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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 22502

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Dr. Masood Alam Khan

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Guest Editor

College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
Interests: immunology; microbiology; biotechnology; biomedical science; immunology of infectious diseases; inflammation

Special Issue Information

Dear Colleagues,

The present Special Issue, Lipids in Drug Delivery and Therapeutics, will deal with the role of lipids in therapy with and the drug delivery of important therapeutic agents, including chemotherapeutic drugs, DNA, RNA, proteins, and natural compounds. Moreover, this Special Issue also invites manuscripts showing the role of lipids in vaccine and antigen delivery to develop effective vaccines against infectious diseases and tumors. The topic of the papers includes the preparation and characterization of novel formulations, their safety, and toxicity in vitro and in vivo systems, their stability and the release kinetics of the entrapped drugs, and their localization within cells. Importantly, it will focus on their therapeutic applications in:
• Natural and synthetic lipids
• Liposomes
• Drug delivery and targeting
• The prophylactic and therapeutic role of lipids
• Lipids in vaccine formulations

Dr. Masood Alam Khan
Guest Editor

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Published Papers (8 papers)

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Research

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16 pages, 4100 KiB

Open AccessArticle

Membrane-Disruptive Effects of Fatty Acid and Monoglyceride Mitigants on E. coli Bacteria-Derived Tethered Lipid Bilayers

by Sue Woon Tan, Bo Kyeong Yoon and Joshua A. Jackman

Molecules 2024, 29(1), 237; https://doi.org/10.3390/molecules29010237 - 1 Jan 2024

Cited by 1 | Viewed by 2167

Abstract

We report electrochemical impedance spectroscopy measurements to characterize the membrane-disruptive properties of medium-chain fatty acid and monoglyceride mitigants interacting with tethered bilayer lipid membrane (tBLM) platforms composed of E. coli bacterial lipid extracts. The tested mitigants included capric acid (CA) and monocaprin (MC) with 10-carbon long hydrocarbon chains, and lauric acid (LA) and glycerol monolaurate (GML) with 12-carbon long hydrocarbon chains. All four mitigants disrupted E. coli tBLM platforms above their respective critical micelle concentration (CMC) values; however, there were marked differences in the extent of membrane disruption. In general, CA and MC caused larger changes in ionic permeability and structural damage, whereas the membrane-disruptive effects of LA and GML were appreciably smaller. Importantly, the distinct magnitudes of permeability changes agreed well with the known antibacterial activity levels of the different mitigants against E. coli, whereby CA and MC are inhibitory and LA and GML are non-inhibitory. Mechanistic insights obtained from the EIS data help to rationalize why CA and MC are more effective than LA and GML at disrupting E. coli membranes, and these measurement capabilities support the potential of utilizing bacterial lipid-derived tethered lipid bilayers for predictive assessment of antibacterial drug candidates and mitigants. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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22 pages, 4407 KiB

Open AccessArticle

Oral Bioactive Self-Nanoemulsifying Drug Delivery Systems of Remdesivir and Baricitinib: A Paradigmatic Case of Drug Repositioning for Cancer Management

by Mohsin Kazi, Yousef Alanazi, Ashok Kumar, Ahmad Abdul-Wahhab Shahba, Syed Rizwan Ahamad and Khalid M. Alghamdi

Molecules 2023, 28(5), 2237; https://doi.org/10.3390/molecules28052237 - 28 Feb 2023

Cited by 8 | Viewed by 2863

Abstract

Oral anticancer therapy mostly faces the challenges of low aqueous solubility, poor and irregular absorption from the gastrointestinal tract, food-influenced absorption, high first-pass metabolism, non-targeted delivery, and severe systemic and local adverse effects. Interest has been growing in bioactive self-nanoemulsifying drug delivery systems (bio-SNEDDSs) using lipid-based excipients within nanomedicine. This study aimed to develop novel bio-SNEDDS to deliver antiviral remdesivir and baricitinib for the treatment of breast and lung cancers. Pure natural oils used in bio-SNEDDS were analyzed using GC-MS to examine bioactive constituents. The initial evaluation of bio-SNEDDSs were performed based on self-emulsification assessment, particle size analysis, zeta potential, viscosity measurement, and transmission electron microscopy (TEM). The single and combined anticancer effects of remdesivir and baricitinib in different bio-SNEDDS formulations were investigated in MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. The results from the GC-MS analysis of bioactive oils BSO and FSO showed pharmacologically active constituents, such as thymoquinone, isoborneol, paeonol and p-cymenene, and squalene, respectively. The representative F5 bio-SNEDDSs showed relatively uniform, nanosized (247 nm) droplet along with acceptable zeta potential values (+29 mV). The viscosity of the F5 bio-SNEDDS was recorded within 0.69 Cp. The TEM suggested uniform spherical droplets upon aqueous dispersions. Drug-free, remdesivir and baricitinib-loaded bio-SNEDDSs (combined) showed superior anticancer effects with IC50 value that ranged from 1.9–4.2 µg/mL (for breast cancer), 2.4–5.8 µg/mL (for lung cancer), and 3.05–5.44 µg/mL (human fibroblasts cell line). In conclusion, the representative F5 bio-SNEDDS could be a promising candidate for improving the anticancer effect of remdesivir and baricitinib along with their existing antiviral performance in combined dosage form. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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22 pages, 3748 KiB

Open AccessArticle

The Fundamental Role of Lipids in Polymeric Nanoparticles: Dermal Delivery and Anti-Inflammatory Activity of Cannabidiol

by Mark Zamansky, Na’ama Zehavi, Amnon C. Sintov and Shimon Ben-Shabat

Molecules 2023, 28(4), 1774; https://doi.org/10.3390/molecules28041774 - 13 Feb 2023

Cited by 6 | Viewed by 2085

Abstract

This report presents a nanoparticulate platform for cannabidiol (CBD) for topical treatment of inflammatory conditions. We have previously shown that stabilizing lipids improve the encapsulation of CBD in ethyl cellulose nanoparticles. In this study, we examined CBD release, skin permeation, and the capability of lipid-stabilized nanoparticles (LSNs) to suppress the release of IL-6 and IL-8. The nanoparticles were stabilized with cetyl alcohol (CA), stearic acid (SA), lauric acid (LA), and an SA/LA eutectic combination (SALA). LSN size and concentration were measured and characterized by differential scanning calorimetry (DSC), in vitro release of loaded CBD, and skin permeability. IL-6 and IL-8 secretions from TNF-α-induced HaCaT cells were monitored following different LSN treatments. CBD released from the LSNs in dispersion at increasing concentrations of polysorbate 80 showed non-linear solubilization, which was explained by recurrent precipitation. A significant high release of CBD in a cell culture medium was shown from SALA-stabilized nanoparticles. Skin permeation was >30% lower from SA-stabilized nanoparticles compared to the other LSNs. Investigation of the CBD-loaded LSNs’ effect on the release of IL-6 and IL-8 from TNF-α-induced HaCaT cells showed that nanoparticles stabilized with CA, LA, or SALA were similarly effective in suppressing cytokine release. The applicability of the CBD-loaded LSNs to treat topical inflammatory conditions has been supported by their dermal permeation and release inhibition of pro-inflammatory cytokines. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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20 pages, 5212 KiB

Open AccessArticle

The Development and Optimization of Lipid-Based Self-Nanoemulsifying Drug Delivery Systems for the Intravenous Delivery of Propofol

by Mohsin Kazi, Athba Alqahtani, Majed Alharbi, Ajaz Ahmad, Muhammad Delwar Hussain, Hani Alothaid and Mohammed S. Aldughaim

Molecules 2023, 28(3), 1492; https://doi.org/10.3390/molecules28031492 - 3 Feb 2023

Cited by 7 | Viewed by 3191

Abstract

Purpose: Propofol is a relatively short-acting potent anesthetic lipophilic drug used during short surgical procedures. Despite the success of propofol intravenous emulsions, drawbacks to such formulations include inherent emulsion instability, the lack of a safe vehicle to prevent sepsis, and concern regarding hyperlipidemia-related side effects. The aim of the current investigation was to develop a novel, lipid-based self-nanoemulsifying drug delivery system (SNEDDS) for propofol with improved stability and anesthetic activity for human use. Methods: A series of SNEDDS formulations were developed using naturally obtained medium-chain/long-chain mono-, di-, and triglycerides, glyceryl monocaprylate, and water-soluble cosolvents with hydrogenated castor oil constructing ternary phase diagrams for propofol. The developed SNEDDS formulations were characterized using visual observation, particle size analysis, zeta potential, transmission electron microscopy, equilibrium solubility, in vitro dynamic dispersion and stability, and in vivo sleeping disorder studies in rats. The in vivo bioavailability of the SNEDDSs in rats was also studied to compare the representative formulations with the marketed product Diprivan^®. Results: Medium-chain triglycerides (M810) with mono-diglycerides (CMCM) as an oil blend and hydrogenated castor oil (KHS15) as a surfactant were selected as key ingredients in ternary phase diagram studies. The nanoemulsifying regions were identified from the studies and a number of SNEDDSs were formulated. Results from the characterization studies demonstrated the formation of efficient nanosized particles (28–45 nm globule size, 0.10–0.20 PDI) in the optimized SNEDDS with a drug loading of 50 mg/g, which is almost 500-fold higher than free propofol. TEM analysis showed the formation of spherical and homogeneous nanoparticles of less than 50 nm. The dissolution rate of the representative SNEDDS was faster than raw propofol and able to maintain 99% propofol in aqueous solution for around 24 h. The optimized liquid SNEDDS formulation was found to be thermodynamically stable. The intravenous administration of the SNEDDS in male Wistar rats induced a sleeping time of 73–88 min. The mean plasma concentrations after the IV administration of propofol nano-formulations PF2-SNEDDS and PF8-SNEDDS were 1348.07 ± 27.31 and 1138.66 ± 44.97 µg/mL, as compared to 891.44 ± 26.05 µg/mL (p = 0.05) observed after the IV administration of raw propofol. Conclusion: Propofol-loaded SNEDDS formulations could be a potential pharmaceutical product with improved stability, bioavailability, and anesthetic activity. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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11 pages, 2017 KiB

Open AccessArticle

Polyamidoamine Dendron-Bearing Lipids as Drug-Delivery Excipients

by Ender Sarigul, Merve Zaim, Mehmet Senel, Tugba Sagir and Sevim Isik

Molecules 2022, 27(22), 7817; https://doi.org/10.3390/molecules27227817 - 13 Nov 2022

Cited by 2 | Viewed by 1692

Abstract

An amine-terminated polyamidoamine (PAMAM) dendron and two long alkyl groups were designed as a novel drug carrier that possesses an interior for the encapsulation of drugs and a biocompatible surface. We synthesized three dendron-bearing lipids, DL-G1, DL-G2, and DL-G3, which included first, second, and third generation polyamidoamine dendrons, respectively. The synthesized dendrimer encapsulating anticancer drug, 5-fluorouracil (5-FU), was prepared by extraction with chloroform from mixtures of the dendrimers and varying amounts of the drug. In vitro cytotoxicity of PAMAM conjugated di-n-dodecylamine micelles (G1, G2, G3) were analyzed on human gastric adenocarcinoma cells (AGS) by water-soluble tetrazolium-1 (WST-1) cell proliferation assay. Upon exposure to 5-FU loaded micelles, the viability of the cells decreased gradually in all generations. Cytotoxicity increased with increasing generation and reached its highest rate of 69.8 ± 3.2% upon 15 µM 5FU-loaded 25 µM PAMAM DL-3 micelle treatment. These results demonstrate that 5FU-loaded PAMAM conjugated di-n-dodecylamine treatment inhibits the proliferation of AGS cells in a generation-dependent manner. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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19 pages, 4851 KiB

Open AccessArticle

Glycosphingolipids (GSLs) from Sphingomonas paucimobilis Increase the Efficacy of Liposome-Based Nanovaccine against Acinetobacter baumannii-Associated Pneumonia in Immunocompetent and Immunocompromised Mice

by Masood Alam Khan, Khaled S. Allemailem, Hamzah Maswadeh and Hina Younus

Molecules 2022, 27(22), 7790; https://doi.org/10.3390/molecules27227790 - 12 Nov 2022

Cited by 2 | Viewed by 1630

Abstract

Due to the high propensity of drug resistance in Acinetobacter baumannii, the number of currently available therapeutic drugs has become very limited. Thus, it becomes incredibly important to prepare an effective vaccine formulation capable of eliciting an effective immune response against A. baumannii. In this study, we prepared a liposomal vaccine formulation bearing glycosphingolipids (GSLs) from Sphingomonas paucimobilis and loaded with the whole cell antigen (WCAgs-GSLs-liposomes) of A. baumannii. The immune-stimulating potential and prophylactic efficacy of WCAgs-GSLs-liposomes were compared with those of WCAgs-liposomes (without GSLs) or free WCAgs in both immunocompetent and immunodeficient mice. The efficacy of vaccine formulations was determined by analyzing antibody titer, cytokine levels, and survival studies in the immunized mice. The findings revealed that vaccination with WCAgs-GSLs-liposomes stimulated a greater secretion of antibodies and cytokines, higher lymphocyte proliferation, and increased expression of the co-stimulatory molecules. Anti-sera from WCAgs-GSLs-liposomes-immunized mice remarkably reduced the biofilm formation by A. baumannii. Most importantly, WCAgs-GSLs-liposomes-vaccinated mice demonstrated a higher defiance against the pathogen, as compared to the immunizations with WCAgs-liposomes (without GSLs) or free WCAgs. Immunocompetent mice immunized with WCAgs-GSLs-liposomes showed a 100% survival rate, while those immunized with WCAgs-liposomes exhibited a 60% survival rate. The protective effect of WCAgs-GSLs-liposomes was also found to be higher in immunocompromised mice, as the immunized mice showed a 50% survival rate, which was greater than the 20% survival rate of those immunized with WCAgs-liposomes. The survival data was also supported by the findings of bacterial load and histological analysis that substantiated the greatest prophylactic potential of the WCAgs-GSLs-liposomes. These findings recommend that WCAgs-GSLs-liposomes may be reckoned as a prospective vaccine to protect the persons against A. baumannii infection. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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24 pages, 7146 KiB

Open AccessArticle

Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis

by Faris Alrumaihi, Masood Alam Khan, Ali Yousif Babiker, Mohammed Alsaweed, Faizul Azam, Khaled S. Allemailem, Ahmad A. Almatroudi, Syed Rizwan Ahamad, Mahdi H. Alsugoor, Khloud Nawaf Alharbi, Nahlah Makki Almansour and Arif Khan

Molecules 2022, 27(7), 2192; https://doi.org/10.3390/molecules27072192 - 28 Mar 2022

Cited by 9 | Viewed by 2642

Abstract

Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC₁₀, IC₂₅, and IC₃₅ of DATSL with the IC₁₀ of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC₅₀ doses by more than 8- and 14-fold, respectively. However, the DATSL IC₁₀, IC₂₅, and IC₃₅ showed escalating chemosensitivity, and treated the cells in combination with DOXL IC₁₀. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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Review

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31 pages, 3499 KiB

Open AccessReview

A Review of Different Types of Liposomes and Their Advancements as a Form of Gene Therapy Treatment for Breast Cancer

by Gloria Yi Wei Tseu and Khairul Azfar Kamaruzaman

Molecules 2023, 28(3), 1498; https://doi.org/10.3390/molecules28031498 - 3 Feb 2023

Cited by 32 | Viewed by 5643

Abstract

Breast cancer incidence and mortality rates have increased exponentially during the last decade, particularly among female patients. Current therapies, including surgery and chemotherapy, have significant negative physical and mental impacts on patients. As a safer alternative, gene therapy utilising a therapeutic gene with the potential to treat various ailments is being considered. Delivery of the gene generally utilises viral vectors. However, immunological reactions and even mortality have been recorded as side effects. As a result, non-viral vectors, such as liposomes, a system composed of lipid bilayers formed into nanoparticles, are being studied. Liposomes have demonstrated tremendous potential due to their limitless ability to combine many functions into a system with desirable characteristics and functionality. This article discusses cationic, anionic, and neutral liposomes with their stability, cytotoxicity, transfection ability, cellular uptake, and limitation as a gene carrier suitable for gene therapy specifically for cancer. Due to the more practical approach of employing electrostatic contact with the negatively charged nucleic acid and the cell membrane for absorption purposes, cationic liposomes appear to be more suited for formulation for gene delivery and therapy for breast cancer treatment. As the other alternatives have numerous complicated additional modifications, attachments need to be made to achieve a functional gene therapy system for breast cancer treatment, which were also discussed in this review. This review aimed to increase understanding and build a viable breast cancer gene therapy treatment strategy. Full article

(This article belongs to the Special Issue Lipids in Drug Delivery and Therapeutics)

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