Highlight on lipids and its use for covalent and non-covalent conjugations
Keywords:Assay, (HPLC) High performance liquid chromatography, (AUP) Area under the peak, Ampicillin Trihydrate (AMP. Tri. H).
Lipids are organic fatty or waxy compounds which are used to make nanocarriers that are promising for drug delivery. When lipids associated covalently (lipid-drug conjugate LDC) or non- covalently (drug-lipid complex) to drugs to form Lipid Drug Conjugates (LDC). Most common types of lipids
used for drug conjugation are fatty acids, glycerides, steroids, and phospholipids. Conjugation with lipids may change the properties of the drug and significantly increase the drug lipophilicity. Lipid-drug conjugation could improve the delivery of drugs by the lymphatic system, enhance bioavailability of oral administered drugs, improve drug targeting in tumor diseases, enhance the loading of drugs into some delivery carriers, increase drug stability, and many others. Lipid-drug conjugates can be prepared through different strategies for conjugation and by chemical linkers depending on the chemical structure of both drugs and lipids, careful selection of lipids and drug are necessary in designing the lipid-drug conjugate to achieve maximum benefits.
Gurr MI, Harwood JL, Frayn KN, Murphy DJ, Michell RH. Lipids: biochemistry, biotechnology and health: John Wiley & Sons; 2016.
Kovačević AB. Lipid nanocarriers for delivery of poorly soluble and poorly permeable drugs. Nanopharmaceuticals: Elsevier; 2020. p. 151-74.
Lambert DM. Rationale and applications of lipids as prodrug carriers. European journal of pharmaceutical sciences. 2000;11: S15-S27.
Hussain A, Usman Mohd Siddique M, Kumar Singh S, Samad A, Beg S, Wais M. Lipid-drug conjugates for oral bioavailability enhancement. Recent Patents on Nanomedicine. 2015; 5:87-95.
Negi JS. Nanolipid Materials for Drug Delivery Systems: A Comprehensive Review. Characterization and Biology of Nanomaterials for Drug Delivery: Elsevier; 2019. p. 137-63.
Neupane YR, Sabir M, Ahmad N, Ali M, Kohli K. Lipid drug conjugate nanoparticle as a novel lipid nanocarrier for the oral delivery of decitabine: ex vivo gut permeation studies. Nanotechnology. 2013; 24:415102.
Irby D, Du C, Li F. Lipid–drug conjugate for enhancing drug delivery. Molecular pharmaceutics. 2017;14(5):1325-38.
Zaro JL. Lipid-based drug carriers for prodrugs to enhance drug delivery. The AAPS journal. 2015; 17:83-92.
Markovic M, Ben-Shabat S, Keinan S, Aponick A, Zimmermann EM, Dahan A. Prospects and challenges of phospholipid-based prodrugs. Pharmaceutics. 2018;10(4):210.
SUGIHARA J, FURUUCHI S, ANDO H, TAKASHIMA K, HARIGAYA S. Studies on intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving lymphatic absorption of naproxen and nicotinic acid. Journal of pharmacobio-dynamics. 1988;11(8):555-62.
Berry SE. Triacylglycerol structure and interesterification of palmitic and stearic acid-rich fats: an overview and implications for cardiovascular disease. Nutrition research reviews. 2009; 22:3-17.
Radwan AA, Alanazi FK. Targeting cancer using cholesterol conjugates. Saudi pharmaceutical journal. 2014; 22:3-16.
Wang H, Feng Z, Wu D, Fritzsching KJ, Rigney M, Zhou J, et al. Enzyme-regulated supramolecular assemblies of cholesterol conjugates against drug-resistant ovarian cancer cells. Journal of the American Chemical Society. 2016;138(34):10758-61.
Yadav K, Bhargava P, Bansal S, Singh M, Gupta S, Sandhu G, et al. Nature of the charged head group dictates the anticancer potential of lithocholic acid-tamoxifen conjugates for breast cancer therapy. MedChemComm. 2015; 6:778-87.
Khan I, Elhissi A, Shah M, Alhnan MA, Ahmed W. Liposome-based carrier systems and devices used for pulmonary drug delivery. Biomaterials and Medical Tribology: Elsevier; 2013. p. 395-443.
Fricker G, Kromp T, Wendel A, Blume A, Zirkel J, Rebmann H, et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharmaceutical research. 2010; 27:1469-86.
Alexander RL, Greene BT, Torti SV, Kucera GL. A novel phospholipid gemcitabine conjugate is able to bypass three drug-resistance mechanisms. Cancer chemotherapy and pharmacology. 2005; 56:15-21.
Mukherjee S, Ray S, Thakur R. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian journal of pharmaceutical sciences. 2009; 71:349.
MacDonald GE, Lada RR, Caldwell CD, Udenigwe C, MacDonald MT. Potential Roles of Fatty Acids and Lipids in Postharvest Needle Abscission Physiology. American Journal of Plant Sciences. 2019; 10:1069-89.
Babič A, Herceg V, Bastien E, Lassalle H-P, Bezdetnaya L, Lange N. 5-aminolevulinic acid-squalene nanoassemblies for tumor photodetection and therapy: In vitro studies. Nanoscale research letters. 2018;13(1):10.
Fumagalli G, Giorgi G, Vágvölgyi Mt, Colombo E, Christodoulou MS, Collico V, et al. Heteronanoparticles by Self-Assembly of Ecdysteroid and Doxorubicin Conjugates to Overcome Cancer Resistance. ACS medicinal chemistry letters. 2018;9(5):468-71.
Qiu Q, Li C, Song Y, Shi T, Luo X, Zhang H, et al. Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy. Acta biomaterialia. 2019; 92:184-95.
Ding Y, Nielsen KA, Nielsen BP, Bøje NW, Müller RH, Pyo SM. Lipid-drug-conjugate (LDC) solid lipid nanoparticles (SLN) for the delivery of nicotine to the oral cavity–optimization of nicotine loading efficiency. European Journal of Pharmaceutics and Biopharmaceutics. 2018; 128:10-7.
Wong T, Narayanan S, Brown DP, Chen Z-S. Synthesis and Cytotoxicity Studies of Stilbene Long-Chain Fatty Acid Conjugates. Journal of Natural Products. 2020.
Thanki K, Prajapati R, Sangamwar AT, Jain S. Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of Amphotericin B. International journal of pharmaceutics. 2018;544(1):1-13.
Chrzanowska A, Roszkowski P, Bielenica A, Olejarz W, Stępień K, Struga M. Anticancer and antimicrobial effects of novel ciprofloxacin fatty acids conjugates. European journal of medicinal chemistry. 2020; 185:111810.
Kubo T, Nishimura Y, Hatori Y, Akagi R, Mihara K, Yanagihara K, et al. Antitumor effect of palmitic acid‐conjugated Dsi RNA for colon cancer in a mouse subcutaneous tumor model. Chemical biology & drug design. 2019;93(4):570-81.
Du Y, Ling L, Ismail M, He W, Xia Q, Zhou W, et al. Redox sensitive lipid-camptothecin conjugate encapsulated solid lipid nanoparticles for oral delivery. International journal of pharmaceutics. 2018;549(1-2):352-62.
Jiang S, Liu Z, Wu L, Yuan Y, Hu Y, Zhang X, et al. Tumor targeting with docosahexaenoic acid‑conjugated docetaxel for inhibiting lung cancer metastasis to bone. Oncology letters. 2018;16(3):2911-20.
Mielczarek-Puta M, Struga M, Roszkowski P. Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA). Medicinal Chemistry Research. 2019;28(12):2153-64.
Augimeri G, Plastina P, Gionfriddo G, Rovito D, Giordano C, Fazio A, et al. N-Eicosapentaenoyl Dopamine, A Conjugate of Dopamine and Eicosapentaenoic Acid (EPA), Exerts Anti-inflammatory Properties in Mouse and Human Macrophages. Nutrients. 2019;11(9):2247.
Zahedifard F, Lee H, No JH, Salimi M, Seyed N, Asoodeh A, et al. Anti-leishmanial activity of Brevinin 2R and its Lauric acid conjugate type against L. major: In vitro mechanism of actions and in vivo treatment potentials. PLoS neglected tropical diseases. 2019;13(2):e0007217.
Morake M, Coertzen D, Ngwane A, Wentzel JF, Wong HN, Smit FJ, et al. Preliminary evaluation of artemisinin–cholesterol conjugates as potential drugs for the treatment of intractable forms of malaria and tuberculosis. ChemMedChem. 2018;13(1):67-77.
Chernikov IV, Meschaninova MI, Chernolovskaya EL. Preparation, Determination of Activity, and Biodistribution of Cholesterol-Containing Nuclease-Resistant siRNAs In Vivo. RNA Interference and CRISPR Technologies: Springer; 2020. p. 57-77.
Hu L, Quach T, Han S, Lim SF, Yadav P, Senyschyn D, et al. Glyceride‐mimetic prodrugs incorporating self‐immolative spacers promote lymphatic transport, avoid first‐pass metabolism, and enhance oral bioavailability. Angewandte Chemie International Edition. 2016; 55:13700-5.
Markovic M, Dahan A, Keinan S, Kurnikov I, Aponick A, Zimmermann EM, et al. Phospholipid-based prodrugs for colon-targeted drug delivery: experimental study and in-silico simulations. Pharmaceutics. 2019;11(4):186.
Ge L, He X, Zhang Y, Zhang Y, Chai F, Jiang L, et al. A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract. Nanomedicine: Nanotechnology, Biology and Medicine. 2018;14(4):1455-64.
Qin L, Niu Y, Wang Y, Chen X. Combination of phospholipid complex and submicron emulsion techniques for improving oral bioavailability and therapeutic efficacy of water-insoluble drug. Molecular pharmaceutics. 2018;15(3):1238-47.
Dahan A, Duvdevani R, Shapiro I, Elmann A, Finkelstein E, Hoffman A. The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. Journal of controlled release. 2008;126(1):1-9.
Semalty A, Semalty M, Singh D, Rawat M. Development and physicochemical evaluation of pharmacosomes of diclofenac. Acta Pharmaceutica. 2009; 59:335-44.
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin–phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. International journal of pharmaceutics. 2007; 330:155-63.
Olbrich C, Gessner A, Kayser O, Müller RH. Lipid-drug-conjugate (LDC) nanoparticles as novel carrier system for the hydrophilic antitrypanosomal drug diminazenediaceturate. Journal of drug targeting. 2002;10(5):387-96.
Jena SK, Singh C, Dora CP, Suresh S. Development of tamoxifen-phospholipid complex: novel approach for improving solubility and bioavailability. International journal of pharmaceutics. 2014;473(1-2):1-9.
Dora CP, Kushwah V, Katiyar SS, Kumar P, Pillay V, Suresh S, et al. Improved oral bioavailability and therapeutic efficacy of erlotinib through molecular complexation with phospholipid. International journal of pharmaceutics. 2017;534(1-2):1-13.
Lu Y, Zhang Y, Yang Z, Tang X. Formulation of an intravenous emulsion loaded with a clarithromycin–phospholipid complex and its pharmacokinetics in rats. International journal of pharmaceutics. 2009;366(1-2):160-9.
Chhikara BS, Mandal D, Parang K. Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate. Journal of medicinal chemistry. 2012; 55:1500-10.
Forrest ML, Yáñez JA, Remsberg CM, Ohgami Y, Kwon GS, Davies NM. Paclitaxel prodrugs with sustained release and high solubility in poly (ethylene glycol)-b-poly (ε-caprolactone) micelle nanocarriers: pharmacokinetic disposition, tolerability, and cytotoxicity. Pharmaceutical research. 2008; 25:194-206.
Duhem N, Danhier F, Pourcelle V, Schumers J-M, Bertrand O, LeDuff CcS, et al. Self-assembling doxorubicin–tocopherol succinate prodrug as a new drug delivery system: Synthesis, characterization, and in vitro and in vivo anticancer activity. Bioconjugate chemistry. 2013; 25:72-81.
Effenberger K, Breyer S, Schobert R. Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones. European journal of medicinal chemistry. 2010;45:1947-54.
Zalipsky S, Saad M, Kiwan R, Ber E, Yu N, Minko T. Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: insights of the mechanism of action. Journal of drug targeting. 2007;15:518-30.
Ashwanikumar N, Kumar NA, Nair SA, Kumar GV. 5-Fluorouracil–lipid conjugate: Potential candidate for drug delivery through encapsulation in hydrophobic polyester-based nanoparticles. Acta biomaterialia. 2014; 10:4685-94.
Semalty A, Semalty M, Rawat BS, Singh D, Rawat M. Pharmacosomes: the lipid-based new drug delivery system. Expert opinion on drug delivery. 2009;6(6):599-612.
Kuche K, Bhargavi N, Dora CP, Jain S. Drug-phospholipid complex—a go through strategy for enhanced oral bioavailability. AAPS PharmSciTech. 2019; 20:43.
Singh C, Bhatt TD, Gill MS, Suresh S. Novel rifampicin–phospholipid complex for tubercular therapy: synthesis, physicochemical characterization and in-vivo evaluation. International journal of pharmaceutics. 2014; 460:220-7.
Beg S, Raza K, Kumar R, Chadha R, Katare O, Singh B. Improved intestinal lymphatic drug targeting via phospholipid complex-loaded nanolipospheres of rosuvastatin calcium. RSC advances. 2016;6(10):8173-87.
Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J. Molecular cell biology. 6th ed: W. H. Freeman; 2007.
Adhikari P, Pal P, Das AK, Ray S, Bhattacharjee A, Mazumder B. Nano lipid-drug conjugate: An integrated review. International journal of pharmaceutics. 2017; 529:629-41.
Han S, Hu L, Quach T, Simpson JS, Edwards GA, Trevaskis NL, et al. Lymphatic transport and lymphocyte targeting of a triglyceride mimetic prodrug is enhanced in a large animal model: studies in greyhound dogs. Molecular pharmaceutics. 2016; 13:3351-61.
Semalty A, Semalty M, Singh D, Rawat M. Development and characterization of aspirin-phospholipid complex for improved drug delivery. International Journal of Pharmaceutical Sciences and Nanotechnology. 2010; 3:940-7.
Yatvin MB, Stowell MH. Covalent polar lipid-conjugates with biologically active compounds for use in salves. Google Patents; 2002.
Kurz M, Scriba GK. Drug–phospholipid conjugates as potential prodrugs: synthesis, characterization, and degradation by pancreatic phospholipase A2. Chemistry and physics of lipids. 2000;107(2):143-57.
Fisher RS, Ho J. Potential new methods for antiepileptic drug delivery. CNS drugs. 2002;16(9):579-93.
You Y-J, Kim Y, Nam N-H, Ahn B-Z. Antitumor activity of unsaturated fatty acid esters of 4′-demethyldeoxypodophyllotoxin. Bioorganic & medicinal chemistry letters. 2003; 13:2629-32.
Kawabata K, Takakura Y, Hashida M. The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharmaceutical research. 1995; 12:825-30.
Gupta A, Asthana S, Konwar R, Chourasia M. An insight into potential of nanoparticles-assisted chemotherapy of cancer using gemcitabine and its fatty acid prodrug: a comparative study. Journal of biomedical nanotechnology. 2013; 9:915-25.
Chue P, Chue J. A review of paliperidone palmitate. Expert review of neurotherapeutics. 2012; 12:1383-97.