delivery
• Promoting penetration into the brain
• Enhancing delivery of genetic medicines
• Facilitating loading of drugs into delivery vehicles
• Achieving extended drug release

Lipid Products for Nanoparticles

BOC Sciences is a leading supplier of nanoparticle lipid products serving the needs of researchers and industry in drug delivery, nanotechnology and biotechnology. We offer a broad range of lipid products and services to support the design, development and optimization of nanoparticles for a variety of applications. We offer a variety of lipid products, including ionizable lipids, phospholipids, cholesterol, PEG lipids, and surfactants, that can be used to formulate lipid nanoparticles with specific properties and functionality.

Delivery Systems for Lipid-Drug Conjugates

Lipid Nanoparticles

Lipid nanoparticles (NPs) can encapsulate LDC in a lipophilic core. The lipid core serves as a reservoir for payload lipophilic drugs. Hydrophilic drugs need to be converted into lipid-drug conjugates to enhance lipid nanoparticle loading. Both solid and liquid lipid nanoparticles have been used for the delivery of LDC. Yu et al. prepared lipid nanoparticles with water-soluble 5-fluorouracil (5-FU) -stearic acid (C18) conjugate by physical coacervation method. The average particle size of the lipid nanoparticles was 240.19 nm, and the drug loading was increased to 20.53%, which had obvious liver targeting effect. Li et al. used stearic acid-octaarginine-modified paclitaxel solid lipid nanoparticles to significantly promote the oral absorption of paclitaxel. Stevens et al. modified paclitaxel with cholesterol and then used dialysis to prepare SLNs. The average particle size is 130nm, the drug/lipid ratio is 1:20, the encapsulation rate is as high as 90%, and it has the effect of targeting folate receptors.

After the introduction of lipid molecules into the structure of some drugs, the fat solubility increases. When preparing nanoparticles, other lipid materials are not required, and the conjugate itself can be used as a skeleton material to prepare SLNs. The butyric acid-cholesterol conjugate synthesized by Minelli et al. was self-assembled into lipid nanoparticles by microemulsion method. The average particle size was about 80nm and the particle size distribution was 0.24. It showed good stability and could effectively inhibit tumor growth. Similarly, capecitabine-fatty acid conjugates were self-assembled into SLNs with a particle size of about 700nm by high-pressure homogenization, which had a strong inhibitory effect on animal breast cancer.

Polymer Nanoparticles

Polylactic-glycolic acid (PLGA) nanoparticles have been widely used for the delivery of LDC. For example, Dalpiaz et al. prepared PLGA NPs to encapsulate ursodeoxycholic acid (UCDA) conjugated to zidovudine (AZT). PLGA NPs were also used to deliver 4-(N)-stearoylgemcitabine. In other studies, PEG-PLA NPs were used to deliver LDC. The presence of PEG stabilizes NPs and prolongs drug circulation in the blood. SN-38 is a topoisomerase I inhibitor. This inhibitor is toxic, unstable, and incompatible with various delivery systems. The formation of tocopheryl succinate derivatives increases the affinity of SN-38 for NPs. PLGA NPs were also surface-modified with targeting ligands such as lectins, aptamers, and cetuximab. These targeting ligands enhance drug tumor cell targeting by interacting with tumor cell-specific receptors.

Micelles

Micelles are composed of amphiphilic macromolecules that can self-assemble into core-shell structured nanocarriers. The hydrophobic core can encapsulate hydrophobic drugs through non-covalent interactions. Conjugating drugs to lipids can significantly improve their interactions with the micelle core. This strategy improves the stability of drug-loaded micellar formulations. Several different micellar formulations have been used to deliver LDC. For example,  Zhu et al. designed a new acid-sensitive micelle loaded with gemcitabine-C18 conjugate. When the drug loading amount was 9.7%, the encapsulation rate was 95% and the particle size was approximately 52nm. In vivo animal experiments show that the micellar carrier prolongs the circulation time of LDC in the body, which is conducive to the accumulation of drugs in the tumor site. The anti-tumor activity of the LDC-carrying micelle group is much stronger than that of the LDC and gemcitabine solution groups. The same gemcitabine-C18 conjugate, PEGDSPE/TPGS mixed micelles prepared by Wang et al. has a particle size of 11.8nm, a PDI of 0.38, and a drug loading capacity and encapsulation efficiency of approximately 13% and 95%, respectively. Compared with the original drug, the LDC-loaded mixed micelles group significantly prolonged the circulation time, and the cumulative amount in the tumor site was 3 times that of the control group, indicating a good therapeutic effect on pancreatic cancer.

Liposomes

Liposomes have excellent encapsulation power, biocompatibility and safety, so liposomes are also a commonly used dosage form for preparing LDC nanocarriers. Pedersen et al. used palmitic acid (C16) and stearic acid (C18) to conjugate chlorambucil respectively, and the resulting liposomes had a particle size of approximately 86 to 125nm. In the presence of PLA2 enzyme, LDC is toxic to HT-29, MT-3 and ES-2 tumor cells. Gabizon et al. used a high-pressure homogenization method to prepare mitomycin-C-lipid conjugate liposomes, with a particle size of approximately 45 to 56nm and a drug/lipid ratio of 5:95 (w/w). Pharmacokinetic study results showed that the half-life of the LDC group was significantly prolonged and the anti-tumor effect was stronger than that of the control group. In addition, liposomes were prepared from LDCs such as gemcitabine, 5-fluorodeoxyuridine, and daunorubicin, and the anti-tumor activity of these LDC liposomes was studied. The tumor activity was higher than that of the original drug.

Emulsions

O/w emulsions are also frequently used to deliver LDC. Emulsions are biocompatible carriers that allow the incorporation of LDC into oil droplets. Emulsions improve LDC delivery by dissolving the drug, reducing toxicity, and reducing drug clearance. Studies have shown that the use of oil-in-water emulsions is well tolerated and can capture lipid-drug conjugates efficiently. In one study, researchers incorporated paclitaxel oleate into a nanoscale emulsion. Paclitaxel oleate nanoemulsion is less toxic than commercial paclitaxel formulations containing the toxic solvent Cremophor EL. Another study showed that dexamethasone palmitate (DXP) had higher encapsulation efficiency than unbound free dexamethasone.

Additionally, emulsions can be further modified to enhance their specificity and targeting capabilities. One study used cholesterol-rich microemulsions (LDEs) to carry paclitaxel oleate. The cholesterol component of the emulsion enhances targeting capabilities by binding its LDL carrier to its corresponding receptor and facilitates drug delivery and cellular internalization. LDL receptors are overexpressed on leukemia cells and other solid tumors. LDE paclitaxel oleate has been tested in clinical studies in patients with breast and gynecological cancers. LDE formulations showed improved PK properties, enhanced drug accumulation in tumors, and reduced toxicity.

Our Lipid Support Services

In addition to offering lipid products, BOC Sciences provides lipid support services to assist researchers in the development and characterization of lipid nanoparticles. Our experienced team of scientists can provide custom formulation services, lipid screening assays, and physicochemical analyzes to help optimize the design and performance of lipid-based drug delivery systems. By leveraging BOC Sciences' expertise and resources, researchers can accelerate the translation of their lipid nanoparticle formulations from the bench to the clinic.

Reference

1. Irby, D. et al. Lipid-Drug Conjugate for Enhancing Drug Delivery. Mol Pharm. 2017, 14(5): 1325-1338.