The impact of phospholipids with high transition temperature to enhance redox-sensitive liposomal doxorubicin efficacy in colon carcinoma model.

In this study, we have developed a redox-sensitive (RS) liposomal doxorubicin formulation by incorporating 10,10'-diselanediylbis decanoic acid (DDA) organoselenium compound as the RS moiety. Hence, several RS liposomal formulations were prepared by using DOPE, HSPC, DDA, mPEG2000-DSPE, and cholesterol. In situ drug loading using a pH gradient and citrate complex yielded high drug to lipid ratio and encapsulation efficiency (100%) for RS liposomes. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell uptake and cytotoxicity, as well as therapeutic efficacy in BALB/c mice bearing C26 tumor cells. The formulations showed an average particle size of 200 nm with narrow size distributions (PDI < 0.3), and negative surface charges varying from -6 mV to -18.6 mV. Our study confirms that the presence of the DDA compound in liposomes is highly sensitive to hydrogen peroxide at 0.1% w/v, resulting in a significant burst release of up to 40%. The in vivo therapeutic efficacy study in BALB/c mice bearing C26 colon carcinoma confirmed the promising function of RS liposomes in the tumor microenvironment which led to a prolonged median survival time (MST). The addition of hydrogenated soy phosphatidylcholine (HSPC) with a high transition temperature (Tm: 52-53.5°C) extended the MST of our 3-component formulation of F14 (DOPE/HSPC/DDA) to 60 days in comparison to Caelyx (PEGylated liposomal Dox), which is not RS-sensitive (39 days). Overall, HSPC liposomes bearing RS-sensitive moiety enhanced therapeutic efficacy against colon cancer in vitro and in vivo. This achievement unequivocally underscores the criticality of high-TM phospholipids, particularly HSPC, in significantly enhancing liposome stability within the bloodstream. In addition, RS liposomes enable the on-demand release of drugs, leveraging the redox environment of tumor cells, thereby augmenting the efficacy of the formulation.

Surface-modified cationic liposomes with a matrix metalloproteinase-degradable polyethylene glycol derivative improved doxorubicin delivery in murine colon cancer.

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.

The effect of m2 peptide targeted nanoliposomes containing crocin on induction of phenotypic change in tumor macrophages to M1 state.

AIMS: Crocin has immunomodulatory and anticancer effects. In this study, crocin was used to induce the M1 phenotype in mouse tumor macrophages. MAIN METHODS: A targeted liposomal formulation with m2 peptide was prepared and characterized to deliver crocin to the M2 macrophages present in the tumor environment. RT-qPCR and IHC were performed for in vitro and in vivo (in C26 colon carcinoma mouse model at a dose of 50 mg/kg) assessment of M1 induction, respectively. KEY FINDINGS: In vitro results indicated that liposome modified with m2 peptide was non-toxic to macrophages and had an improved uptake by macrophages compared to the non-targeted formulation and induced M1 phenotype through an IL6-independent pathway. M2 peptide- modified liposome showed considerable tumor accumulation and anti-tumor effects and significantly shifted the phenotype of tumor macrophages towards an anti-tumor M1 phenotype. SIGNIFICANCE: Probably the remarkable anti-tumor responses observed in this study with m2 peptide-targeted liposomal formulations containing crocin were due to the enhanced delivery of crocin to the tumor macrophage and the subsequent initiation of anti-tumor immune responses.

Doxorubicin-loaded liposomes surface engineered with the matrix metalloproteinase-2 cleavable polyethylene glycol conjugate for cancer therapy.

Background: Colorectal cancer is one of the prominent leading causes of fatality worldwide. Despite recent advancements within the field of cancer therapy, the cure rates and long-term survivals of patients suffering from colorectal cancer have changed little. The application of conventional chemotherapeutic agents like doxorubicin is limited by some drawbacks such as cardiotoxicity and hematotoxicity. Therefore, nanotechnology has been exploited as a promising solution to address these problems. In this study, we synthesized and compared the anticancer efficacy of doxorubicin-loaded liposomes that were surface engineered with the 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-matrix metalloproteinase-2 (MMP-2) cleavable peptide-polyethylene glycol (PEG) conjugate. The peptide linker was used to cleave in response to the upregulated MMP-2 in the tumor microenvironment, thus exposing a positive charge via PEG-deshielding and enhancing liposomal uptake by tumor cells/vasculature. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell binding and uptake, and cytotoxicity. Results: The formulations had particle sizes of ~ 100-170 nm, narrow distribution (PDI ˂ 0.2), and various surface charges (- 10.2 mV to + 17.6 mV). MMP-2 overexpression was shown in several cancer cell lines (C26, 4T1, and B16F10) as compared to the normal NIH-3T3 fibroblast cells by gelatin zymography and qRT-PCR. In vitro results demonstrated enhanced antitumor efficacy of the PEG-cleavable cationic liposomes (CLs) as compared to the commercial Caelyx® (up to fivefold) and the chick chorioallantoic membrane assay showed their great antiangiogenesis potential to target and suppress tumor neovascularization. The pharmacokinetics and efficacy studies also indicated higher tumor accumulation and extended survival rates in C26 tumor-bearing mice treated with the MMP-2 cleavable CLs as compared to the non-cleavable CLs with no remarkable sign of toxicity in healthy tissues. Conclusion: Altogether, the MMP-2-cleavable CLs have great potency to improve tumor-targeted drug delivery and cellular/tumor-vasculature uptake which merits further investigation. Supplementary Information: The online version contains supplementary material available at 10.1186/s12645-023-00169-8.

The comparison of biodistribution of glutathione PEGylated nanoliposomal doxorubicin formulations prepared by pre-insertion and post-insertion methods for brain delivery in normal mice.

Several obstacles limit the efficacy of brain tumour treatment, most notably the blood-brain barrier (BBB), which prevents the brain uptake of the majority of accessible medicines due to tight junctions. The presence of glutathione (GSH) receptors on the BBB surface has been demonstrated in numerous papers; consequently, products containing glutathione as a targeting ligand coupled with nanoliposomes are used to enhance drug delivery across the BBB. Here, the 5% pre-inserted PEG2000-GSH PEGylated liposomal doxorubicin was conducted according to 2B3-101 being tested in clinical trials. In addition, PEGylated nanoliposomal doxorubicin connected to the spacer-GSH targeting ligand (GSGGCE) and the PEG3400 was conducted using post-insertion method. Next, in vivo biodistribution of the produced formulations was tested on healthy mice to see if GSGGCE, as the targeted ligand, could cross the BBB compared to 5% pre-inserted PEG2000-GSH and Caelyx® . Compared to the pre-inserted formulation and Caelyx® , the post-inserted formulations' concentration was lower in the heart and higher in brain tissues, resulting in boosting the brain concentration of accumulated doxorubicin with fewer possible side effects, including cardiotoxicity. In comparison to the pre-insertion procedure, the post-insertion method is easier, faster, and more cost-effective. Moreover, employing PEG3400 and the post-insertion approach in the PEG3400-GSGGCE liposomal formulations was found to be effective in crossing the BBB.

The role of size in PEGylated liposomal doxorubicin biodistribution and anti-tumour activity.

The size of nanoliposome-encapsulated drugs significantly affects their therapeutic efficacy, biodistribution, targeting ability, and toxicity profile for the cancer treatment. In the present study, the biodistribution and anti-tumoral activity of PEGylated liposomal Doxorubicin (PLD) formulations with different sizes were investigated. First, 100, 200, and 400 nm PLDs were prepared by remote loading procedure and characterised for their size, zeta potential, encapsulation efficacy, and release properties. Then, in vitro cellular uptake and cytotoxicity were studied by flow cytometry and MTT assay, and compared with commercially available PLD Caelyx® . In vivo studies were applied on BALB/c mice bearing C26 colon carcinoma. The cytotoxicity and cellular uptake tests did not demonstrate any statistically significant differences between PLDs. The biodistribution results showed that Caelyx® and 100 nm liposomal formulations had the most doxorubicin (Dox) accumulation in the tumour tissue and, as a result, considerably suppressed tumour growth compared with 200 and 400 nm PLDs. In contrast, larger nanoparticles (200 and 400 nm formulations) had more accumulation in the liver and spleen. This study revealed that 90 nm Caelyx® biodistribution profile led to the stronger anti-tumour activity of the drug and hence significant survival extension, and showed the importance of vesicle size in the targeting of nanoparticles to the tumour microenvironment for the treatment of cancer.

Redox-sensitive doxorubicin liposome: a formulation approach for targeted tumor therapy.

In this study redox-sensitive (RS) liposomes manufactured using 10,10'-diselanediylbis decanoic acid (DDA), an organoselenium RS compound, to enhance the therapeutic performance of doxorubicin (Dox). The DDA structure was confirmed by 1H NMR and LC-MS/MS. Various liposomal formulations (33 formulations) were prepared using DOPE, Egg PC, and DOPC with Tm Ë‚ 0 and DDA. Some formulations had mPEG2000-DSPE and cholesterol. After extrusion, the external phase was exchanged with sodium bicarbonate to create a pH gradient. Then, Dox was remotely loaded into liposomes. The optimum formulations indicated a burst release of 30% in the presence of 0.1% hydrogen peroxide at pH 6.5, thanks to the redox-sensitive role of DDA moieties; conversely, Caelyx (PEGylated liposomal Dox) showed negligible release at this condition. RS liposomes consisting of DOPE/Egg PC/DDA at 37.5 /60/2.5% molar ratio, efficiently inhibited C26 tumors among other formulations. The release of Dox from RS liposomes in the TME through the DDA link fracture triggered by ROS or glutathione is seemingly the prerequisite for the formulations to exert their therapeutic action. These findings suggest the potential application of such intelligent formulations in the treatment of various malignancies where the TME redox feature could be exploited to achieve an improved therapeutic response.

A novel and easy to prepare azo-based bioreductive linker and its application in hypoxia-sensitive cationic liposomal doxorubicin: Synthesis, characterization, in vitro and in vivo studies in mice bearing C26 tumor.

This study designed and synthesized a cost-effective azo-based hypoxia-sensitive linker (AHSL) using commercially accessible, inexpensive raw materials and simple methods to apply in cationic nanoliposomes. Then, AHSL was post-inserted into the cationic liposome (Cat-lip), and PEG-Azo-Cat-lip was prepared and characterized using DLS. The decrease in the zeta-potential of formulation from + 18.4 mV for Cat-lip to + 6.1 mV and the increase in the size of the PEG-Azo-Cat-lip indicated the successful post insertion of AHSL into the liposomes. The Doxorubicin (Dox) release study showed that PEGylation results in a more stable PEG-Azo-Cat-lip than the Cat-lip. The increased cytotoxicity of the PEG-Azo-Cat-lip in the hypoxic condition also indicated the cleavage of the AHSL in the hypoxic environment. In vivo biodistribution using animal imaging has shown higher tumor accumulation of the MPEG-Azo-Cat-lip than Cat-lip during the 120 h of the study. The results of anti-tumor activities and biosafety of the formulations also showed the higher efficiency of the MPEG-Azo-Cat-lip compared with the Cat-lip. The results of this study indicated the antitumor efficacy of this hypoxia-sensitive which merits further investigation.

Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: An implication in colorectal cancer therapy.

Cis-Diaminedichloroplatinum (cisplatin, CDDP) remained among the most widely used anti-cancer agents; however, management of the dose-limiting side effects is still a great hurdle to its therapeutic potential. In the framework of this investigation, novel approach was developed for CDDP encasement within liposome based on the formation of a coordination bond between the platinum (II) atom and a carboxylic group in aspartic acid (AA) and glutamic acid (GA). We have also compared two methods of preparation based on equilibration and conventional lipid film hydration. For this, first FTIR spectra of the conjugates confirmed coordination bond between Pt and the carboxylate moieties. The PEGylated liposomes composed of HSPC, cholesterol and DPPG had a size of 134 to 197 nm and negative zeta potential (-14.20 to -20.90 mv). Cytotoxicity study revealed IC50 values of <7 µg/ml for liposomes. In vivo plasma retention following iv administration indicated the potential of liposome in maintaining cisplatin levels within the circulation, while free cisplatin and cisplatin conjugates were promptly eliminated. Anti-tumor efficacy studies following iv injections at 3 mg/kg cisplatin weekly for three weeks in C26 tumor bearing BALB/c mice demonstrated the potential of the cisplatin liposomes in tumor growth inhibition. Pt-complexes were not as effective as liposomal formulations showing the crucial role of liposomes in maintaining cisplatin levels within blood circulation. Overall, the developed cisplatin liposome seems to be a promising therapeutic approach for targeting solid tumors.

Neuroprotection by curcumin: A review on brain delivery strategies.

Neurodegenerative diseases are a major global public health concern in the elderly population but therapeutic options are limited. Curcumin is a hydrophobic polyphenol extracted from the dried rhizomes of Curcuma longa L. and shows good potential for the treatment of neurodegenerative diseases and brain tumors. The blood-brain barrier (BBB) is the major obstacle for the delivery of curcumin into the brain, limiting its therapeutic potential. The development of promising approaches to facilitate curcumin transportation across the BBB may resolve some of the problems associated with drug delivery. Studies have shown nano delivery of curcumin can improve a number of outcome measures in neurodegenerative diseases. The present review highlights current and emerging strategies to facilitate curcumin permeation across the BBB for the treatment of various neurodegenerative diseases.

Development of nano-carriers for Leishmania vaccine delivery.

Introduction: Leishmaniasis is a neglected tropical infection caused by several species of intracellular protozoan parasites of the genus Leishmania. It is strongly believed that the development of vaccines is the most appropriate approach to control leishmaniasis. However, there is no vaccine available yet and the lack of an appropriate adjuvant delivery system is the main reason.Areas covered: Adjuvants are the utmost important part of a vaccine, to induce the immune response in the right direction. Limitations and drawbacks of conventional adjuvants have been necessitated the development of novel particulate delivery systems as adjuvants to obtain desirable protection against infectious diseases such as leishmaniasis. This review focused on particulate adjuvants especially nanoparticles that are in use to develop vaccines against leishmaniasis. The list of adjuvants includes generally lipids-, polymers-, or mineral-based delivery systems that target antigens specifically to the site of action within the host's body and enhance immune responses.Expert opinion: Over the past few years, there has been an increasing interest in developing particulate adjuvants as alternatives to immunostimulatory types. The composition of nano-carriers and particularly the physicochemical properties of nanoparticles have great potential to overcome challenges posed to leishmaniasis vaccine developments.

Endogenous stimuli-responsive linkers in nanoliposomal systems for cancer drug targeting.

There are various drug delivery systems (DDSs) among which nanoliposomal formulations are among the most prominent. Despite the superiority of nanoliposomal DDSs compared to conventional drug delivery methods, recent reports have claimed that they can deliver small amounts of the injected dose to target site by passive targeting. However, our understanding of tumor microenvironment features, including dysregulation of pH, the high intracellular concentration of glutathione, change in the amount and expression of some enzymes, reactive oxygen species, hypoxia, and ATP concentrations, has driven the scope of research into the use of these endogenous stimuli for a design of smart linkers. These linkers optimize the release of payloads in favorable target sites and avoid premature releasing in non-favorable off-target sites. In this review, we discuss particular linkers, which are able to respond to the specific endogenous conditions, and could be used in nanoliposomal DDSs, based on pathophysiological changes that occur in tumors. Furthermore, structural and chemical properties of these linkers and other potential linkers, which could be used in nanoliposomal DDSs, have been reviewed.

Liposomal nanocarriers for statins: A pharmacokinetic and pharmacodynamics appraisal.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are a well-known class of drug with beneficial therapeutic effects in cardiovascular disease and lipid disorders and have potential use against cancer. However, the bioavailability of statins is hampered due to low aqueous solubility and rapid metabolism. To improve pharmacokinetic profiles of statins, development of drug delivery systems is promising. Hence, the use of liposomes for selective delivery of statins to a selected site or for bioavailability enhancement is an effective strategy to increase statin therapeutic effects. Moreover, liposomal delivery can reduce the required dose of statins especially in terms of antitumor effects. Liposomes, because of their unique properties and biphasic and amphiphilic nature, have attracted much interest and can be considered as a suitable choice for delivery of both hydrophilic and lipophilic statins. In this review article, we focus on liposomes and evaluate the effects of different liposomal delivery systems, based on differences in size, phospholipid composition, circulation half-life, and cholesterol content, on statin function.

Liposomal adjuvant development for leishmaniasis vaccines.

Leishmaniasis is a parasitic disease that ranges in severity from skin lesions to fatality. Since long-lasting protection is induced upon recovery from cutaneous leishmaniasis, development of an effective vaccine is promising. However, there is no vaccine for use in humans yet. It seems limited efficacy in leishmaniasis vaccines is due to lack of an appropriate adjuvant or delivery system. Hence, the use of particulate adjuvants such as liposomes for effective delivery to the antigen presenting cells (APCs) is a valuable strategy to enhance leishmaniasis vaccine efficacy. The extraordinary versatility of liposomes because of their unique amphiphilic and biphasic nature allows for using antigens or immunostimulators within the core, on the surface or within the bilayer, and modulates both the magnitude and the T-helper bias of the immune response. In this review article, we attempt to summarize the role of liposomal adjuvants in the development of Leishmania vaccines and describe the main physicochemical properties of liposomes like phospholipid composition, surface charge, and particle size during formulation design. We also suggest potentially useful formulation strategies in order for future experiments to have a chance to succeed as liposomal vaccines against leishmaniasis.