Liposomal and Lipid-Based Drug Delivery Systems and Vaccines

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (10 November 2023) | Viewed by 25109

Special Issue Editor


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Guest Editor
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
Interests: liposomes; lipid-based formulations; drug delivery; lipid chemistry; synthesis; lipophilic prodrugs; vaccines; immunotherapy

Special Issue Information

Dear Colleagues,

After the discovery of liposomes by Bangham in the early 1960s, they have been explored extensively, both as vehicles for drug delivery and as adjuvant carriers in vaccinology, starting from the first works by Gregoriadis, Ryman, and Allison in the 1970s. The advantage of liposomal and related lipid-based formulations lies in their flexibility, high biocompatibility, and multifunctionality. Nowadays, along with significant successes in the production and clinical implementation of traditional small molecule drugs in liposomal formulations for the treatment of oncological diseases, the first lipid-based formulations for gene therapy are being introduced in clinics. Finally, against the background of pandemic challenges, it is noteworthy to cite Gregory Gregoriadis, “that it took fifty or so years for the two technologies, mRNA and lipid vesicles, to come together at more or less the same time of their need” (https://doi.org/10.1016/j.medidd.2021.100104).

This Special Issue is addressed to those authors who are currently engaged in research on the use of liposomes, lipid nanoparticles (non-vesicular supramolecular systems, as opposed to classical liposomes), and other lipid-based formulations for the development of drug delivery systems and vaccines. The issue is aimed at considering a wide variety of the aspects surrounding the creation and characterization of lipid-based formulations (structural and functional), including delivery systems for small molecule drugs, peptides, oligonucleotides, aptamers, proteins, antibodies, and nucleic acid molecules. Systems for the targeted delivery of therapeutic agents, both to organs and tissues and to intracellular organelles, will also be considered in the scope. The undesirable effects mediated by the immune system in response to the introduction of lipid-based formulations (such as hypersensitivity reactions and others) and the mechanisms of their emergence will also be addressed.

Dr. Elena L. Vodovozova
Guest Editor

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Keywords

  • liposomes
  • lipid nanoparticles
  • lipid-based formulations
  • drug delivery
  • gene delivery
  • mRNA and saRNA
  • vaccines
  • immunotherapy
  • nanomedicine

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Published Papers (10 papers)

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Editorial

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4 pages, 147 KiB  
Editorial
Editorial for Special Issue: “Liposomal and Lipid-Based Drug Delivery Systems and Vaccines”
by Elena L. Vodovozova
Pharmaceutics 2024, 16(2), 238; https://doi.org/10.3390/pharmaceutics16020238 - 6 Feb 2024
Cited by 1 | Viewed by 1451
Abstract
Liposomes and lipid-based supramolecular systems have been used in clinical practice for more than 30 years as drug carriers and vaccines for the treatment of oncological diseases and infections [...] Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)

Research

Jump to: Editorial, Review

12 pages, 1652 KiB  
Article
Enhancing T Cell and Antibody Response in Mucin-1 Transgenic Mice through Co-Delivery of Tumor-Associated Mucin-1 Antigen and TLR Agonists in C3-Liposomes
by Ameneh Arabi, Shahab Aria (Soltani), Brandon Maniaci, Kristine Mann, Holly Martinson and Max Kullberg
Pharmaceutics 2023, 15(12), 2774; https://doi.org/10.3390/pharmaceutics15122774 - 14 Dec 2023
Cited by 2 | Viewed by 1674
Abstract
Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds [...] Read more.
Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds for direct delivery to antigen-presenting cells (APCs). C3-liposomes bind complement C3, which interacts with C3-receptors on APCs, resulting in liposomal uptake and the delivery of tumor antigens to APCs in a manner that mimics pathogenic uptake. In this study, MUC1 and Toll-like receptor (TLR) agonists were encapsulated in C3-liposomes to provoke an immune response in transgenic mice tolerant to MUC1. The immune response to the C3-bound MUC1 liposomal vaccine was assessed by ELISA, ELISpot, and flow cytometry. Co-administering TLR 7/8 agonists with MUC1 encapsulated in C3-liposomes resulted in a significant antibody response compared to non-encapsulated MUC1. This antibody response was significantly higher in females than in males. The co-encapsulation of three TLR agonists with MUC1 in C3-liposomes significantly increased antibody responses and eliminated sex-based differences. Furthermore, this immunization strategy resulted in a significantly increased T cell-response compared to other treatment groups. In conclusion, the co-delivery of MUC1 and TLR agonists via C3-liposomes greatly enhances the immune response to MUC1, highlighting its potential for antigen-specific cancer immunotherapy. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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25 pages, 7001 KiB  
Article
Protein Corona Attenuates the Targeting of Antitumor Sialyl Lewis X-Decorated Liposomes to Vascular Endothelial Cells under Flow Conditions
by Natalia R. Onishchenko, Alexey A. Moskovtsev, Maria K. Kobanenko, Daria S. Tretiakova, Anna S. Alekseeva, Dmitry V. Kolesov, Anna A. Mikryukova, Ivan A. Boldyrev, Marina R. Kapkaeva, Olga N. Shcheglovitova, Nicolai V. Bovin, Aslan A. Kubatiev, Olga V. Tikhonova and Elena L. Vodovozova
Pharmaceutics 2023, 15(6), 1754; https://doi.org/10.3390/pharmaceutics15061754 - 16 Jun 2023
Cited by 3 | Viewed by 2064
Abstract
Previously, we showed in the human umbilical vein endothelial cells (HUVECs) model that a liposome formulation of melphalan lipophilic prodrug (MlphDG) decorated with selectin ligand tetrasaccharide Sialyl Lewis X (SiaLeX) undergoes specific uptake by activated cells and in an in vivo [...] Read more.
Previously, we showed in the human umbilical vein endothelial cells (HUVECs) model that a liposome formulation of melphalan lipophilic prodrug (MlphDG) decorated with selectin ligand tetrasaccharide Sialyl Lewis X (SiaLeX) undergoes specific uptake by activated cells and in an in vivo tumor model causes a severe antivascular effect. Here, we cultured HUVECs in a microfluidic chip and then applied the liposome formulations to study their interactions with the cells in situ under hydrodynamic conditions close to capillary blood flow using confocal fluorescent microscopy. The incorporation of 5 to 10% SiaLeX conjugate in the bilayer of MlphDG liposomes increased their consumption exclusively by activated endotheliocytes. The increase of serum concentration from 20 to 100% in the flow resulted in lower liposome uptake by the cells. To elucidate the possible roles of plasma proteins in the liposome–cell interactions, liposome protein coronas were isolated and analyzed by shotgun proteomics and immunoblotting of selected proteins. Proteomic analysis showed that a gradual increase in SiaLeX content correlated with the overall enrichment of the liposome-associated proteins with several apolipoproteins, including the most positively charged one, ApoC1, and serum amyloid A4, associated with inflammation, on the one hand, and a decrease in the content of bound immunoglobulins, on the other. The article discusses the potential interference of the proteins in the binding of liposomes to selectins of endothelial cells. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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27 pages, 7036 KiB  
Article
Multicomponent Lipid Nanoparticles for RNA Transfection
by Nataliya Gretskaya, Mikhail Akimov, Dmitry Andreev, Anton Zalygin, Ekaterina Belitskaya, Galina Zinchenko, Elena Fomina-Ageeva, Ilya Mikhalyov, Elena Vodovozova and Vladimir Bezuglov
Pharmaceutics 2023, 15(4), 1289; https://doi.org/10.3390/pharmaceutics15041289 - 20 Apr 2023
Cited by 7 | Viewed by 3071
Abstract
Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without [...] Read more.
Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without a hydrophobic core from natural lipids in order to evaluate the efficiency of LNPs with the widely used cationic lipoid DOTAP (1,2-dioleoyloxy-3-[trimethylammonium]-propane) and the previously unstudied oleoylcholine (Ol-Ch), as well as the ability of LNPs containing GM3 gangliosides to transfect cells with mRNA and siRNA. LNPs containing cationic lipids, phospholipids and cholesterol, and surfactants were prepared according to a three-stage procedure. The average size of the resulting LNPs was 176 nm (PDI 0.18). LNPs with DOTAP mesylate were more effective than those with Ol-Ch. Core LNPs demonstrated low transfection activity compared with bilayer LNPs. The type of phospholipid in LNPs was significant for the transfection of MDA-MB-231 and SW 620 cancer cells but not HEK 293T cells. LNPs with GM3 gangliosides were the most efficient for the delivery of mRNA to MDA-MB-231 cells and siRNA to SW620 cells. Thus, we developed a new lipid platform for the efficient delivery of RNA of various sizes to mammalian cells. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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18 pages, 3398 KiB  
Article
HER2/neu Oncogene Silencing in a Breast Cancer Cell Model Using Cationic Lipid-Based Delivery Systems
by Adhika Balgobind, Aliscia Daniels, Mario Ariatti and Moganavelli Singh
Pharmaceutics 2023, 15(4), 1190; https://doi.org/10.3390/pharmaceutics15041190 - 8 Apr 2023
Cited by 10 | Viewed by 2216
Abstract
The overexpression of the human epidermal growth factor 2 (HER2/neu) oncogene is predictive of adverse breast cancer prognosis. Silencing the HER2/neu overexpression using siRNA may be an effective treatment strategy. Major requirements for siRNA-based therapy are safe, stable, and efficient delivery [...] Read more.
The overexpression of the human epidermal growth factor 2 (HER2/neu) oncogene is predictive of adverse breast cancer prognosis. Silencing the HER2/neu overexpression using siRNA may be an effective treatment strategy. Major requirements for siRNA-based therapy are safe, stable, and efficient delivery systems to channel siRNA into target cells. This study assessed the efficacy of cationic lipid-based systems for the delivery of siRNA. Cationic liposomes were formulated with equimolar ratios of the respective cholesteryl cytofectins, 3β-N-(N′, N′-dimethylaminopropyl)-carbamoyl cholesterol (Chol-T) or N, N-dimethylaminopropylaminylsuccinylcholesterylformylhydrazide (MS09), with the neutral helper lipid, dioleoylphosphatidylethanolamine (DOPE), with and without a polyethylene glycol stabilizer. All cationic liposomes efficiently bound, compacted, and protected the therapeutic siRNA against nuclease degradation. Liposomes and siRNA lipoplexes were spherical, <200 nm in size, with moderate particle size distributions (PDI < 0.4). The siRNA lipoplexes exhibited minimal dose-dependent cytotoxicity and effective HER2/neu siRNA transfection in the HER2/neu overexpressing SKBR-3 cells. The non-PEGylated Chol-T-siRNA lipoplexes induced the highest HER2/neu silencing at the mRNA (10000-fold decrease) and protein levels (>111.6-fold decrease), surpassing that of commercially available Lipofectamine 3000 (4.1-fold reduction in mRNA expression). These cationic liposomes are suitable carriers of HER2/neu siRNA for gene silencing in breast cancer. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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15 pages, 9386 KiB  
Article
Efficient mRNA Delivery with mRNA Lipoplexes Prepared Using a Modified Ethanol Injection Method
by Min Tang, Ayane Sagawa, Nodoka Inoue, Satomi Torii, Kana Tomita and Yoshiyuki Hattori
Pharmaceutics 2023, 15(4), 1141; https://doi.org/10.3390/pharmaceutics15041141 - 4 Apr 2023
Cited by 8 | Viewed by 3052
Abstract
Messenger RNA (mRNA)-based therapies are a novel class of therapeutics used in vaccination and protein replacement therapies for monogenic diseases. Previously, we developed a modified ethanol injection (MEI) method for small interfering RNA (siRNA) transfection, in which cationic liposome/siRNA complexes (siRNA lipoplexes) were [...] Read more.
Messenger RNA (mRNA)-based therapies are a novel class of therapeutics used in vaccination and protein replacement therapies for monogenic diseases. Previously, we developed a modified ethanol injection (MEI) method for small interfering RNA (siRNA) transfection, in which cationic liposome/siRNA complexes (siRNA lipoplexes) were prepared by mixing a lipid-ethanol solution with a siRNA solution. In this study, we applied the MEI method to prepare mRNA lipoplexes and evaluated the in vitro and in vivo protein expression efficiencies. We selected six cationic lipids and three neutral helper lipids to generate 18 mRNA lipoplexes. These were composed of cationic lipids, neutral helper lipids, and polyethylene glycol-cholesteryl ether (PEG-Chol). Among them, mRNA lipoplexes containing N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16) or 11-((1,3-bis(dodecanoyloxy)-2-((dodecanoyloxy)methyl) propan-2-yl) amino)-N,N,N-trimethyl-11-oxoundecan-1-aminium bromide (TC-1-12) with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and PEG-Chol exhibited high protein expression in cells. Furthermore, mRNA lipoplexes composed of DC-1-16, DOPE, and PEG-Chol exhibited high protein expression in the lungs and spleen of mice after systemic injection and induced high antigen-specific IgG1 levels upon immunization. These results suggest that the MEI method can potentially increase the efficiency of mRNA transfection, both in vitro and in vivo. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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20 pages, 4059 KiB  
Article
Liposomal Forms of Fluoroquinolones and Antifibrotics Decorated with Mannosylated Chitosan for Inhalation Drug Delivery
by Irina Le-Deygen, Anastasia Safronova, Polina Mamaeva, Yana Khristidis, Ilya Kolmogorov, Anna Skuredina, Peter Timashev and Elena Kudryashova
Pharmaceutics 2023, 15(4), 1101; https://doi.org/10.3390/pharmaceutics15041101 - 29 Mar 2023
Cited by 5 | Viewed by 2289
Abstract
The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose [...] Read more.
The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose an approach to the creation of lipid–polymer delivery systems for fluoroquinolones and pirfenidone based on liposomes of various compositions decorated with mucoadhesive mannosylated chitosan. A generalizing study on the physicochemical patterns of the interactions of drugs with bilayers of various compositions was carried out, and the main binding sites were identified. The role of the polymer shell in the stabilization of vesicles and the delayed release of the contents has been demonstrated. For the liquid–polymer formulation of moxifloxacin, a prolonged accumulation of the drug in lung tissues was found after a single endotracheal administration to mice, significantly exceeding the control intravenous and endotracheal administration of the drug. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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13 pages, 3155 KiB  
Article
Influence of Lipid Composition of Cationic Liposomes 2X3-DOPE on mRNA Delivery into Eukaryotic Cells
by Vera Vysochinskaya, Sergey Shishlyannikov, Yana Zabrodskaya, Elena Shmendel, Sergey Klotchenko, Olga Dobrovolskaya, Nina Gavrilova, Darya Makarova, Marina Plotnikova, Ekaterina Elpaeva, Andrey Gorshkov, Dmitry Moshkoff, Mikhail Maslov and Andrey Vasin
Pharmaceutics 2023, 15(1), 8; https://doi.org/10.3390/pharmaceutics15010008 - 20 Dec 2022
Cited by 12 | Viewed by 3323
Abstract
The design of cationic liposomes for efficient mRNA delivery can significantly improve mRNA-based therapies. Lipoplexes based on polycationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were formulated in different molar ratios (1:1, 1:2, 1:3) to efficiently deliver model mRNAs to BHK-21 [...] Read more.
The design of cationic liposomes for efficient mRNA delivery can significantly improve mRNA-based therapies. Lipoplexes based on polycationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were formulated in different molar ratios (1:1, 1:2, 1:3) to efficiently deliver model mRNAs to BHK-21 and A549. The objective of this study was to examine the effect of 2X3-DOPE composition as well as lipid-to-mRNA ratio (amino-to-phosphate group ratio, N/P) on mRNA transfection. We found that lipoplex-mediated transfection efficiency depends on both liposome composition and the N/P ratio. Lipoplexes with an N/P ratio of 10/1 showed nanometric hydrodynamic size, positive ζ potential, maximum loading, and transfection efficiency. Liposomes 2X3-DOPE (1:3) provided the superior delivery of both mRNA coding firefly luciferase and mRNA-eGFP into BHK-21 cells and A549 cells, compared with commercial Lipofectamine MessengerMax. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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23 pages, 4704 KiB  
Article
Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning
by Darya A. Kuznetsova, Gulnara A. Gaynanova, Elmira A. Vasilieva, Rais V. Pavlov, Irina V. Zueva, Vasily M. Babaev, Denis M. Kuznetsov, Alexandra D. Voloshina, Konstantin A. Petrov, Lucia Y. Zakharova and Oleg G. Sinyashin
Pharmaceutics 2022, 14(9), 1950; https://doi.org/10.3390/pharmaceutics14091950 - 15 Sep 2022
Cited by 15 | Viewed by 2702
Abstract
One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were [...] Read more.
One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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Review

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18 pages, 1173 KiB  
Review
Design of Folate-Containing Liposomal Nucleic Acid Delivery Systems for Antitumor Therapy
by Elena V. Shmendel, Pavel A. Puchkov and Michael A. Maslov
Pharmaceutics 2023, 15(5), 1400; https://doi.org/10.3390/pharmaceutics15051400 - 3 May 2023
Cited by 3 | Viewed by 2200
Abstract
The delivery of therapeutic nucleic acids is a prospective method for the treatment of both inherited and acquired diseases including cancer. To achieve maximal delivery efficiency and selectivity, nucleic acids should be targeted to the cells of interest. In the case of cancer, [...] Read more.
The delivery of therapeutic nucleic acids is a prospective method for the treatment of both inherited and acquired diseases including cancer. To achieve maximal delivery efficiency and selectivity, nucleic acids should be targeted to the cells of interest. In the case of cancer, such targeting may be provided through folate receptors overexpressed in many tumor cells. For this purpose, folic acid and its lipoconjugates are used. Compared to other targeting ligands, folic acid provides low immunogenicity, rapid tumor penetration, high affinity to a wide range of tumors, chemical stability, and easy production. Different delivery systems can utilize targeting by folate ligand including liposomal forms of anticancer drugs, viruses, and lipid and polymer nanoparticles. This review focuses on the liposomal gene delivery systems that provide targeted nucleic acid transport into tumor cells due to folate lipoconjugates. Moreover, important development step, such as rational design of lipoconjugates, folic acid content, size, and ζ-potential of lipoplexes are discussed. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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