What are Lipid-Drug Conjugates (LDCs)?

Lipid-drug conjugates (LDCs) technology is to form new compounds by covalent binding of drugs and lipids, that is, lipophilic modification of drugs by medium and long chain fatty acids, glycerides or phospholipids, giving drugs new dissolution characteristics. LDC has many advantages in drug delivery:

1) Lipophilic modification can significantly change the physical and chemical properties of drug molecules, significantly improve the lipophilicity of the drug and the ability to be encapsulated by lipid carriers, and increase the transmembrane ability, thereby improving the pharmacokinetics and pharmacodynamic behavior of the drug.

2) Lipophilic modification can be considered as introducing lipid ligands into the structure of drug molecules, which is more conducive to the recognition and uptake of LDC by various active receptors on biological membranes, and promotes the active transport and absorption of drugs.

3) Lipophilic modification can increase drug stability, avoid first-pass effects, and improve bioavailability.

4) Lipophilic modified LDC has the advantages of controlled release, targeting tumor cells, enhancing efficacy, prolonging action time, reducing adverse reactions of the original drug, and reducing toxicity.

Currently, the U.S. Food and Drug Administration (FDA) has approved several peptide fatty acid conjugates, such as insulin detemir injection (insulin detemir) and liraglutide (liraglutide). LDC is one of the breakthroughs in promoting drug absorption, targeting tumors and enhancing efficacy. It is also a hot topic in the current field of pharmacy and related scientific research, and has eye-catching application prospects.

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Lipid-Drug Conjugation Strategies

The lipid materials commonly used in LDC are fatty acids, glycerides and phospholipids, and the carboxyl, hydroxyl or phosphate groups in their structures are active sites for the reaction. These active functional groups form covalent bonds with the drug through an acylation reaction, aiming to increase the lipid solubility of the drug. The way different lipid materials covalently bond with drugs is shown in Fig 1.

Conjugation strategies for synthesizing LDCsFig. 1. Conjugation strategies for synthesizing LDCs (Mol Pharm. 2017, 14(5): 1325-1338).

The covalent bonds formed between drugs and fatty acid conjugates mostly exist in the form of ester bonds or amide bonds. Saturated fatty acids contain carboxyl groups (-COOH), and drug structures often contain hydroxyl groups (-OH) or amino groups (-NH2). In order to increase the reactivity of fatty acids, fatty acids are usually converted into more active fatty acyl chlorides, and then acylated with drugs in a weakly alkaline environment to obtain drug-lipid conjugates. For the reaction between drugs and unsaturated fatty acids, in addition to the binding site of the carboxyl group, addition reactions can also be performed at the position of the unsaturated bond (ω-position) to introduce the fatty chain into the structure of the drug.

Drugs bind to glycerides in a manner similar to fatty acids, and since diglycerides and monoglycerides contain two and single hydroxyl groups (-OH) in their structures, respectively, drugs containing carboxyl groups are often considered good candidates. If there is no carboxyl group in the drug structure, the intermediate succinic acid can be introduced during the reaction, but it may affect the drug release, which in turn affects the drug activity.

The phospholipid structure contains not only hydroxyl groups but also phosphate groups, so it has two binding sites, but most reactions focus on the hydroxyl group of the phosphate group. In addition, some recently reported synthesis methods of phospholipids and drugs are to replace the aliphatic chain part at the sn-2 position in the phospholipid molecule with drugs. This synthesis mostly adopts an enzyme-catalyzed reaction to hydrolyze glycerol phosphate through phospholipases A2 (PLA2). The ester bond at the sn-2 position of the ester is removed, and 1 molecule of fatty acid is removed, so that the sn-2 position has an active reactive group hydroxyl group, and the drug molecule is combined with the hydroxyl group in the form of a covalent bond.

Types of Lipid-Drug Conjugates (LDCs)

Fatty acids, glycerides and phospholipids are mostly derived from natural animal and vegetable oils. They are not only highly lipophilic, but also have good safety and compatibility, so they are the best materials for preparing LDC. According to the type of lipid material, LDC is divided into fatty acids, glycerides, phospholipids and cholesterol-drug conjugates. Different drug-lipid conjugates produce different biological activities.

LDC enhanced drug targeting into lymph systemFig. 2. LDC enhanced drug targeting into lymph system (Mol Pharm. 2017, 14(5): 1325-1338).

Conjugate Drugs with Fatty Acids

Since there are many types of fatty acids, we will discuss them in two types: saturated fatty acids and unsaturated fatty acids.

  • Conjugate Drugs with Saturated Fatty Acids

There are currently many literature reports on the use of saturated fatty acids for lipophilic modification of drugs, including short, medium and long-chain fatty acids, covering a wide range of drugs. After modifying the hydrophilic diminazene with stearic acid (C18), Olbrich et al. found that the lipophilicity of the conjugate was enhanced, which prolonged the release rate of the drug in the body and indirectly played a role in the targeted treatment of sleepiness. The stearic acid (C18)-decitabine synthesized by Neupane et al. significantly increased the permeability of the rat small intestine, thereby promoting the absorption of the original drug. Lauric acid (C12)-thyrotropin releasinghormone increased the lipophilicity of the original drug. The intestinal perfusion experiment showed that the conjugate significantly increased the absorption of the intestinal segment and maintained the original activity.

  • Conjugate Drugs with Unsaturated Fatty Acids

LDC prepared from unsaturated fatty acids is mainly used in anti-tumor applications. Most of them are long-chain unsaturated fatty acids with more than 16 carbon atoms (C16), such as oleic acid, linolenic acid, docosahexaenoic acid (DHA) and squalene, etc. Camptothecin and its derivatives have strong anti-tumor effects. Because their structure contains a lactone ring, their water solubility and stability are poor. After the introduction of lipids into the structure of camptothecin derivatives, its stability has been greatly improved (steric hindrance effect avoids ring-opening degradation of the lactone ring), and avoids metabolic inactivation after the original drug enters the body and binds to plasma proteins. Secondly, it shows high anti-cancer activity against a variety of tumor cells (T-47D, Caco-2 and Raji cells) and enhances the uptake rate of Caco-2 cells.

Conjugate Drugs with Glycerides

Glycerides are combined with a variety of drugs with different activities, including antivirals, nonsteroidal anti-inflammatory drugs, and antineoplastic drugs.

  • Glyceride-Antiviral Conjugates

The typical drug is didanosine, which belongs to nucleoside anti-HIV drugs. It has strong hydrophilicity, is prone to first-pass effect, and has low bioavailability. Skanji et al. designed the conjugate of dedanoxin and diacylglycerol. The pharmacokinetic study found that the half-life of dedanoxin-lipid conjugate was prolonged by 3 times, and a large number of conjugates still existed in different tissues at 24 h time point, and the conjugate had a significant inhibitory effect on HIV-1 virus.

  • Glyceride-NSAID Conjugates

Because nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal irritation adverse reactions, the lipophilic modification of ibuprofen or mefenamic acid with glycerides was carried out in order to obtain safe and effective anti-inflammatory drugs. The concentrations of ibuprofen and methanoate-glyceride conjugates in plasma were higher than those of the original drug, which improved the oral bioavailability and delayed the time of maximum anti-inflammatory activity. In particular, the methanoate-glycerol ester conjugate showed a strong analgesic effect, and the gastric stimulation of the two LDCs was lower than that of the original drug.

  • Glyceride-Antineoplastic Drug Conjugates

In order to increase the anti-tumor effect of drugs, the design of lipophilic anti-tumor drugs has become one of the hotspots in the field of pharmacy. For example, after melphalan and methotrexate were modified with diacylglycerol, the lipophilicity of the original drug was significantly increased. In particular, the methotrexate-glycerol conjugate overcomes the drug resistance of tumor cells and has a significant inhibitory effect on the folate carrier necessary for the growth of tumor cells. The effect of inhibiting folic acid is 114 times that of the original drug.

Conjugate Drugs with Phospholipids

At present, research on phospholipid prodrugs mainly focuses on anti-tumor drugs. There are also a few literature reports on phospholipid modification of non-steroidal anti-inflammatory drugs and antiviral drugs. Here are some typical examples of drugs using phospholipid modification. Prostaglandin drugs can inhibit the growth of tumor cells, and their anti-tumor activity is directly proportional to the lipophilicity of the drug. Therefore, Pedersen et al. designed prostaglandin-phospholipid conjugates and found through stability experiments that PLA2 can hydrolyze LDC. In cytotoxicity experiments, prostaglandin-phospholipid conjugates produced lethal effects on HT-29 and Colo205 tumor cells regardless of the presence or absence of PLA2, indicating that the conjugates inhibited tumor cell growth. Deoxycytidine analog-phospholipid conjugates are toxic to MCF-7 tumor cells and BC-19 cells that represent multidrug resistance expression, indicating that LDC has a significant inhibitory effect on tumor cells prone to drug resistance. In addition, gemcitabine-phospholipid conjugates among deoxycytidine analogs are well tolerated and can prolong patient survival time and improve survival rate. The cytotoxicity test of bexarotene-phospholipid conjugate showed that the anti-tumor activity was stronger than that of its original drug. Although the oral bioavailability of cladribine and fludarabine-phospholipid conjugates is equivalent to that of the original drugs, their inhibitory effect on malignant tumor cells is lower than that of the original drugs. Through degradation experiments, it was found that LDC hydrolyzes to release the original drug slowly, and only the original drug has anti-tumor activity, so it exhibits sustained low and slow biological activity.

Conjugate Drugs with Steroids

Cholesterol and cholic acid derivatives are steroids bound to drug molecules. In most studies, the hydroxyl group attached to the steroid ring is the primary site for conjugation. Combining drugs with cholesterol has the advantages of reduced side effects, targeted tumor delivery, and efficient cellular uptake. Cancer cells overexpress low-density lipoprotein (LDL) receptors and require large amounts of cholesterol to grow rapidly. Therefore, cholesterol-drug conjugates help load anticancer drugs into lipoproteins. In addition, as endogenous carriers, lipoprotein-loaded drugs can effectively target LDL receptors on malignant cells. For example, cholesterol-conjugated 5-fluorouracil (5-FU) exhibits better anticancer effects than free unconjugated 5-FU. The conjugation strategy uses the hydroxyl group on cholesterol to form a carbonyl linkage with fluorouracil. Cholesterol conjugates have also been formed with paclitaxel and small interfering RNA (siRNA).

Cholic acid is another steroid used in lipid drug conjugates in the form of ursodeoxycholic acid (UDCA) and lithocholic acid. Unlike cholesterol, UDCA has three hydroxyl groups available for conjugation. The OH functionality furthest from the steroid ring system has been used as the conjugation site. For example, bile acid-conjugated zidovudine (AZT) could potentially enhance its antiviral efficacy against HIV because it reduces hydrolysis rates in human plasma, enhances CNS permeability, and reduces transport-mediated resistance sex.

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

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