Liposomes For Cancer Therapy Research Articles

Liposome-Based Drug Delivery Systems in Cancer Research: An Analysis of Global Landscape Efforts and Achievements.

Lipid-bilayer-based liposomes are gaining attention in scientific research for their versatile role in drug delivery. With their amphiphilic design, liposomes efficiently encapsulate and deliver drugs to targeted sites, offering controlled release. These artificial structures hold great promise in advancing cancer therapy methodologies. Bibliometric research analyzes systematic literary data statistically. This study used bibliometric indicators to examine, map, and evaluate the applications of liposomes in cancer therapy. A Scopus search was conducted to identify all English-language peer-reviewed scientific publications on the applications of liposomes in cancer therapy within the past twenty years. Bibliometric indicators were calculated using VOSviewer and Biblioshiny. We produced thematic, conceptual, and visualization charts. A total of 14,873 published documents were obtained. The procedure of keyword mapping has effectively identified the main areas of research concentration and prevailing trends within this specific field of study. The significant clusters discovered through theme and hotspot analyses encompassed many topics such as the use of multiple strategies in chemotherapy and different forms of cancer, the study of pharmacokinetics and nanomedicine, as well as the investigation of targeted drug delivery, cytotoxicity, and gene delivery. Liposomes were employed as drug delivery systems so as to selectively target cancer cells and improve the bioavailability of anticancer drugs. The work showcased the capacity to tailor these liposomes for accurate drug delivery by including potent anticancer medications. Our findings not only bring attention to the latest progress in utilizing liposomes for cancer treatment but also underscore the vital need for ongoing research, collaborative efforts, and the effective translation of these breakthroughs into tangible clinical applications, emphasizing the dynamic and evolving nature of cancer therapeutics.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Liposomes in Cancer Therapy: How Did We Start and Where Are We Now

Since their first discovery in the 1960s by Alec Bangham, liposomes have been shown to be effective drug delivery systems for treating various cancers. Several liposome-based formulations received approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with many others in clinical trials. Liposomes have several advantages, including improved pharmacokinetic properties of the encapsulated drug, reduced systemic toxicity, extended circulation time, and targeted disposition in tumor sites due to the enhanced permeability and retention (EPR) mechanism. However, it is worth noting that despite their efficacy in treating various cancers, liposomes still have some potential toxicity and lack specific targeting and disposition. This explains, in part, why their translation into the clinic has progressed only incrementally, which poses the need for more research to focus on addressing such translational limitations. This review summarizes the main properties of liposomes, their current status in cancer therapy, and their limitations and challenges to achieving maximal therapeutic efficacy.

Tumor-derived extracellular vesicles hybridized liposomes in cancer therapy.

Extracellular vesicles (EVs) have gained widespread interest due to their potential in the treatment of inflammation, autoimmune diseases, and immuno-cancer therapy. Among various classes of EVs such as microvesicles (MVs), exosomes, and apoptotic bodies, exosomes are of endosomal origin that are released into the extracellular environment. Exosomes carry complex sets of cargo from their cells of origin, including proteins, lipids, mRNA, and DNA, hence exhibit “Mother Nature”. These are typically 30-150 nm lipidic vesicles rich in integrin proteins that facilitate intrinsic cellular targeting. Within the background, we hypothesized that when these exosomes are hybridized with synthetic liposomes, it would help navigate the hybrid construct in the complex biological environment to find its target. Toward this endeavor, we have re-engineered a synthetic liposome with the exosomes (herein called LEVs) derived from mouse breast cancer and incorporated a fluorescent dye to investigate its potential for cellular targeting. Using the membrane extrusion, we have successfully hybridized both entities resulting in the formation of LEVs and characterized for their colloidal properties and stability over a period. LEVs were monodispersed with an average hydrodynamic size of 120±6. Using Elisa and western-blot, we monitored and quantified exosome-specific protein CD63, which was taken as a handle to ensure the reproducibility of exosome and LEVs. These LEVs were rapidly taken up by immune cells and their parent cells thereby confirming their targeting properties, which can be exploited in drug delivery applications. We will discuss biomedical applications such as its distribution in an animal model, biocompatibility, and imaging in this presentation. We anticipate that this study can picture future opportunities for drug delivery solutions that are superior in target recognition.

Clinical Trials of Liposomes in Children's Anticancer Therapy: A Comprehensive Analysis of Trials Registered on ClinicalTrials.gov.

ObjectiveClinical trials have become essential for driving the development of medicine. However, little is known about the current status of clinical trials on liposomes in children’s anticancer therapy (LCAT). This study aimed to synthesize current finding from clinical trials of LCAT in ClinicalTrials.gov.MethodsA cross-sectional descriptive study of clinical trials on LCAT was conducted, using studies registered on ClinicalTrials.gov through December 30, 2021.ResultsA total of 74 eligible trials were identified, accounting for 4.8% (74/1552) of all trials on liposomes for cancer therapy. Among these trials, 70 (94.6%) were interventional trials, and the remaining 4 (5.4%) were observational trials. Of the 70 interventional trials, 63 (90.0%) were for treatment, 48.6% were involving unlabeled allocations, 30.0% were randomized, 52.9% were single group assignment, 71.4% were without masking, 28.6% were Phase 3 trials, 30.0% were Phase 1 trials, and 24.3% were Phase 2 trials. Furthermore, 17 liposomal drugs for 123 types of cancer were investigated in the interventional trials, and these were mainly focused on organic chemicals (43/70, 61.4%). Of these cancers, the highest proportion was leukemia (15.4%), followed by lymphoma (9.8%) and ovarian cancer (8.9%).ConclusionHigh quality, adequately powered, masked, appropriately sized, and randomized clinical trials represent the critical priorities for conducting a high-quality clinical trial. However, most of these trials for LCAT were non-randomized, single group assignment, and non-blinded interventional trials of small scale, with various eligibility criteria and outcome measures. Our analysis highlights the need for improvement in the completeness of study designs curated on clinicalTrials.gov. We urge for decision-makers to avoid adopting entrenched positions about the study design of cancer clinical trials to avoid this problem. As such, tackling the problematic challenges related to cancer and designing efficient trials for cancer requires developing and applying new approaches and multiple strategies.

Application of Liposomes in Cancer Therapy: An Assessment of the Advancement of Technology Through Patent Documents.

Cancer is caused by mutations in oncogenes and loss of tumor suppressor activity. Despite the efforts of the pharmaceutical industry to fight cancer, it is necessary to investigate new methods to enhance the action against this disease. In this scenario, liposome technology has emerged as a drug delivery system for cancer treatment. The objective of this study was to evaluate the use of liposome technology in the treatment of cancer through analysis of patent documents. We analyzed prospective documents in the Derwent Innovation Index database. A total of 203 patent documents were related to the area of interest, published between 2000 and 2020, and the USA and Japan were shown as countries with the largest number of publications. Moreover, most of these publications came from companies, however, also with the representation of important universities, mainly the University of California. According to the International Patent Classification, the codes most applicable to the documents were in the areas of human necessities and chemistry. The results of this study showed that the study and application of liposomes for the development of cancer treatment tended to grow, along with the number of related patents.

Integrating of lipophilic platinum(IV) prodrug into liposomes for cancer therapy on patient-derived xenograft model

Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, cholesPt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of CholesPt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, CholesPt(IV)-Liposomes showed a small particle size (105.6 nm), the rapid release of platinum (Pt) ions, and notable apoptosis of cancer cells. In addition, according to the fluidity and safety results of animal experiments in mice, CholesPt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patient-derived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.

Carbohydrate-functionalized Liposomes in Cancer Therapy

Existing cancer treatments are often accompanied by adverse side effects that can greatly reduce the quality of life of cancer patients; this sets the platform for the development and application of nanocarrier-based platforms for the delivery of anticancer drugs. Among these nanocarriers, liposomes have demonstrated excellent potential in drug delivery applications. Furthermore, the overexpression of certain receptors on cancer cells has led to the development of active targeting approaches where liposome surfaces are decorated with ligands against these receptors. Given the central role that sugars play in cancer biology, more and more researchers are integrating “glycoscience” into their anticancer therapeutic designs. Carbohydrate functionalized liposomes present an attractive drug delivery system due to their biocompatibility, biodegradability, low toxicity, and specific cell targeting ability. This review presents an overview of the preparation methods, characterization, evaluation, and applications of carbohydrate functionalized liposomes in cancer therapy.

Angiotensin-II regulates dosing time-dependent intratumoral accumulation of macromolecular drug formulations via 24-h blood pressure rhythm in tumor-bearing mice

One approach to increasing pharmacotherapy effects is administering drugs at times of day when they are most effective and/or best tolerated. Circadian variation in expression of pharmacokinetics- and pharmacodynamics-related genes was shown to contribute to dosing time-dependent differences in therapeutic effects of small molecule drugs. However, influence of dosing time of day on effects of high molecular weight formulations, such as drugs encapsulated in liposomes, has not been studied in detail. This study demonstrates that blood pressure rhythm affects dosing time-dependent variation in effects of high molecular weight formulations. Systolic blood pressure in sarcoma 180-bearing mice showed significant 24-h oscillation. Intratumoral accumulation of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA), an indicator of tumor vascular permeability, varied with dosing time of day, matching phases of blood pressure circadian rhythm. Furthermore, intratumoral accumulation of liposome-encapsulated oxaliplatin (Lipo-L-OHP) increased with increases in systolic blood pressure. Our findings suggest that circadian blood pressure oscillations may be an important factor to consider in dosing strategies for macromolecular drugs and liposomes in cancer therapy.

Revisiting the use of sPLA2-sensitive liposomes in cancer therapy

The first developed secretory phospholipase A2 (sPLA2) sensitive liposomal cisplatin formulation (LiPlaCis®) is currently undergoing clinical evaluation. In the present study we revisit and evaluate critical preclinical parameters important for the therapeutic potential and safety of platinum drugs, here oxaliplatin (L-OHP), formulated in sPLA2 sensitive liposomes. We show the mole percentage of negatively charged phospholipid needed to obtain enzyme-sensitivity for saturated systems is ≥25% for 16-carbon chain lipid membranes, and >40% for 18-chain lipid membranes, which was surprising as 25% is used clinically in LiPlaCis®. Efficient sPLA2-dependent growth inhibition of colorectal cancer cells was demonstrated in vitro, where cell membrane degradation and cytolysis depends on the sensitivity of the formulation towards the enzyme and is governed by the amount of lysolipids generated and the presence of serum proteins. We found that serum proteins did not affect the lipase activity of the enzyme towards the membranes but instead sequester the lysolipid byproducts consequently inhibiting their detergent-like cytotoxic properties. In vivo therapeutic potential and safety of the liposomes was investigated in nude mice bearing sPLA2-deficient FaDu squamous carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. After intravenous injections, the tumor growth was suppressed for liposomal L-OHP relative to free drug, but only a weak response was observed for both slow- and fast-releasing sPLA2-sensitive formulations compared to non-sensitive liposomes. Also, the mice did not show longer survival. In turn, for the highly sPLA2-sensitive liposomes, multiple high doses caused petechial cutaneous hemorrhages, along with multifocal hepatonecrotic lesions, suggestive of premature activation in skin and liver irrespective of sPLA2-status of the tumor engraft. These results indicate that although liposomal carriers can improve the antitumor efficacy of platinum drugs, sPLA2-triggered release suffers from a narrow therapeutic index and has safety concerns.

Liposomal Drug Delivery System for Cancer Therapy: Advancement and Patents.

In this review article, authors reviewed about the liposomes which are amongst various drug delivering systems for the delivery of the therapeutic agents at the target site. Advances in liposomal drug delivery systems for the cancer therapy have enhanced the therapeutic levels of the anticancer moieties. Liposomes show promising action on the tumor by incorporating less amount of drug at the target site, with minimum toxic effect and maximum therapeutic effect and thereby enhancing the bioavailability. Liposome-based drug delivery systems provide the potential to elevate the effect of drug concentration in tumor cells. Manuscript briefly describes the role of liposomes in cancer therapy and various patents based on the same.

Liposome and Their Applications in Cancer Therapy

Liposomes, the vesicles of phospholipid bilayer, can encapsulate both hydrophilic and lipophilic drugs and protect them from degradation. Liposomes have been extensively studied and continue to create intense interest in research since their discovery in the mid-1960s. Since then, liposomes have been considered to be the most successful nanocarriers for drug deliver and have made their way to the market. Currently, a number of liposomal formulations are on the marker for cancer treatment and many more are in pipe line. This review discusses about the liposome components, methods of preparation, drug encapsulation mechanism and the potential therapeutic applications of liposomes in cancer therapy.

Patenting Networking and Knowledge Translation in Liposomes for Cancer Therapy

We have constructed a citation network model of the 20% most cited patent families on cancer and liposomes. This model was structurally analyzed through a combination of two Cytoscape plugins: Clust&see and AllegroMCODE. We found four patent meta-families (densely interconnected regions) in the network model. Three of the four patent meta-families are related to specific anti-cancer liposomal formulations: LEP-ETU, LE-DT, Doxil and Marqibo. This model was compared with a previous study on the knowledge translation in literature network. Both models show that liposome used as a carrier of old drugs is simultaneously the paradigm and the dominant design for liposomes and cancer. Our results evidence that the innovation process in this field, is conservative and continuous.

Polymer–Liposome Complexes with a Functional Hydrogen-Bond Cross-Linker for Preventing Protein Adsorption and Improving Tumor Accumulation

To solve biostability and organ distribution problems in polymer-coated liposomes, this study developed tumor–extracellular matrix pH-induced targeting polymer–liposome complexes (ECM-targeting liposomes) that are highly stable in a protein-rich environment and can trigger targeting ability in tumor ECM environment. Experimental results show that the ECM-targeting liposomes significantly reduced adsorption of various proteins (HSA, IgG, and fibrinogen) and leakage of encapsulated drug doxorubicin–hydrochloride from liposomes, significantly improved uptake efficiency in HCT116 colon cancer cells, improved HCT116 tumor accumulation, and reduced distribution in normal organs (e.g., liver, spleen, lung, etc.). We demonstrate that ECM-targeting liposomes overcome the limitations of conventional liposomes and stealth liposomes in cancer therapy.

Abstract 5514: Targeted liposomes in cancer therapy

Abstract The purpose of this project was to design a liposomal formulation which targets the SLC transporter. Daunorubicin, an anticancer drug, used as a model was encapsulated in the targeted liposomal formulation and the cellular uptake and cytotoxicity of targeted liposomal daunorubicin (TLD) as well as the mechanisms of cellular uptake were evaluated using the A549 lung cancer cell line. A quantity of 3×105/2ml cells of A549 were cultured in each well of 6 well plates in RPMI medium. The cells were treated with TLD, non targeted liposomal (NTL) daunorubicin and free, non-encapsulated daunorubicin containing 10µM and 5µM drug. They were incubated for 5-6 hours at 37oC and analyzed using flow cytometry and fluorescence imaging. The cytotoxicity of the formulations was determined using MTS assay. The IC50 was determined from the growth inhibition curves of cell viability. Furthermore, the mechanism of internalization of the TLD formulation was studied using inhibitors specific to each pathway of internalization. The results show that the cellular uptake TLD showed a significant increase of 2- fold compared to that of NTL and free drug for both concentrations (10µM and 5µM). These results were also consistent with the cytotoxicity study showing higher cytotoxicity of TLD compared to NTL and free drug, The IC50 of TDL showed a 2.3-fold and 3.4-fold decrease compared to NTL and free drug, respectively. Also the data showed decrease in the cellular uptake of TLD when the macropinocytosis pathway was inhibited. Depletion of cholesterol in the cellular wall also reduced the cellular uptake of the TLD formulation. The results indicate that our novel targeted liposomal formulation shows enhanced cellular uptake and cytotoxicity likely due to macropinocytosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5514.

Antibody-targeted liposomes in cancer therapy and imaging

Background: Targeted liposomes can be broadly defined as liposomes that are engineered to interact with a particular population of cells with the objective of delivering a payload or increasing their retention within the targeted cell population by means of a chemical interaction with cell-surface molecules or other tissue-specific ligands. Objective: The authors review recent advances in the field with an emphasis on pre-clinical studies and place them in the context of historical developments. Methods: The review focuses on immunoliposomes (antibody-mediated targeting) as these constructs are presently the most prevalent. Conclusion: The field has advanced in tandem with advances in liposome design and antibody and protein engineering. Targeted liposomes have been used in diagnosis to deliver magnetic resonance contrast agents and radionuclides for magnetic resonance and nuclear medicine imaging, respectively. They have been used in gene therapy to deliver a variety of gene expression modifiers, including plasmids, anti-sense oligonucleotides and short interfering RNA. Targeted liposomes provide a delivery advantage over untargeted liposomes not because of increased localization to tumor sites but because of increased interaction with the target cell population once localized to the tumor site. The increased interaction can take on the form of fusion with the cellular membrane or internalization by endocytosis. To the extent that the spatial distribution of targeted liposomes within a solid tumor may become more non-uniform than has been found for untargeted liposomes, this may be a drawback. However, systematic comparisons of the spatial distribution in tumors of targeted versus untargeted liposomes have yet to be performed. The majority of reported studies have been in the area of chemotherapy delivery. Their use in radionuclide and chemo- and radiosensitizer delivery is just emerging. Multifunctional liposomes containing ‘layered functionalities’ could potentially be the future direction in targeted liposome-based therapy.

Recent developments in medical applications of liposomes: sterically stabilized liposomes in cancer therapy and gene delivery in vivo

In the first part, medical applications of liposomes loaded with small molecular weight drugs is discussed and the use of sterically stabilized liposomes containing doxorubicin in cancer therapy is presented. A brief theoretical description of the origin of liposome stabilization by the surface-attached polymer is also included. The second part deals with gene delivery by the use of cationic lipids, the structure of the DNA-lipid complexes and structure-transfection activity relationships. Structurally the complexes contain ordered domains in which parallel helices of two-dimensionally ordered DNA are adsorbed onto lipid bilayers. The periodicity between stacked lipid bilayers with sandwiched DNA is 6.5 nm, while the interhelical separation of 3.6 nm within the DNA layer was observed by X-ray scattering as well as electron and atomic force microscopy. Typically cationic lipids are formulated with neutral lipid and cholesterol was shown to be the most effective for transfection in vivo, which was correlated to the formation of small and dense DNA-lipid complexes. Following structure-activity studies, a model of gene transfection is proposed.

Omega-3 fatty acid-containing liposomes in cancer therapy.

omega-3 fatty acids are associated with reduced growth and incidence of certain cancers, and in this report we demonstrate that a fish oil diet (rich in omega-3 fatty acids) enhances the longevity of mice bearing the myeloid leukemia T27A. We have proposed that the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6 delta 4,7,10,13,16,19) may induce structural changes in tumor cell plasma membranes resulting in reduced tumor growth in vitro. Here, we test whether liposomes containing DHA (18:0, 22:6 PC) have antitumor effects in vivo, leading to enhanced longevity of the tumor-bearing host. Male BALB/c mice (6-8 weeks old) were inoculated intraperitoneally with a T27A tumor dose known to cause 100% mortality of syngeneic (BALB/c) mice in less than 2 weeks. Small unilamellar vesicles (liposomes) were prepared, composed of phosphatidylcholine (PC) with 18:0 in the sn-l position and one of the following fatty acids in the sn-2 position: 18:0, 18:1 omega 9 (oleic), 18:3 omega 3 (alpha-linolenic), 20:4 omega 6 (arachidonic), 22:6 omega 3 (docosahexaenoic). The liposomes were injected intraperitoneally into tumor-bearing mice at various times: concurrently with the tumor inoculum, at select times during tumor growth, and when the mice were moribund. Mouse survival was then charted. DHA-containing lipid vesicles (18:0, 22:6 PC) caused a statistically significant increase in survival of the tumor-bearing mice when compared with 18:0, 18:1 PC. Lipid vesicles of 18:0, 18:0 PC showed no benefit, and 18:0, 20:4 PC was not significantly different than 18:0, 18:1 PC. Lipid vesicles containing a different omega-3 fatty acid, 18:0, 18:3 PC, also effectively enhanced tumor-bearing mouse survival. The greatest benefit was achieved if either the liposome treatments were spaced throughout the tumor growth period, or if the tumor inoculum was suspended in the liposome preparation (without further liposome treatments). Neither lipid peroxidation nor prolonged inflammatory responses appeared to be pertinent, leaving membrane structural changes as a feasible mode of liposome action. With antitumor properties of their own, omega-3 fatty acid-containing lipid vesicles may offer an important new avenue in combination cancer therapies.

A new application for liposomes in cancer therapy: Immunoliposomes bearing enzymes (immuno-enzymosomes) for site-specific activation of prodrugs

We have tested a new type of immunoliposomes which may effectively mediate the targeting of enzymes to be used for site-specific prodrug activation (immuno-enzymosomes). The enzyme β-glucuronidase, capable of activating the prodrug epirubicin-glucuronide (epi-glu), was coupled to the external surface of immunoliposomes directed towards ovarian cancer cells. A significant increase in cytotoxicity of the prodrug epi-glu was shown when the in vitro cultured cancer cells were pretreated with these immuno-enzymosomes.

Liposomes in cancer therapy

Liposomes in cancer therapy