Chemo-immunotherapy by nanoliposomal epacadostat and docetaxel combination to IDO1 inhibition and tumor microenvironment suppression.

The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.

Lipid nanoparticle (LNP) mediated mRNA delivery in cardiovascular diseases: Advances in genome editing and CAR T cell therapy.

Cardiovascular diseases (CVDs) are the leading cause of global mortality among non-communicable diseases. Current cardiac regeneration treatments have limitations and may lead to adverse reactions. Hence, innovative technologies are needed to address these shortcomings. Messenger RNA (mRNA) emerges as a promising therapeutic agent due to its versatility in encoding therapeutic proteins and targeting "undruggable" conditions. It offers low toxicity, high transfection efficiency, and controlled protein production without genome insertion or mutagenesis risk. However, mRNA faces challenges such as immunogenicity, instability, and difficulty in cellular entry and endosomal escape, hindering its clinical application. To overcome these hurdles, lipid nanoparticles (LNPs), notably used in COVID-19 vaccines, have a great potential to deliver mRNA therapeutics for CVDs. This review highlights recent progress in mRNA-LNP therapies for CVDs, including Myocardial Infarction (MI), Heart Failure (HF), and hypercholesterolemia. In addition, LNP-mediated mRNA delivery for CAR T-cell therapy and CRISPR/Cas genome editing in CVDs and the related clinical trials are explored. To enhance the efficiency, safety, and clinical translation of mRNA-LNPs, advanced technologies like artificial intelligence (AGILE platform) in RNA structure design, and optimization of LNP formulation could be integrated. We conclude that the strategies to facilitate the extra-hepatic delivery and targeted organ tropism of mRNA-LNPs (SORT, ASSET, SMRT, and barcoded LNPs) hold great prospects to accelerate the development and translation of mRNA-LNPs in CVD treatment.

Liposomal factor VIII as an efficient pharmaceutical system for the treatment of hemophilia.

Objectives: Currently, the most important treatment approach for hemophilia type A is recombinant Factor VIII. However, due to its low retention time in the blood, the patients usually need successive injections. In addition, neutralization of injected proteins by antibodies complicates treatment. We examined the prolongation of the persistence time of injectable FVIII in the blood and the potential effects on survival using promising PEGylated liposomes (PEGLip) utilizing hydrogenated soy phosphatidylcholine (HSPC, Tm= 54.5 ºC) and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC, Tm= - 2 ºC). Materials and Methods: Nanoliposomes with different percentages of PEG (3% and 5%) were obtained via the thin film hydration procedure and extrusion. Liposomal FVIII formulation was prepared and characterization was done. Results: The results revealed that the formulations are in the 80-120 nm range with uniform dispersion, which was confirmed using transmission electron microscopy (TEM) imaging. The phase transition temperature (Tm) of the liposomes was obtained by differential scanning calorimetry (DSC). With an attachment efficacy of approximately 87%, proteins bind non-covalently yet with a strong affinity to the exterior of PEGLip. The final formulations underwent additional examination. No significant change was observed in size, charge, and PDI between the FVIII-conjugated liposomal formulations and their liposomal nanoparticles. The selected formulations were injected into BALB/c mice. The circulation time and potential clotting effectiveness of PEGLip-FVIII are vastly improved over free protein, in non-hemophilic mice. Conclusion: The obtained results showed that using phospholipids with high Tm (HSPC) can improve the hemostatic efficiency of liposomes more than phospholipids with low Tm (POPC).

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.

Development of nano-liposomal human growth hormone as a topical formulation for preventing uvb-induced skin damage.

Due to its involvement in skin maintenance and repair, topical administration of recombinant human growth hormone (rhGH) is an interesting strategy for therapeutic purposes. We have formulated and characterized a topical rhGH-loaded liposomal formulation (rhGH-Lip) and evaluated its safety, biological activity, and preventive role against UVB-induced skin damage. The rhGH-Lip had an average size and zeta potential of 63 nm and -33 mV, respectively, with 70 % encapsulation efficiency. The formulation was stable at 4 °C for at least one year. The SDS-PAGE and circular dichroism results showed no structural alterations in rhGH upon encapsulation. In vitro, studies in HaCaT, HFFF-2, and Ba/F3-rhGHR cell lines confirmed the safety and biological activity of rhGH-Lip. Franz diffusion cell study showed increased rhGH skin permeation compared to free rhGH. Animal studies in nude mice showed that liposomal rhGH prevented UVB-induced epidermal hyperplasia, angiogenesis, wrinkle formation, and collagen loss, as well as improving skin moisture. The results of this study show that rhGH-Lip is a stable, safe, and effective skin delivery system and has potential as an anti-wrinkle formulation for topical application. This study also provides a new method for the topical delivery of proteins and merits further investigation.

Retraction notice to "The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model" [Cancer Lett. 419 (2018) 30-39].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor. After publication, the Editors were contacted by a concerned reader regarding alleged image duplication. These allegations are in regard to Fig. 3a being duplicated from a previously published paper in the journal Stem Cells (Stem Cells. 2008 Sep;26 (9):2332-8. doi: 10.1634/stemcells.2008-0084) and Fig. 8a being duplicated from a previously published paper in the journal Molecular Cancer (Mol Cancer 13, 255 (2014). https://doi.org/10.1186/1476-4598-13-255). After a thorough investigation by the editorial team, the Editors determined that there are multiple identical details between Fig. 5A (Cancer Letters) and Fig. 3A (Stem Cells) and the authors did not produce satisfactory evidence that the published images in Cancer Letters were original. Due to this, the Editor does not have confidence in the results and conclusions presented and has made the decision to retract.

Evaluation of the efficiency of nanomicellar formulation of fat-soluble vitamins in patients with cystic fibrosis: the study protocol for a randomized controlled trial.

BACKGROUND: Cystic fibrosis is an inherited disease, which is caused by the CFTR protein defects due to mutations in the CFTR gene. Along with CFTR dysfunction, exocrine pancreatic insufficiency plays a key role in persistent fat malabsorption in CF patients; therefore, deficiency of fat-soluble vitamins (A, D, E, and K) is still a therapeutic challenge. Even with efficient pancreatic enzyme medication and CF-specific vitamins, many patients with CF have fat-soluble vitamins deficiency. The present study aims to evaluate the efficiency of nanomicelle formulation of fat-soluble vitamins in children with CF in order to achieve the appropriate serum levels of these vitamins. METHODS: This prospective, single-blind control trial will be conducted at the Akbar Children's Hospital in Mashhad, Iran. Patients with CF will be enrolled based on the eligibility criteria. The control group will receive the standard formulation of fat-soluble vitamins similar to the routine CF treatment, and for the intervention group, the nanomicelle formulation of fat-soluble vitamins will be administered for 3 months. The primary outcome of this study is the measurement of serum levels of fat-soluble vitamins. The secondary outcomes are clinical assessment by the Shwachman-Kulczycki score, anthropometrics, and quality of life. Outcomes will be assessed before and after 3 months. DISCUSSION: Due to persistent fat-soluble vitamin deficiency in CF disease, the nanomicelle formulation could be proposed as a new delivery method of fat-soluble vitamins in the treatment of cystic fibrosis. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20220415054541N1. Registered on July 23, 2022.

Harnessing CRISPR technology for viral therapeutics and vaccines: from preclinical studies to clinical applications.

The CRISPR/Cas system, identified as a type of bacterial adaptive immune system, have attracted significant attention due to its remarkable ability to precisely detect and eliminate foreign genetic material and nucleic acids. Expanding upon these inherent capabilities, recent investigations have unveiled the potential of reprogrammed CRISPR/Cas 9, 12, and 13 systems for treating viral infections associated with human diseases, specifically targeting DNA and RNA viruses, respectively. Of particular interest is the RNA virus responsible for the recent global outbreak of coronavirus disease 2019 (COVID-19), which presents a substantial public health risk, coupled with limited efficacy of current prophylactic and therapeutic techniques. In this regard, the utilization of CRISPR/Cas technology offers a promising gene editing approach to overcome the limitations of conventional methods in managing viral infections. This comprehensive review provides an overview of the latest CRISPR/Cas-based therapeutic and vaccine strategies employed to combat human viral infections. Additionally, we discuss significant challenges and offer insights into the future prospects of this cutting-edge gene editing technology.

Microfluidic-assisted preparation of PLGA nanoparticles loaded with insulin: a comparison with double emulsion solvent evaporation method.

Poly lactic-co-glycolic acid (PLGA) is an ideal polymer for the delivery of small and macromolecule drugs. Conventional preparation methods of PLGA nanoparticles (NPs) result in poor control over NPs properties. In this research, a microfluidic mixer was designed to produce insulin-loaded PLGA NPs with tuned properties. Importantly; aggregation of the NPs through the mixer was diminished due to the coaxial mixing of the precursors. The micromixer allowed for the production of NPs with small size and narrow size distribution compared to the double emulsion solvent evaporation (DESE) method. Furthermore, encapsulation efficiency and loading capacity indicated a significant increase in optimized NPs produced through the microfluidic method in comparison to DESE method. NPs prepared by the microfluidic method were able to achieve a more reduction of trans-epithelial electrical resistance values in the Caco-2 cells compared to those developed by the DESE technique that leads to greater paracellular permeation. Compatibility and interaction between components were evaluated by differential scanning calorimetry and fourier transform infrared analysis. Also, the effect of NPs on cell toxicity was investigated using MTT test. Numerical simulations were conducted to analyze the effect of mixing patterns on the properties of the NPs. It was revealed that by decreasing flow rate ratio, i.e. flow rate of the organic phase to the flow rate of the aqueous phase, mixing of the two streams increases. As an alternative to the DESE method, high flexibility in modulating hydrodynamic conditions of the microfluidic mixer allowed for nanoassembly of NPs with superior insulin encapsulation at smaller particle sizes.

Preparation and characterization of solid lipid nanoparticles encapsulated noscapine and evaluation of its protective effects against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterized by thickening the epidermis with erythema, scaling, and proliferation. Noscapine (NOS) has several anti-inflammatory, anti-angiogenic, and anti-fibrotic effects, but its low solubility and large size results in its lower efficacy in the clinic. In this regard, solid lipid nanoparticles (SLN) encapsulated NOS (SLN-NOS) were fabricated using the well-known response surface method based on the central composite design and modified high-shear homogenization and ultrasound method. As a result, Precirol® was selected as the best lipid base for the SLN formulation based on Hildebrand-Hansen solubility parameters, in which SLN-NOS 1 % had the best zeta potential (-35.74 ± 2.59 mV), average particle size (245.66 ± 17 nm), polydispersity index (PDI, 0.226 ± 0.09), high entrapment efficiency (89.77 %), and ICH-based stability results. After 72 h, the SLN-NOS 1 % released 83.23 % and 58.49 % of the NOS at pH 5.8 and 7.4, respectively. Moreover, Franz diffusion cell's results indicated that the skin levels of NOS for SLN and cream formulations were 46.88 % and 13.5 % of the total amount, respectively. Our pharmacological assessments revealed that treatment with SLN-NOS 1 % significantly attenuated clinical parameters, namely ear thickness, length, and psoriasis area and severity index, compared to the IMQ group. Interestingly, SLN-NOS 1 % reduced the levels of interleukin (IL)-17, tumor necrosis factor-α, and transforming growth factor-ß, while elevating IL-10, compared to the IMQ group. Histology studies also showed that topical application of SLN-NOS 1 % significantly decreased parakeratosis, hyperkeratosis, acanthosis, and inflammation compared to the IMQ group. Taken together, SLN-NOS 1 % showed a high potential to attenuate skin inflammation.

Novel liposomal glatiramer acetate: Preparation and immunomodulatory evaluation in murine model of multiple sclerosis.

The frequent administration rate required for Glatiramer acetate (GA), a first-line therapy for Multiple sclerosis (MS), poses patient compliance issues. Only a small portion of the subcutaneously administered GA is available for phagocytosis by macrophages, as most of it is hydrolyzed at its administration site or excreted renally. To unravel these hurdles, we have prepared liposomal formulations of GA through thin film-hydration method plus extrusion. The clinical and histopathological efficacy of GA-loaded liposomes were assessed in prophylactic and therapeutic manners on murine model of MS (experimental autoimmune encephalomyelitis (EAE)). The selected GA liposomal formulation showed favorable size (275 nm on average), high loading efficiency, and high macrophage localization. Moreover, administration of GA-liposomes in mice robustly suppressed the inflammatory responses and decreased the inflammatory and demyelinated lesion regions in CNS compared to the free GA with subsequent reduction of the EAE clinical score. Our study indicated that liposomal GA could be served as a reliable nanomedicine-based platform to hopefully curb MS-related aberrant autoreactive immune responses with higher efficacy, longer duration of action, fewer administration frequencies, and higher delivery rate to macrophages. This platform has the potential to be introduced as a vaccine for MS after clinical translation and merits further investigations.

The crossroad of nanovesicles and oral delivery of insulin.

INTRODUCTION: Diabetes mellitus is one of the challenging health problems worldwide. Multiple daily subcutaneous injection of insulin causes poor compliance in patients. Development of efficient oral formulations to improve the quality of life of such patients has been an important goal in pharmaceutical industry. However, due to serious issues such as low bioavailability and instability, it has not been achieved yet. AREAS COVERED: Due to functional properties of the vesicles and the fact that hepatic-directed vesicles of insulin could reach the clinical phases, we focused on three main vesicular delivery systems for oral delivery of insulin: liposomes, niosomes, and polymersomes. Recent papers were thoroughly discussed to provide a broad overview of such oral delivery systems. EXPERT OPINION: Although conventional liposomes are unstable in the presence of bile salts, their further modifications such as surface coating could increase their stability in the GI tract. Bilosomes showed good flexibility and stability in GI fluids. Also, niosomes were stable, but they could not induce significant hypoglycemia in animal studies. Although polymersomes were effective, they are expensive and there are some issues about their safety and industrial scale-up. Also, we believe that other modifications such as addition of a targeting agent or surface coating of the vesicles could significantly increase the bioavailability of insulin-loaded vesicles.

Application of ensemble machine learning approach to assess the factors affecting size and polydispersity index of liposomal nanoparticles.

Liposome nanoparticles have emerged as promising drug delivery systems due to their unique properties. Assessing particle size and polydispersity index (PDI) is critical for evaluating the quality of these liposomal nanoparticles. However, optimizing these parameters in a laboratory setting is both costly and time-consuming. This study aimed to apply a machine learning technique to assess the impact of specific factors, including sonication time, extrusion temperature, and compositions, on the size and PDI of liposomal nanoparticles. Liposomal solutions were prepared and subjected to sonication with varying values for these parameters. Two compositions: (A) HSPC:DPPG:Chol:DSPE-mPEG2000 at 55:5:35:5 molar ratio and (B) HSPC:Chol:DSPE-mPEG2000 at 55:40:5 molar ratio, were made using remote loading method. Ensemble learning (EL), a machine learning technique, was employed using the Least-squares boosting (LSBoost) algorithm to accurately model the data. The dataset was randomly split into training and testing sets, with 70% allocated for training. The LSBoost algorithm achieved mean absolute errors of 1.652 and 0.0105 for modeling the size and PDI, respectively. Under conditions where the temperature was set at approximately 60 °C, our EL model predicted a minimum particle size of 116.53 nm for composition (A) with a sonication time of approximately 30 min. Similarly, for composition (B), the model predicted a minimum particle size of 129.97 nm with sonication times of approximately 30 or 55 min. In most instances, a PDI of less than 0.2 was achieved. These results highlight the significant impact of optimizing independent factors on the characteristics of liposomal nanoparticles and demonstrate the potential of EL as a decision support system for identifying the best liposomal formulation. We recommend further studies to explore the effects of other independent factors, such as lipid composition and surfactants, on liposomal nanoparticle characteristics.

Aptamer-modified chitosan-capped mesoporous silica nanoparticles for co-delivery of cytarabine and daunorubicin in leukemia.

In this study, surface modified mesoporous silica nanoparticles (MSNs) were prepared for the targeted delivery of the anticancer agents, daunorubicin (DNR) and cytarabine (CTR), against K562 leukemia cancer cell lines. The MSNs were surface-modified with pH-sensitive chitosan (CS) to prevent the burst release of anticancer agents at the physiological pH of 7.4 and to enable a higher drug release at lower pH and higher concentration of glutathione. Finally, the MSNs were surface modified with KK1B10 aptamer (Apt) to enhance their uptake by K562 cells through ligand-receptor interactions. The MSNs were characterized using different methods and both in vitro and in vivo experiments were utilized to demonstrate their suitability as targeted anticancer agents. The resultant MSNs exhibited an average particle size of 295 nm, a surface area of 39.06 m2/g, and a cumulative pore volume of 0.09 cm3/g. Surface modification of MSNs with chitosan (CS) resulted in a more regulated and acceptable continuous release rate of DNR. The drug release rate was significantly higher at pH 5 media enriched with glutathione, compared to pH 7.4. Furthermore, MSNs coated with CS and conjugated with aptamer (MSN-DNR + CTR@CS-Apt) exhibited a lower IC50 value of 2.34 µg/ml, compared to MSNs without aptamer conjugation, which displayed an IC50 value of 12.27 µg/ml. The results of the cell cycle analysis indicated that the administration of MSN-DNR + CTR@CS-Apt led to a significant increase in the population of apoptotic cells in the sub-G1 phase. Additionally, the treatment arrested the remaining cells in various other phases of the cell cycle. Furthermore, the interactions between Apt-receptors were found to enhance the uptake of MSNs by cancer cells. The results of in vivo studies demonstrated that the administration of MSN-DNR + CTR@CS-Apt led to a significant reduction in the expression levels of CD71 and CD235a markers, as compared to MSN-DNR + CTR@CS (p < 0.001). In conclusion, the surface modified MSNs prepared in this study showed lower IC50 against cancer cell lines and higher anticancer activity in animal models.

Optimizing nanoliposomal formulations: Assessing factors affecting entrapment efficiency of curcumin-loaded liposomes using machine learning.

BACKGROUND: Curcumin faces challenges in clinical applications due to its low bioavailability and poor water solubility. Liposomes have emerged as a promising delivery system for curcumin. This study aims to apply ensemble learning, a machine learning technique, to determine the most effective experimental conditions for formulating stable curcumin-loaded liposomes with a high entrapment efficiency (EE). METHODS: Two liposomal formulations composed of HSPC:DPPG:Chol:DSPE-mPEG2000 and HSPC:Chol:DSPE-mPEG2000 at 55:5:35:5 and 55:40:5 M ratios, respectively, were prepared using the remote loading method, and their particle size and polydispersity index (PDI) were determined using Dynamic Light Scattering. To model the impact of five factors (molar ratios, particle size, sonication time, pH, and PDI) on EE%, the Least-squares boosting (LSBoost) ensemble learning algorithm was employed due to its capability to effectively handle nonlinear and non-stationary problems. The implementation and optimization of LSBoost were performed using MATLAB R2020a. The dataset was randomly split into training and testing sets, with 70% allocated for training. The mean absolute error (MAE) was used as the cost function to evaluate model performance. Additionally, a novel approach was employed to visualize the results using 3D plots, facilitating practical interpretation. RESULTS: The optimal model exhibited an MAE of 3.61, indicating its robust predictive capability. The study identified several optimal conditions for achieving the highest EE value of 100%. However, to ensure both the highest EE value and a suitable particle size, it is recommended to set the following conditions: a molar ratio of 55:5:35:5, a PDI within the range of 0.09-0.13, a particle size of approximately 130 nm, a sonication time of 30 min, and a pH within the range of 7.2-8. It is worth mentioning that adjusting the molar ratio to 55:40:5 resulted in a maximum EE of 88.38%. CONCLUSION: These findings underscore the high performance of ensemble learning in accurately predicting and optimizing the EE of the curcumin-loaded liposomes. The application of this technique provides valuable insights and holds promise for the development of efficient drug delivery systems.

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.

Poly-γ-glutamic acid nanoparticles as adjuvant and antigen carrier system for cancer vaccination.

Vaccination is an innovative strategy for cancer treatment by leveraging various components of the patients' immunity to boost an anti-tumor immune response. Rationally designed nanoparticles are well suited to maximize cancer vaccination by the inclusion of immune stimulatory adjuvants. Also, nanoparticles might control the pharmacokinetics and destination of the immune potentiating compounds. Poly-γ-glutamic acid (γ-PGA) based nanoparticles (NPs), which have a natural origin, can be easily taken up by dendritic cells (DCs), which leads to the secretion of cytokines which ameliorates the stimulation capacity of T cells. The intrinsic adjuvant properties and antigen carrier properties of γ-PGA NPs have been the focus of recent investigations as they can modulate the tumor microenvironment, can contribute to systemic anti-tumor immunity and subsequently inhibit tumor growth. This review provides a comprehensive overview on the potential of γ-PGA NPs as antigen carriers and/or adjuvants for anti-cancer vaccination.

Improving the efficacy of peptide vaccines in cancer immunotherapy.

Peptide vaccines have shown great potential in cancer immunotherapy by targeting tumor antigens and activating the patient's immune system to mount a specific response against cancer cells. However, the efficacy of peptide vaccines in inducing a sustained immune response and achieving clinical benefit remains a major challenge. In this review, we discuss the current status of peptide vaccines in cancer immunotherapy and strategies to improve their efficacy. We summarize the recent advancements in the development of peptide vaccines in pre-clinical and clinical settings, including the use of novel adjuvants, neoantigens, nano-delivery systems, and combination therapies. We also highlight the importance of personalized cancer vaccines, which consider the unique genetic and immunological profiles of individual patients. We also discuss the strategies to enhance the immunogenicity of peptide vaccines such as multivalent peptides, conjugated peptides, fusion proteins, and self-assembled peptides. Although, peptide vaccines alone are weak immunogens, combining peptide vaccines with other immunotherapeutic approaches and developing novel approaches such as personalized vaccines can be promising methods to significantly enhance their efficacy and improve the clinical outcomes for cancer patients.

Alleviation of acetaminophen-induced liver failure using silibinin nanoliposomes: An in vivo study.

BACKGROUND: Acetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity. METHODS: We have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model. RESULTS: Data demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment. CONCLUSION: The results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.

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.