Lipid-Drug Conjugate for Enhancing Drug Delivery

Abstract

Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. The conjugation of lipids to drug molecules increases lipophilicity and also changes other properties of drugs. The conjugates demonstrate several advantages including improved oral bioavailability, improved targeting to the lymphatic system, enhanced tumor targeting, and reduced toxicity. Based on the chemical nature of drugs and lipids, various conjugation strategies and chemical linkers can be utilized to synthesize LDCs. Linkers and/or conjugation methods determine how drugs are released from LDCs and are critical for the optimal performance of LDCs. In this review, different lipids used for preparing LDCs and various conjugation strategies are summarized. Although LDCs can be administered without a delivery carrier, most of them are loaded into appropriate delivery systems. The lipid moiety in the conjugates can significantly enhance drug loading into hydrophobic components of delivery carriers and thus generate formulations with high drug loading and superior stability. Different delivery carriers such as emulsions, liposomes, micelles, lipid nanoparticles, and polymer nanoparticles are also discussed in this review.

Keywords: chemical bonds; conjugation; drug delivery; lipid; prodrug.

Figure 1

Conjugation strategies for synthesizing LDCs. (A) Drugs can be conjugated with fatty acids at the carboxylic acid end or an ω-carbon. (B) Drugs can be conjugated with steroids at the hydroxyl group of the steroidal ring system. (C) Drugs can be conjugated to glycerides at the sn2 hydroxyl. (D) Drugs can be conjugated to phospholipids via the sn2 hydroxyl group or via phosphate group to form a phosphoester.

Figure 2

Various chemical bonds used for preparing LDCs. (A) Ester bond: Paclitaxel conjugated with oleic acid via ester bond. (B) Amide bond: Gemcitabine conjugated with stearic acid via amide bond. (C) Hydrazone bond: Doxorubicin conjugated with palmitic acid via a hydrazone bond. (D) Disulfide bond: Mitomycin C conjugated with lipid through a disulfide bond.

Figure 3

LDC enhanced drug targeting into lymph system. Triglyceride (TG) mimetic prodrugs are converted to monoglyceride (MG) and fatty acid (FA) in the GI tract through hydrolysis. The absorbed MG and FA are resynthesized to TG in enterocytes. TG will be incorporated into lipoproteins and be transported into the lymph system. Similarly, other lipophilic LDC (log P > 5) will also be transferred into lymph system.

Figure 4

Lipophilic siRNA conjugates have different in vivo activities. (a) Structure of lipid conjugated siRNAs. The desired lipid (L) is conjugated to the 3′-end of the sense strand of the apoB siRNA4 (siRNA-apoB1) via a trans-4-hydroxyprolinol linker (Hyp). Sense 5′-GUCAUCACACUGAAUACCAAU*Hyp-L-3′ and antisense 5′-AUU-GGUAUUCAGUGUGAUGAc*a*C-3′. Lowercase letters represent 2′-O-methyl-sugar-modified nucleotides, and asterisks stand for phosphorothioate backbone. (b) Chemical structure of different lipids used for synthesizing lipid conjugated siRNAs. (c) In vivo silencing of apoB mRNA by lipid conjugated siRNAs. Liver apoB mRNA levels were normalized to GAPDH mRNA 24 h after three daily intravenous injections of saline or 50 mg/kg stearoyl-siRNA-apoB1, dodecyl-siRNA-apoB1, lithocholic-oleyl-siRNA-apoB1, or docosanyl-siRNA-apoB1 (n = 5 per group). Data show apoB mRNA levels as a percentage of the saline treatment group and are expressed as mean ± SD. Data marked with asterisks are statistically significant relative to the saline treatment group as calculated by ANOVA without replication, alpha value 0.05 (*, P < 0.05; **, P < 0.005). Reprinted with permission from ref . Copyright 2007 Nature Publishing Group.

Figure 5

Different delivery carriers for LDCs: (A) emulsion, (B) liposome, (C) micelle, (D) lipid nanoparticle, (D) polymer nanoparticle, and (F) carbon nanotube.