Immunogenic cell death-based cancer vaccines: promising prospect in cancer therapy.

Tumor immunotherapy is a promising approach for addressing the limitations of conventional tumor treatments, such as chemotherapy and radiotherapy, which often have side effects and fail to prevent recurrence and metastasis. However, the effectiveness and sustainability of immune activation in tumor immunotherapy remain challenging. Tumor immunogenic cell death, characterized by the release of immunogenic substances, damage associated molecular patterns (DAMPs), and tumor associated antigens, from dying tumor cells (DTCs), offers a potential solution. By enhancing the immunogenicity of DTCs through the inclusion of more immunogenic antigens and stimulating factors, immunogenic cell death (ICD) based cancer vaccines can be developed as a powerful tool for immunotherapy. Integrating ICD nanoinducers into conventional treatments like chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, and radiotherapy presents a novel strategy to enhance treatment efficacy and potentially improve patient outcomes. Preclinical research has identified numerous potential ICD inducers. However, effectively translating these findings into clinically relevant applications remains a critical challenge. This review aims to contribute to this endeavor by providing valuable insights into the in vitro preparation of ICD-based cancer vaccines. We explored established tools for ICD induction, followed by an exploration of personalized ICD induction strategies and vaccine designs. By sharing this knowledge, we hope to stimulate further development and advancement in the field of ICD-based cancer vaccines.

Analysis of standard unit carbon emission and cost assessment of the changing building envelope over material production phase.

It is undeniable that the material production stage is crucial to the whole life cycle of structures. This study proposes the window-to-envelope ratio (WER) based on standard units to determine the inherent relationship between changes in door and window areas and carbon emissions, presuming six distinct types of engineering practices for various buildings are selected. It was concluded that larger door and window areas would result in more embodied carbon emissions. Additionally, as the size of windows and doors increases, the costs and embodied carbon of prefabricated and cast-in-place construction become more comparable. According to the analysis, when the building scale is larger and the door and window opening area is also larger, prefabrication has more potential for saving carbon than cast-in-place building, but with a cost of approximately 10-20% higher. Considering the perspective of consumers, producers, and markets, this study revealed a costing assessment methodology based on standard units for prefabricated structures. In this methodology, producers choose and create various residential layouts based on the distinctive requirements of consumers, while tracking the trends in carbon emissions and production costs. This assessment method tries to create a favorable atmosphere for moral market activity and offers an acceptable solution for the trade-off between environmental and economic factors throughout the material production phase of the building.

Parameter-Insensitive Min Cut Clustering With Flexible Size Constrains.

Clustering is a fundamental topic in machine learning and various methods are proposed, in which K-Means (KM) and min cut clustering are typical ones. However, they may produce empty or skewed clustering results, which are not as expected. In KM, the constrained clustering methods have been fully studied while in min cut clustering, it still needs to be developed. In this paper, we propose a parameter-insensitive min cut clustering with flexible size constraints. Specifically, we add lower limitations on the number of samples for each cluster, which can perfectly avoid the trivial solution in min cut clustering. As far as we are concerned, this is the first attempt of directly incorporating size constraints into min cut. However, it is a NP-hard problem and difficult to solve. Thus, the upper limits is also added in but it is still difficult to solve. Therefore, an additional variable that is equivalent to label matrix is introduced in and the augmented Lagrangian multiplier (ALM) is used to decouple the constraints. In the experiments, we find that the our algorithm is less sensitive to lower bound and is practical in image segmentation. A large number of experiments demonstrate the effectiveness of our proposed algorithm.

Tunable electronic band structure and magnetic anisotropy in two-dimensional Dirac half-metal MnBr3 by external stimulus: strain, magnetization direction, and interlayer coupling.

Advancing technology and growing interdisciplinary fields create the need for new materials that simultaneously possess several significant physics qualities to meet human demands. Dirac half-metals with massless fermions hold great promise in spintronic devices and optoelectronic devices associated with nontrivial band topologies. In this work, we predict that a MnBr3 monolayer will be an intrinsic Dirac half-metal based on first-principles calculations. The lattice dynamics and thermodynamic stabilities were demonstrated by calculating the phonon spectra and performing molecular dynamics simulations. One property of a MnBr3 monolayer is that facile magnetization of its in-plane can be accomplished. A change in the magnetization direction significantly modifies the electronic band structure. When considering the spin-orbit coupling effect, the Dirac cone around the Fermi level in the spin-up channel opens a gap of 35 meV, which becomes a topological nontrivial insulator with a Chern number of -1. The Chern number sign and the chiral edge current can be tuned by changing the magnetization direction. The electronic band structure and magnetic anisotropy energy can be further modulated by applying biaxial and uniaxial strain, as well as introducing interlayer coupling in the bilayer. The unique performance of MnBr3 will broaden the utilization of two-dimensional magnetism in widespread application.

Treatment with Mesenchymal Stem Cell-Derived Nanovesicle-Containing Gelatin Methacryloyl Hydrogels Alleviates Osteoarthritis by Modulating Chondrogenesis and Macrophage Polarization.

Osteoarthritis is a degenerative disorder that can severely affect joints, and new treatment strategies are urgently needed. Administration of mesenchymal stem cell (MSC)-derived exosomes is a promising therapeutic strategy in osteoarthritis treatment. However, the poor yield of exosomes is an obstacle to the use of this modality in the clinic. Herein, a promising strategy is developed to fabricate high-yield exosome-mimicking MSC-derived nanovesicles (MSC-NVs) with enhanced regenerative and anti-inflammatory capabilities. MSC-NVs are prepared using an extrusion approach and are found to increase chondrocyte and human bone marrow MSC differentiation, proliferation, and migration, in addition to inducing M2 macrophage polarization. Furthermore, gelatin methacryloyl (GelMA) hydrogels loaded with MSC-NVs (GelMA-NVs) are formulated, which exhibit sustained release of MSC-NVs and are shown to be biocompatible with excellent mechanical properties. In a mouse osteoarthritis model constructed by surgical destabilization of the medial meniscus (DMM), GelMA-NVs effectively ameliorate osteoarthritis severity, reduce the secretion of catabolic factors, and enhance matrix synthesis. Furthermore, GelMA-NVs induce M2 macrophage polarization and inflammatory response inhibition in vivo. The findings demonstrate that GelMA-NVs hold promise for osteoarthritis treatment through modulation of chondrogenesis and macrophage polarization.

Robust Supervised and Semisupervised Least Squares Regression Using ℓ2,p-Norm Minimization.

Least squares regression (LSR) is widely applied in statistics theory due to its theoretical solution, which can be used in supervised, semisupervised, and multiclass learning. However, LSR begins to fail and its discriminative ability cannot be guaranteed when the original data have been corrupted and noised. In reality, the noises are unavoidable and could greatly affect the error construction in LSR. To cope with this problem, a robust supervised LSR (RSLSR) is proposed to eliminate the effect of noises and outliers. The loss function adopts l2,p -norm ( ) instead of square loss. In addition, the probability weight is added to each sample to determine whether the sample is a normal point or not. Its physical meaning is very clear, in which if the point is normal, the probability value is 1; otherwise, the weight is 0. To effectively solve the concave problem, an iterative algorithm is introduced, in which additional weights are added to penalize normal samples with large errors. We also extend RSLSR to robust semisupervised LSR (RSSLSR) to fully utilize the limited labeled samples. A large number of classification performances on corrupted data illustrate the robustness of the proposed methods.

Generalized and Robust Least Squares Regression.

As a simple yet effective method, least squares regression (LSR) is extensively applied for data regression and classification. Combined with sparse representation, LSR can be extended to feature selection (FS) as well, in which l1 regularization is often applied in embedded FS algorithms. However, because the loss function is in the form of squared error, LSR and its variants are sensitive to noises, which significantly degrades the effectiveness and performance of classification and FS. To cope with the problem, we propose a generalized and robust LSR (GRLSR) for classification and FS, which is made up of arbitrary concave loss function and the l2,p -norm regularization term. Meanwhile, an iterative algorithm is applied to efficiently deal with the nonconvex minimization problem, in which an additional weight to suppress the effect of noises is added to each data point. The weights can be automatically assigned according to the error of the samples. When the error is large, the value of the corresponding weight is small. It is this mechanism that allows GRLSR to reduce the impact of noises and outliers. According to the different formulations of the concave loss function, four specific methods are proposed to clarify the essence of the framework. Comprehensive experiments on corrupted datasets have proven the advantage of the proposed method.

Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization.

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.

Exosomes as drug delivery system in gastrointestinal cancer.

Gastrointestinal cancer is one of the most common malignancies with relatively high morbidity and mortality. Exosomes are nanosized extracellular vesicles derived from most cells and widely distributed in body fluids. They are natural endogenous nanocarriers with low immunogenicity, high biocompatibility, and natural targeting, and can transport lipids, proteins, DNA, and RNA. Exosomes contain DNA, RNA, proteins, lipids, and other bioactive components, which can play a role in information transmission and regulation of cellular physiological and pathological processes during the progression of gastrointestinal cancer. In this paper, the role of exosomes in gastrointestinal cancers is briefly reviewed, with emphasis on the application of exosomes as drug delivery systems for gastrointestinal cancers. Finally, the challenges faced by exosome-based drug delivery systems are discussed.

Unsupervised Adaptive Embedding for Dimensionality Reduction.

High-dimensional data are highly correlative and redundant, making it difficult to explore and analyze. Amount of unsupervised dimensionality reduction (DR) methods has been proposed, in which constructing a neighborhood graph is the primary step of DR methods. However, there exist two problems: 1) the construction of graph is usually separate from the selection of projection direction and 2) the original data are inevitably noisy. In this article, we propose an unsupervised adaptive embedding (UAE) method for DR to solve these challenges, which is a linear graph-embedding method. First, an adaptive allocation method of neighbors is proposed to construct the affinity graph. Second, the construction of affinity graph and calculation of projection matrix are integrated together. It considers the local relationship between samples and global characteristic of high-dimensional data, in which the cleaned data matrix is originally proposed to remove noise in subspace. The relationship between our method and local preserving projections (LPPs) is also explored. Finally, an alternative iteration optimization algorithm is derived to solve our model, the convergence and computational complexity of which are also analyzed. Comprehensive experiments on synthetic and benchmark datasets illustrate the superiority of our method.

Schisandrin B regulates macrophage polarization and alleviates liver fibrosis via activation of PPARγ.

BACKGROUND: Schisandrin B (Sch B), the main ingredient of Schisandra chinensis, displays many bioactivities. This study aimed to identify the drug target of Sch B against liver fibrosis and describe the related molecular mechanisms. METHODS: The effects of Sch B on liver fibrosis and macrophage polarization was investigated in vivo and in vitro. Furthermore, we analyzed the regulatory effect of Sch B on peroxisome proliferator-activated receptor gamma (PPARγ). RESULTS: Our data showed that Sch B dramatically alleviated liver inflammation and fibrosis and inhibited macrophage activation via PPARγ. Sch B binds with PPARγ by molecular docking. Immunofluorescence double staining showed that PPARγ was mainly expressed in macrophages rather than hepatic stellate cells (HSCs) in liver fibrosis. Importantly, Sch B strongly inhibited macrophage polarization in fibrotic livers compared with the model group. Further, the results revealed that Sch B efficiently inhibited macrophage polarization and also decreased the levels of inflammatory cytokines in vitro. Knockdown of PPARγ by small interfering RNA (siRNA) inhibited the effect of Sch B on macrophage polarization. Mechanistically, Sch B regulated macrophage polarization through inhibition of the nuclear factor (NF)-κB signaling pathway via PPARγ both in vivo and in vitro. CONCLUSIONS: These results suggested that Sch B alleviated carbon tetrachloride (CCl4)-induced liver inflammation and fibrosis by inhibiting macrophage polarization via targeting PPARγ.

Immunotherapy of Tumor RNA-Loaded Lipid Nanoparticles Against Hepatocellular Carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity. METHODS: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo. RESULTS: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth. CONCLUSION: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.

Preparation and Evaluation of Cabazitaxel-Loaded Bovine Serum Albumin Nanoparticles for Prostate Cancer.

PURPOSE: Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment. METHODS: CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo. RESULTS: The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile. CONCLUSION: In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.

The Matrine Derivate MASM Inhibits Recruitment of Gr1hi Monocyte and Alleviates Liver Injury.

BACKGROUNDS: (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), a novel derivative of matrine, exhibits better anti-inflammatory activity. This study was designed to evaluate the protective effect of MASM on acute and chronic liver injuries and explore the possible mechanisms. METHODS: Acute and chronic liver injury models were established by the CCl4 intraperitoneal injection and the protective effect of MASM was assessed by biochemical and histological examination. The infiltration of different monocyte subsets into the liver was characterized and analyzed by flow cytometry. The in vitro effect of MASM on liver nonparenchymal cells was evaluated by real-time PCR and transwell chemotaxis assays. RESULTS: Administration of MASM markedly attenuated acute liver injury and liver fibrosis induced by CCl4 injection. Meanwhile, the infiltrations of Gr1hi monocytes in injured livers and induced hepatic expression of monocyte chemoattractant protein-1 (MCP-1) were greatly inhibited. Cellular experiments demonstrated that MASM not only decreased the expression of MCP-1 but also inhibited its chemotactic activity. CONCLUSIONS: This study demonstrates that the protective effect of MASM on liver injury could be contributed to the suppression of Gr1hi monocyte infiltration to the liver and the inhibition of MCP-1 production and activity. These findings provide new insights into the protective role of MASM in liver injury.

Construction of ß-cyclodextrin-based supramolecular hyperbranched polymers self-assemblies using AB2-type macromonomer and their application in the drug delivery field.

Despite some efforts have been made in the research of supramolecular hyperbranched polymers (SHPs) self-assemblies, the study which has not been consideration to date is the influence of incoming stimuli-responsive polymer chain on their self-assembly property undergo outer stimuli. The introduction of stimuli-responsive segments which could maintain their hydrophilic property are expected to affect the self-assembly behaviour of SHPs and expand their further biomedical application. In this paper, AB2-type macromolecular monomer, LA-(CD-PDMA)2, which consisted one lithocholic acid (LA) and two ß-cyclodextrin terminated poly(2-(dimethylamino)ethyl methacrylate) segments (CD-PDMA) was synthesized. LA-(CD-PDMA)2 based SHP were obtained based on the host-guest inclusion interactions of CD/LA moietes and with PDMA as pH-responsive hydrophilic chains. As a control to study the influence of incoming PDMA chains, both LA-(CD-PDMA)2 based SHPs-1 and LA-CD2 based SHPs-2 self-assemblies were comparatively investiged through 2D 1H NMR ROESY, transmission electron microscopy (TEM) and dynamic light scattering (DLS). The results suggested that except for the higher drug loading efficiency LA-(CD-PDMA)2 based SHPs-1 pocessing, the release rates of SHPs-1 increased notably at pH 5.0 than that of pH 7.4 due to the repulsion and stretch of protonated PDMA chains while the release rates of SHPs-2 showed no obvious difference. Finally, basic cell experiments demonstrated that the SHPs based self-assemblies can be internalized into cancer cells, indicating their potential application in the drug delivery field.

Effects of D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles on the absorption, pharmacokinetics, and pharmacodynamics of salinomycin sodium.

Although salinomycin sodium (SS) has shown in-vitro potential to inhibit cancer stem cell growth and development, its low water solubility makes it a poor candidate as an oral chemotherapeutic agent. To improve the bioavailability of SS, SS was encapsulated here using D-α-tocopherol polyethylene glycol succinate (TPGS)-emulsified poly(lactic-co-glycolic acid) (PLGA) nanoparticles and compared with its parent SS in terms of absorption, pharmacokinetics, and efficacy in suppressing nasopharyngeal carcinomas stem cells. The pharmacokinetics of SS and salinomycin sodium-loaded D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles (SLN) prepared by nanoprecipitation were analyzed in-vivo by timed-interval blood sampling and oral administration of SS and SLN to rats. Sensitive liquid chromatography-mass spectrometry (LC-MS) was developed to quantify plasma drug concentrations. SS and SLN transport in Caco-2 cells was also investigated. The therapeutic efficacy of SS and SLN against cancer stem cells was determined by orally administering the drugs to mice bearing CNE1 and CNE2 nasopharyngeal carcinoma xenografts and then evaluating CD133 cell proportions and tumorsphere formation. The in-vivo trial with rats showed that the Cmax, AUC(0-t), and Tmax for orally administered SLN were all significantly higher than those for SS (P<0.05). These findings were corroborated by a Caco-2 cell Transwell assay showing that relative SLN absorption was greater than that of SS on the basis of their apparent permeability coefficients (Papp). Significantly, therapeutic SLN efficacy against nasopharyngeal carcinoma stem cells was superior to that of SS. TPGS-emulsified PLGA nanoparticles effectively increase SS solubility and bioavailability. SLN is, therefore, promising as an oral chemotherapeutic agent against cancer stem cells.

Co-Delivery of Docetaxel and Salinomycin to Target Both Breast Cancer Cells and Stem Cells by PLGA/TPGS Nanoparticles.

PURPOSE: Conventional chemotherapy is hampered by the presence of breast cancer stem cells (BCSCs). It is crucial to eradicating both the bulky breast cancer cells and BCSCs, using a combination of conventional chemotherapy and anti-CSCs drugs. However, the synergistic ratio of drug combinations cannot be easily maintained in vivo. In our previous studies, we demonstrated that the simultaneous delivery of two drugs via nanoliposomes could maintain the synergistic drug ratio for 12 h in vivo. However, nanoliposomes have the disadvantage of quick drug release, which makes it difficult to maintain the synergistic drug ratio for a long time. Herein, we developed a co-delivery system for docetaxel (DTX)-a first-line chemotherapy drug for breast cancer-and salinomycin (SAL)-an anti-BCSCs drug-in rigid nanoparticles constituted of polylactide-co-glycolide/D-alpha-tocopherol polyethylene glycol 1000 succinate (PLGA/TPGS). METHODS: Nanoparticles loaded with SAL and DTX at the optimized ratio (NSD) were prepared by the nanoprecipitation method. The characterization, cellular uptake, and cytotoxicity of nanoparticles were investigated in vitro, and the pharmacokinetics, tissue distribution, antitumor and anti-CSCs activity of nanoparticles were evaluated in vivo. RESULTS: We demonstrated that a SAL/DTX molar ratio of 1:1 was synergistic in MCF-7 cells and MCF-7-MS. Moreover, the enhanced internalization of nanoparticles was observed in MCF-7 cells and MCF-7-MS. Furthermore, the cytotoxicity of NSD against both MCF-7 cells and MCF-7-MS was stronger than the cytotoxicity of any single treatment in vitro. Significantly, NSD could prolong the circulation time and maintain the synergistic ratio of SAL to DTX in vivo for 24 h, thus exhibiting superior tumor targeting and anti-tumor activity compared to other treatments. CONCLUSION: Co-encapsulation of SAL and DTX in PLGA/TPGS nanoparticles could maintain the synergistic ratio of drugs in vivo in a better manner; thus, providing a promising strategy for synergistic inhibition of breast cancer.

Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles.

PURPOSE: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells. METHODS: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo. RESULTS: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity. CONCLUSION: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs.

Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer.

PURPOSE: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR) in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) liposomes (liposomal pemetrexed) were developed as a strategy to overcome MDR to pemetrexed in breast cancer. MATERIALS AND METHODS: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. RESULTS: Liposomal pemetrexed was small in size (160.77 nm), with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5) was 2.6-fold more effective than pemetrexed. The in vivo biodistribution study showed that the liposomes significantly accumulated in tumors 24 h after injection. The antitumor assay in mice bearing MDR breast cancer xenograft tumors confirmed the superior antitumor activity of liposomal pemetrexed over pemetrexed. It was also found that the improved therapeutic effect of liposomal pemetrexed may be attributed to apoptosis through both extrinsic and intrinsic pathways. CONCLUSION: Liposomal pemetrexed represents a potential therapeutic approach for overcoming breast cancer MDR.

Enhanced doxorubicin delivery to hepatocellular carcinoma cells via CD147 antibody-conjugated immunoliposomes.

HAb18G/CD147, an important marker in the progression of hepatocellular carcinoma (HCC), is highly expressed on the surface of HCC cells. To increase the therapeutic efficacy of Doxil (PEGylated liposomal doxorubicin) against HCC, we constructed CD147-targeted doxorubicin-loaded immunoliposomes (Anti-CD147 ILs-DOX) by conjugating F(ab')2 of a CD147-specific monoclonal antibody to DSPE-PEG-MAL, and then inserted the antibody-conjugated polymer to Doxil. Anti-CD147 ILs-DOX delivered DOX to CD147-overexpressing HCC cells specifically and efficiently in vitro and in vivo, resulting in enhanced therapeutic effects than non-targeted controls. Strikingly, Anti-CD147 ILs-DOX reduced the CD133-positive fraction of HCC cells, suggesting its potential in reducing the number of HCC stem cells. Pharmacokinetic and biodistribution studies of Anti-CD147 ILs-DOX confirmed its long circulation time and efficient accumulation in tumors. The superior antitumor effects of Anti-CD147 ILs-DOX than other treatments were demonstrated in both HCC cells and patient-derived HCC xenograft models. Anti-CD147 ILs-DOX represent a novel approach for targeted HCC therapy.