Lipid-based Delivery Systems Research Articles

Impact of excipient emulsions made from different types of oils on the bioavailability and metabolism of curcumin in gastrointestinal tract

Low bioavailability currently limits the potential of curcumin as a health-promoting dietary compound. This study therefore explored the potential of excipient emulsions to improve curcumin bioavailability. Oil-in-water excipient emulsions were prepared using different types of oils: corn oil, olive oil, and medium chain triglycerides (MCT). The excipient emulsions increased the transportation rate of curcumin across the Caco-2 cell monolayer and showed ability to protect curcumin from metabolism in the enterocytes, with the olive oil-based systems exhibiting the highest efficacy. In addition, most of curcumin metabolites were present as hexahydro-curcumin (HHC) and its conjugates. Our results show that excipient emulsions can improve curcumin bioavailability by increasing its trans-enterocyte absorption and reducing cellular metabolism. Moreover, they show that these effects depend on the type of oil used to produce them. These findings have important implications for the rational design of lipid-based delivery systems to enhance the bioavailability of hydrophobic nutraceuticals like curcumin.

Lipids and Lipid Derivatives for RNA Delivery.

RNA-based therapeutics have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown of pathological genes, expression of therapeutic proteins, and programmed gene editing. Due to the inherent instability and negative-charges of RNA molecules, RNA-based therapeutics can make the most use of delivery systems to overcome biological barriers and to release the RNA payload into the cytosol. Among different types of delivery systems, lipid-based RNA delivery systems, particularly lipid nanoparticles (LNPs), have been extensively studied due to their unique properties, such as simple chemical synthesis of lipid components, scalable manufacturing processes of LNPs, and wide packaging capability. LNPs represent the most widely used delivery systems for RNA-based therapeutics, as evidenced by the clinical approvals of three LNP-RNA formulations, patisiran, BNT162b2, and mRNA-1273. This review covers recent advances of lipids, lipid derivatives, and lipid-derived macromolecules used in RNA delivery over the past several decades. We focus mainly on their chemical structures, synthetic routes, characterization, formulation methods, and structure-activity relationships. We also briefly describe the current status of representative preclinical studies and clinical trials and highlight future opportunities and challenges.

A Systemic Review on the Self Micro Emulsifying Drug Delivery System

Comfort direction and painless method made oral route the most favored. Mainstream of recent active constituents have less oral bioavailability because of dissolution rate limited absorption. While many inventive methods like complexation, cocrystals exist, solid dispersions, pH modification and, lipid-based delivery systems conclusively improved appliance with the seeming rise in drug absorption. Among lipid-based formulations, self-micro emulsifying formulations (SMEDDS) (droplet size < 100 nm) are evident to enhance permeation across intestinal membrane, protection of drug against gastric effect, unit dosage is possible, increased bioavailability of drug, reduces the dose of drug etc. Numerous components are used to formulate these dosage forms like Oil, surfactants, Co-surfactant and lipids mixture contribute to the enhancement in oral bioavailability through promoting the lymphatic passage; thus, hepatic first pass metabolism can be overcoming. The present review highlights comprehensive information on the formulation design, probable mechanisms and characterization of SMEDDS

Lipid-Based Nanoparticles for Delivery of Vaccine Adjuvants and Antigens: Toward Multicomponent Vaccines.

Despite the many advances that have occurred in the field of vaccine adjuvants, there are still unmet needs that may enable the development of vaccines suitable for more challenging pathogens (e.g., HIV and tuberculosis) and for cancer vaccines. Liposomes have already been shown to be highly effective as adjuvant/delivery systems due to their versatility and likely will find further uses in this space. The broad potential of lipid-based delivery systems is highlighted by the recent approval of COVID-19 vaccines comprising lipid nanoparticles with encapsulated mRNA. This review provides an overview of the different approaches that can be evaluated for the design of lipid-based vaccine adjuvant/delivery systems for protein, carbohydrate, and nucleic acid-based antigens and how these strategies might be combined to develop multicomponent vaccines.

Physical Stability, Oxidative Stability, and Bioactivity of Nanoemulsion Delivery Systems Incorporating Lipophilic Ingredients: Impact of Oil Saturation Degree.

There is great interest in the application of a lipid-based delivery system (like nanoemulsion) to improve the bioavailability of lipophilic components. Although emulsion characteristics are believed to be influenced by oil types, there is still a lack of systematic research concentrating on the effect of oil saturation degree on the nanoemulsion quality, especially for evaluation of the bioactivity. Here, we aimed to test the effect of oil saturation degree on the physical stability, oxidative stability, and bioactivity of the designed nanoemulision system. Our findings suggest that the oxidative stability and bioactivity of a nanoemulsion incorporating tocopherol and sesamol highly depend on the oil saturation. A nanoemulsion with an oil with a high degree of unsaturation was more susceptible to oxidation, and addition of tocopherol and sesamol could retard the lipid oxidation. Sesamol exhibited better bioactivity during the experiment compared with tocopherol in the Caenorhabditis elegans (C. elegans) model. The lipid-lowering effect of tocopherol and sesamol increased with lower saturation oil groups. The antioxidant activity of tocopherol and sesamol was higher in the high saturation oil groups. Overall, the obtained data is meaningful for applications using the designed systems to deliver lipophilic ingredients.

Nanoencapsulation of lutein within lipid-based delivery systems: Characterization and comparison of zein peptide stabilized nano-emulsion, solid lipid nanoparticle, and nano-structured lipid carrier

Three lipid-based carriers encapsulating lutein, nano-emulsion (NE), solid lipid nanoparticle (SLN), and nano-structured lipid carrier (NLC), were developed from zein peptides hydrolyzed by trypsin (TZP) and flavourzyme (FZP) as stabilizers. The physiochemical properties of FZP and TZP were evaluated. The particle size, potential, microstructure, environmental stability, rheological properties, in vitro digestion stability, and bioavailability of the lutein-loaded NE, SLN, and NLC were compared. The results showed that the surface hydrophobicity of TZP was higher than that of FZP. Except for the SLN, most samples were stable against droplet aggregation during storage, and carriers stabilized by TZP exhibited more favorable storage stabilities than those prepared from FZP. All the samples presented characteristics of fluid with good fluidity. The bioavailability of lutein was between 42.61% and 62.81%. In summary, these results provide valuable insights into the design of lipid-based delivery systems for fat-soluble biologically active compounds using zein peptides as stabilizers.

Fabrication strategies and supramolecular interactions of polymer-lipid complex nanoparticles as oral delivery systems

Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug absorption. Both lipid-based (e.g., nanoemulsion, solid lipid nanoparticles) and polymer-based (e.g., protein and polysaccharide nanoparticles) nanoscale delivery systems have demonstrated capability to overcome some of these physiological barriers during transportation and metabolism stages. To better deal with those barriers, polymer-lipid complex nanoparticles are being explored and developed to merge the beneficial features and overcome the respective shortcomings of lipid-based and polymer-based nanoparticles. This paper aims to provide an overview of the various preparation strategies and supramolecular interactions of orally administered polymer-lipid complex nanoparticles by reviewing recent studies. Two types of polymer-lipid complex nanoparticles have been developed, i.e., lipid core with polymer shell nanoparticles and polymer core with lipid shell nanoparticles (lipid-polymer hybrid nanoparticles). Besides, both natural and synthetic polymers used for fabrication are discussed and their advantages and disadvantages are highlighted. Further research work is needed to optimize the fabrication and scaling up processes, so that these versatile polymer-lipid complex nanoparticles could have a significant impact on the oral delivery of nutrient/drug.

Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance.

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.

Systemic gene delivery using lipid envelope systems and its potential in overcoming challenges

Nonviral vectors which offer a safer and versatile alternative to viral vectors have been developed to overcome problems caused by viral carriers. However, their transfection efficacy or level of expression is substantially lower than viral vectors. Among various nonviral gene vectors, lipid envelops systems are an ideal platform for the incorporation of safety and efficacy into a single delivery system. Emerging strategies for gene delivery using lipid-based delivery systems mainly aim at improving the transfection efficiency and potency while reducing toxicity, achieving prolonged release, cell-specific targeting, co-delivery of drug and gene. Earlier efforts to improve the transfection efficiency while overcoming the toxicity led to the need for preparing conjugates of lipids with polyamines. In this review, we highlight current lipidic vectors that have been developed for gene therapy, challenges, and their solutions.

Insight Into the Prospects for RNAi Therapy of Cancer.

RNA interference (RNAi), also known as gene silencing, is a biological process that prevents gene expression in certain diseases such as cancer. It can be used to improve the accuracy, efficiency, and stability of treatments, particularly genetic therapies. However, challenges such as delivery of oligonucleotide drug to less accessible parts of the body and the high incidence of toxic side effects are encountered. It is therefore imperative to improve their delivery to target sites and reduce their harmful effects on noncancerous cells to harness their full potential. In this study, the role of RNAi in the treatment of COVID-19, the novel coronavirus disease plaguing many countries, has been discussed. This review aims to ascertain the mechanism and application of RNAi and explore the current challenges of RNAi therapy by identifying some of the cancer delivery systems and providing drug information for their improvement. It is worth mentioning that delivery systems such as lipid-based delivery systems and exosomes have revolutionized RNAi therapy by reducing their immunogenicity and improving their cellular affinity. A deeper understanding of the mechanism and challenges associated with RNAi in cancer therapy can provide new insights into RNAi drug development.

Rationale and Application of PEGylated Lipid-Based System for Advanced Target Delivery of siRNA.

RNA interference (RNAi) technology has become a powerful tool in application of unraveling the mechanism of disease and may hold the potential to be developed for clinical uses. Small interfering RNA (siRNA) can bind to target mRNA with high specificity and efficacy and thus inhibit the expression of related protein for the purpose of treatment of diseases. The major challenge for RNAi application is how to improve its stability and bioactivity and therefore deliver therapeutic agents to the target sites with high efficiency and accuracy. PEGylated lipid-based delivery system has been widely used for development of various medicines due to its long circulating half-life time, low toxicity, biocompatibility, and easiness to be scaled up. The PEGylated lipid-based delivery system may also provide platform for targeting delivery of nucleic acids, and some of the research works have moved to the phases for clinical trials. In this review, we introduced the mechanism, major challenges, and strategies to overcome technical barriers of PEGylated lipid-based delivery systems for advanced target delivery of siRNA in vivo. We also summarized recent advance of PEGylated lipid-based siRNA delivery systems and included some successful research works in this field.

Lipid-based carriers for food ingredients delivery

The encapsulation in the food industry has gained relevant importance, mainly due to its contribution to solve food problems by reducing the loss of nutrients, prolong the shelf-life, and improve food quality and safety. The lipid-based delivery systems as microemulsions, liposomes, solid lipid nanoparticles and nanostructured lipid carriers are widely used to deliver food ingredients due to their ability to protect and deliver it, enhancing its functionality and bioavailability. Despite the benefits on delivering food ingredients the toxicity profile of such carriers is usually neglected. The aim of this review is to provide a detailed overview on the application of lipid-based carriers to deliver food ingredients. Herein, the encapsulation advantages and disadvantages, and microencapsulation techniques used to obtain lipid-based carriers are discussed. More importantly, the different types of lipid-based carriers used for food ingredients delivery are thoroughly scrutinized, as well as their application in foods and possible toxicity concerns. • Food ingredients are loaded into lipid carriers to achieve high bioavailability. • Lipid carriers protect food ingredients from degradation increasing its shelf-life. • Microemulsions, liposomes, SLN and NLC provide to food superior added value. • Microencapsulation may be tuned to produce lipid carriers with desired properties. • Efforts are needed to have these systems in the market with good cost-effectiveness.

Environment-Responsive Lipid/siRNA Nanoparticles for Cancer Therapy.

RNA interference (RNAi) is a promising technology to regulate oncogenes for treating cancer. The primary limitation of siRNA for clinical application is the safe and efficacious delivery of therapeutic siRNA into target cells. Lipid-based delivery systems are developed to protect siRNA during the delivery process and to facilitate intracellular uptake. There is a significant progress in lipid nanoparticle systems that utilize cationic and protonatable amino lipid systems to deliver siRNA to tumors. Among these lipids, environment-responsive lipids are a class of novel lipid delivery systems that are capable of responding to the environment changes during the delivery process and demonstrate great promise for clinical translation for siRNA therapeutics. Protonatable or ionizable amino lipids and switchable lipids as well as pH-sensitive multifunctional amino lipids are the presentative environment-responsive lipids for siRNA delivery. These lipids are able to respond to environmental changes during the delivery process to facilitate efficient cytosolic siRNA delivery. Environment-responsive lipid/siRNA nanoparticles (ERLNP) are developed with the lipids and are tested for efficient delivery of therapeutic siRNA into the cytoplasm of cancer cells to silence target genes for cancer treatment in preclinical development. This review summarizes the recent developments in environment-response lipids and nanoparticles for siRNA delivery in cancer therapy.

Potential of Nanonutraceuticals in Increasing Immunity.

Nutraceuticals are defined as foods or their extracts that have a demonstrably positive effect on human health. According to the decision of the European Food Safety Authority, this positive effect, the so-called health claim, must be clearly demonstrated best by performed tests. Nutraceuticals include dietary supplements and functional foods. These special foods thus affect human health and can positively affect the immune system and strengthen it even in these turbulent times, when the human population is exposed to the COVID-19 pandemic. Many of these special foods are supplemented with nanoparticles of active substances or processed into nanoformulations. The benefits of nanoparticles in this case include enhanced bioavailability, controlled release, and increased stability. Lipid-based delivery systems and the encapsulation of nutraceuticals are mainly used for the enrichment of food products with these health-promoting compounds. This contribution summarizes the current state of the research and development of effective nanonutraceuticals influencing the body’s immune responses, such as vitamins (C, D, E, B12, folic acid), minerals (Zn, Fe, Se), antioxidants (carotenoids, coenzyme Q10, polyphenols, curcumin), omega-3 fatty acids, and probiotics.

Nanoformulation design and therapeutic potential of a novel tubulin inhibitor in pancreatic cancer

Successful treatment of pancreatic cancer remains a challenge due to desmoplasia, development of chemoresistance, and systemic toxicity. Herein, we synthesized (6-(3-hydroxy-4-methoxylphenyl)pyridin-2-yl) (3,4,5-trimethoxyphenyl)methanone (CH-3-8), a novel microtubule polymerization inhibitor with little susceptible to transporter-mediated chemoresistance. CH-3-8 binding to the colchicine-binding site in tubulin protein was confirmed by tubulin polymerization assay and molecular modeling. CH-3-8 disrupted microtubule dynamics at the nanomolar concentration in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines. CH-3-8 significantly inhibited the proliferation of these cells, induced G2/M cell cycle arrest, and led to apoptosis. CH-3-8 is hydrophobic with an aqueous solubility of 0.97 ± 0.16 μg/mL at pH 7.4. We further conjugated it with dodecanol through diglycolate linker to increase hydrophobicity and thus loading in lipid-based delivery systems. Hence, we encapsulated CH-3-8 lipid conjugate (LDC) into methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (mPEG-b-PCC-g-DC) polymeric nanoparticles (NPs) by solvent evaporation, resulting in a mean particle size of 125.6 ± 2.3 nm and drug loading of 10 ± 1.0% (w/w) while the same polymer could only load 1.6 ± 0.4 (w/w) CH-3-8 using the same method. Systemic administration of 6 doses of CH-3-8 and LDC loaded NPs at the dose of 20 mg/kg into orthotopic pancreatic tumor-bearing NSG mice every alternate day resulted in significant tumor regression. Systemic toxicity was negligible, as evidenced by histological evaluations. In conclusion, CH-3-8 LDC loaded NPs have the potential to improve outcomes of pancreatic cancer by overcoming transporter-mediated chemoresistance and reducing systemic toxicity.

Evolution of drug delivery system from viewpoint of controlled intracellular trafficking and selective tissue targeting toward future nanomedicine

Due to the rapid changes that have occurred in the field of drug discovery and the recent developments in the early 21st century, the role of drug delivery systems (DDS) has become increasingly more important. For the past 20 years, our laboratory has been developing gene delivery systems based on lipid-based delivery systems. One of our efforts has been directed toward developing a multifunctional envelope-type nano device (MEND) by modifying the particle surface with octaarginine, which resulted in a remarkably enhanced cellular uptake and improved intracellular trafficking of plasmid DNA (pDNA). When we moved to in vivo applications, however, we were faced with the PEG-dilemma and we shifted our strategy to the incorporation of ionizable cationic lipids into our system. This resulted in some dramatic improvements over our original design and this can be attributed to the development of a new lipid library. We have also developed a mitochondrial targeting system based on a membrane fusion mechanism using a MITO-Porter, which can deliver nucleic acids/pDNA into the matrix of mitochondria. After the appearance of antibody medicines, Opdivo, an immune checkpoint inhibitor, has established cancer immunology as the 4th strategy in cancer therapy. Our DDS technologies can also be applied to this new field of cancer therapy to cure cancer by controlling our immune mechanisms. The latest studies are summarized in this review article.

Wax-based delivery systems: Preparation, characterization, and food applications.

The development of lipid-based delivery systems has attracted much attention over the last years and a wide variety of strategies and formulations are currently available to encapsulate, protect, and target delivery of bioactive and functional lipophilic constituents within the food and pharmaceutical industries. Waxes are crystalline lipid material, consisting of a complex mixture of long-chain fatty acids and fatty alcohols, hydrocarbons, aldehydes, and ketones and show great promises as constituents of carrier systems. Most of waxes are classified under food-grade category and show high availability at a low cost. This review article has provided a comprehensive summary of research on major carriers containing wax as one of the main constituents, including solid lipid nanoparticles, nanostructured lipid carriers, oleogels, and Pickering emulsions, with a focus on their food applications. The physical and chemical nature of natural waxes are described in the first while the second part deals with the structure, formulation, main methods of preparation, characterization, and finally utilization of each type of wax-based delivery system for specific food applications.

Recent Advances in Lipid-based Nanodrug Delivery Systems in Cancer Therapy.

Cancer is the second leading cause of death globally, with every sixth death being attributable to cancer. Nevertheless, the efficacy of conventional chemotherapeutic drugs is often limited due to their poor solubility, unfavorable pharmacokinetic profile, and lack of tumor selectivity. The use of nanotechnology provides an opportunity to enhance the efficacy of a chemotherapeutic drug by improving its bioavailability and pharmacokinetic profile while facilitating preferential accumulation at the tumor tissue. To date, a variety of platforms have been investigated as nanocarriers in oncology, which include lipid-based, polymer-based, inorganic materials, and even viruses. Among different nanocarriers, lipid-based delivery systems have been extensively used in oncology because of their biocompatibility, biodegradability, ability to encapsulate diverse drug molecules, high temporal and thermal stability, and offer prolonged and controlled drug release. This review discusses the current status of the lipid-based nanocarriers and their applications in cancer treatment as well as an overview of the different liposomal formulations commercially available for cancer therapy.

Withdrawal Notice: Lipid Carriers Mediated Targeted Delivery of Neurotherapeuticals: Challenges, Role of Blood Brain Barrier and Promises of Nanotechnology Based Approaches in Neuronal Disorders

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Gelation of the internal core of liposomes as a strategy for stabilization and modified drug delivery I. Physico-chemistry study.

Since the application of nanotechnology to drug delivery, both polymer-based and lipid-based nanocarriers have demonstrated clinical benefits, improving both drug efficacy and safety. However, to further address the challenges of the drug delivery field, hybrid lipid-polymer nanocomposites have been designed to merge the beneficial features of both polymer-based and lipid-based delivery systems in a single nanocarrier. Within this scenario, this work is aimed at developing novel hybrid vesicles following the recent strategy of modifying the internal structure of liposomes. Specifically, polyethylene glycol-dimethacrylate (PEG-DMA, molecular weight 750 or 4000), was entrapped within unilamellar liposomes made of hydrogenated soybean phosphatidylcholine/cholesterol, and photo-crosslinked, in order to transform the aqueous inner core of liposomes into a soft and elastic hydrogel. After appropriate optimization of the preparation and gelation procedures, the primary objective of this work was to analyze the effect of the molecular weight of PEG-DMA on the main properties of these Gel-in-Liposome (GiL) systems. Indeed, by varying the molecular weight of PEG-DMA also its hydrophilic/lipophilic balance was modified and different arrangements of the polymer within the structure of liposomes as well as different interaction with their membrane were obtained. Both polymers were found in the inner core of the liposomes, however, the more hydrophobic PEG750-DMA also formed localized clusters within the liposome membrane, whereas the more hydrophilic PEG4000-DMA formed a polymeric corona on the vesicle surface. Preliminary cytotoxicity studies were also performed to evaluate the biological safety of these GiL systems and their suitability as innovative materials drug delivery application.