Synthesis of Doxorubicin α-Linolenic Acid Conjugate and Evaluation of Its Antitumor Activity

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.

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“…54 Hydrazone bonds have been successfully used to synthesize pH-sensitive lipid conjugated doxorubicin (Figure 2C). 55–57 …”

Section: Chemical Bondsmentioning

confidence: 99%

Lipid–Drug Conjugate for Enhancing Drug Delivery

2017

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“…At the difference with ester or amide linkages between the phenolic compound and the PUFA part, non hydrolysable bounds have been obtained [38] [18][19]29] (dopamine and analogues) 11 [26,29,67] (vanillyl amine) 14 [17] ( [28] (Farinosone C analogue) 21 [20] (juglone) 22 [23] (shikonin) Dox-hyd-PUFA: 24a Dox-3-ami-PUFA: 24b (doxorubicin) [25,[63][64][65] 23 [27] (podophyllotoxin analogue) DDPT 15 [37] (phloroglucinol) 4'-PUFA:17a [22,37] 3-DHA: 17b (resveratrol) 18 [21] (trimethoxy anilide) 19 [24,66] (diisopropylphenol) 3 5 4' 3 3 2 [34][35] (EGC) 3 [36] (quercetin) 4 [15] (naringin) 5 [10][11][13][14][15] (rutin) 6 [12] (phloridzin) 7 [12] (isoquercitrin) 8 [38] 9 [30] 10 [ linker [39]. Since pH in tumor cells is lower than in healthy tissue, the hydrazone bond, stable at pH 7.4, is rapidly cleaved at lower pH in cancerous cells.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…However, saturated heptadecanoyl analogue reduced metabolic activity of the cell lines more than the unsaturated DOX-hyd-ALA. In parallel, Liang et al [65] studied in vitro (MCF-7, MDA-MB-231, and HepG2) and in vivo (mice) activities of DOX-ALA and DOX-PA (palmitate) either linked through an hydrazone bound (DOX-Hyd-ALA 24a) or by the daunosamine residue (DOX-ami-ALA 24b). In this study, saturated or unsaturated fatty acid on the 3 0 amino group lead to a decrease in antitumor activity compared to DOX and DOX-hyd-ALA. DOX-hyd-ALA showed the highest cytotoxicity, stability in bloodstream, and fastest release of DOX in acidic tumor cells.…”

Section: Anti-cancer Activitymentioning

confidence: 99%

“…However Zhong et al reported an increased activity of the EGCG-PUFA esters (1) compared to EGCG after oral administration [31]. Liang et al studied the stability of DOX-hyd ALA 24a and DOX-ami-ALA 24b in rat serum [65]. The results clearly demonstrate the stability of the hydrazone and the amide bound that released less than 25% of Doxorubicine in 48 h. Siddiqui et al studied the stability of Propofol-DHA (19), a diisopropylphenol conjugate of DHA, in human and mouse serum at 37 C for 2 h [66].…”

Section: From Administration To the Cellsmentioning

confidence: 99%

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Omega-3 polyunsaturated lipophenols, how and why?

et al. 2016

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Polyphenols and n-3 polyunsaturated fatty acids (PUFAs) are two classes of natural compounds, which have been highlighted in epidemiological studies for their health benefits. The biological activities of those two families of metabolites on oxidation, inflammation, cancer, cardiovascular and degenerative diseases have been reported in vitro and in vivo. On the other hand, chemical bonding between the two structures leading to n-3 lipophenol derivatives (or phenolipids) has been studied in numerous works over the last decade, and some examples could also be found from natural sources. Interest in lipophilization of phenolic structures is various and depends on the domain of interest: in food industry, the development of lipidic antioxidants could be performed to protect lipidic food matrix from oxidation. Whereas, on pharmaceutical purpose, increasing the lipophilicity of polar phenolic drugs could be performed to improve their pharmacological profile. Moreover, combining both therapeutic aspects of n-3 PUFAs and of polyphenols in a single lipophenolic molecule could also be envisaged. An overview of the synthesis and of the natural sources of n-3 lipophenols is presented here, in addition to their biological activities which point out in several cases the benefit of the conjugated derivatives.

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“…It is also reported that fatty acids exhibit broad spectrum of activity which make them attractive molecules for preparing various biologically active compounds of interest in biomedical fields. In view of these properties, various fatty acids have been combined with therapeutically active compounds to produce novel hybrid molecules anticipating enhanced biological activity 13,14 .…”

Section: Introductionmentioning

confidence: 99%