Promising Potential In Cancer Therapy Research Articles

Electrospun nanofibrous scaffolds reinforced with therapeutic lithium/manganese-doped calcium phosphates: Advancing skin cancer therapy through apoptosis induction

In the current study we fabricated potent materials by incorporating therapeutic elements into calcium phosphates (CPs) to combat cancer. This involved synthesizing manganese (Mn)- and lithium (Li)-doped CPs and loading them into electrospun nanofibers (NFs) composed of chitosan (CS) and polyethylene oxide (PEO). The characterized CPs exhibited excellent properties, including a particle size of 47–75 nm, surface charge of –(30−56) mV, and specific surface area of 75–266 m2/g. The electrochemical analysis revealed that Mn and Mn/Li-doped CPs are promising for generating oxygen free radicals and H2O2, crucial for cancer therapy. Biological evaluation showcased the outstanding performance of the developed materials. MTT assay revealed a cytotoxic effect of nano-constructs on melanoma A375 cell line without adverse effects on normal L929 cells over 72 h. Annexin V/PI apoptosis assay indicated substantial apoptosis rates in A375 cells treated with PC-20 % (62.55 ± 4.59 %). The obtained data of qPCR analysis of pro-apoptotic and anti-apoptotic genes (P53, Bax, Bcl-2) in A375 cells treated with different CP nanoparticles (NPs) showed a significant increase in P53 and Bax gene expression, indicating high levels of A375 cell apoptosis. Additionally, the samples containing Mn ion exhibited high reactive oxygen species (ROS) generation. In conclusion, the fabricated NFs scaffolds hold promising potential for cancer therapy.

From defense to offense: antimicrobial peptides as promising therapeutics for cancer.

Antimicrobial peptides (AMPs), naturally occurring components of innate immunity, are emerging as a promising new class of anticancer agents. This review explores the potential of AMPs as a novel class of anticancer agents. AMPs, naturally occurring peptides with broad-spectrum antimicrobial activity, exhibit several characteristics that make them attractive candidates for cancer therapy, including selectivity for cancer cells, broad-spectrum activity, and immunomodulatory effects. Analysis of a dataset of AMPs with anticancer activity reveals that their effectiveness is influenced by various structural properties, including net charge, length, Boman index, and hydrophobicity. These properties contribute to their ability to target and disrupt cancer cell membranes, interfere with intracellular processes, and modulate the immune response. The review highlights the promising potential of AMPs as a new frontier in cancer treatment, offering hope for more effective and less toxic therapies. AMPs demonstrate promising potential in cancer therapy through multiple mechanisms, including direct cytotoxicity, immune response modulation, and targeting of the tumor microenvironment, as evidenced by extensive preclinical studies in animal models showing tumor regression, metastasis inhibition, and improved survival rates. AMPs show significant potential as cancer therapeutics through their direct cytotoxicity, immune response modulation, and tumor microenvironment targeting, with promising results from preclinical studies and early-phase clinical trials. Future research should focus on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies to fully realize their potential as effective cancer treatments, while addressing challenges related to stability, delivery, and potential toxicity.

Recent Advancements in Polymeric N-Nitrosamine-Based Nitric Oxide (NO) Donors and their Therapeutic Applications.

Nitric oxide (NO), a gasotransmitter, is known for its wide range of effects in vasodilation, cardiac relaxation, and angiogenesis. This diatomic free radical also plays a pivotal role in reducing the risk of platelet aggregation and thrombosis. Furthermore, NO demonstrates promising potential in cancer therapy as well as in antibacterial and antibiofilm activities at higher concentrations. To leverage their biomedical activities, numerous NO donors have been developed. Among these, N-nitrosamines are emerging as a notable class, capable of releasing NO under suitable photoirradiation and finding a broad range of therapeutic applications. This review discusses the design, synthesis, and biological applications of polymeric N-nitrosamines, highlighting their advantages over small molecular NO donors in terms of stability, NO payload, and target-specific delivery. Additionally, various small-molecule N-nitrosamines are explored to provide a comprehensive overview of this burgeoning field. We anticipate that this review will aid in developing next-generation polymeric N-nitrosamines with improved physicochemical properties.

DNA aptamer-empowered self-assembly full-API nanodrug for enhanced photodynamic and chemotherapy synergistic cancer therapy

Nanomedicine holds promising potential for cancer therapy, yet challenges such as low active pharmaceutical ingredient (API), nanocarrier toxicity, complex preparation processes, and a lack of targeting ability hinder clinical applications. Here, we present a versatile method for preparing DNA aptamer-based full-API nanodrugs (ICS AFANDs). This approach involves the self-assembly of FDA-approved chemotherapeutics (irinotecan), photosensitive drugs (Chlorin e6, Ce6), and the DNA molecule of the Sgc8 aptamer. DNA aptamers are firstly confirmed to not only impart solubilization and targeting ability to ICS AFANDs but also play a pivotal role in engineering and stabilizing the formation of self-assembled nanodrugs. Our method not only significantly enhances the chemotherapy effectiveness of irinotecan by 102-fold, but also improves the near-infrared (NIR) fluorescence properties and photoactivity of Ce6. Combining photodynamic therapy (PDT) and chemotherapy (CT), our ICS AFANDs achieve complete suppression of colorectal cancer growth, with only one dose and one laser treatment, all without apparent side effects. Our strategy is a versatile method for preparing carrier-free and multifunctional DNA nanodrugs for synergistic tumor therapy. The smart and efficient full-API DNA nanodrug not only broadens the scope of synergistic tumor therapy but also facilitates the practical translation of DNA nanodrugs to clinical use.

A Phyto-mycotherapeutic Supplement, Namely Ganostile, as Effective Adjuvant in Brain Cancer Management: An In Vitro Study Using U251 Human Glioblastoma Cell Line.

The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening quality of life (QoL). Recently, Complementary and Integrative Medicine's (CIM) innovative approaches have shown positive impacts in terms of better response to treatment, side effect reduction, and QoL improvement. In particular, promising potential in cancer therapy has been found in compounds coming from phyto- and mycotherapy. The objective of this study was to demonstrate the beneficial effects of a new phyto-mycotherapy supplement, named Ganostile, in the human glioblastoma cell line U251, in combination with chemotherapeutic agents, i.e., Cisplatin and a new platinum-based prodrug. Choosing a supplement dosage that mimicked oral supplementation in humans (about 1 g/day), through in vitro assays, microscopy, and cytometric analysis, it has emerged that the cells, after 48hr continuous exposure to Ganostile in combination with the chemical compounds, showed a higher mortality and a lower proliferation rate than the samples subjected to the different treatments administered individually. In conclusion, our data support the use of Ganostile in integrative oncology protocols as a promising adjuvant able to amplify conventional and new drug effects and also reducing resistance mechanisms often observed in brain tumors.

Amino acid‐decorated mesoporous silica nanoparticles loaded with titanocene derivatives for targeted anticancer studies

Nanostructured materials possess promising potential for cancer therapy through precise adjustment of their functionalization and physicochemical attributes. This study primarily focuses on the synthesis and characterization of mesoporous silica nanoparticles (MSN) that are functionalized with titanocene dichloride (a therapeutic agent) and one of several amino acids—cysteine, captopril, penicillamine, or methionine—utilizing 3‐aminopropyltriethoxysilane (AP) as a linker. This synthesis yielded four innovative metallodrug‐functionalized nanostructured materials (MSN‐AP‐Cys‐Ti, MSN‐AP‐Cap‐Ti, MSN‐AP‐Pen‐Ti, and MSN‐AP‐Met‐Ti), meticulously characterized using diverse analytical techniques such as X‐ray diffraction (XRD), X‐ray fluorescence (XRF), diffuse reflectance ultraviolet–visible (DR UV–Vis), Fourier transform infrared (FTIR), solid‐state nuclear magnetic resonance (NMR) spectroscopy, and transmission electron microscopy (TEM). The textural properties of the nanomaterials post‐functionalization displayed slight modifications, confirming the successful integration of the therapeutic agents. Evaluation of cytotoxicity in the breast cancer cell line MDA‐MB‐231, with the healthy cell line Hek‐293T as control via MTT assays, revealed the active nature of the functionalized silica‐based materials. The viability of both cell lines indicated a concentration‐dependent response to the materials. Among the tested systems, cysteine and captopril exhibited the highest activity concerning IC50 relative to material concentration. The enhanced biological activity of higher functionalized nanosystems suggests a favorable cell internalization facilitated by the amino acid fragment. Additionally, qualitative DNA binding studies hinted at potential DNA adsorption on the surface of the metallodrug‐functionalized nanomaterials, forming DNA adducts where a strand of DNA covalently bonds to the metallodrug moiety. This was deduced from the hypsochromic shift in absorbance of the characteristic π–π* and n–π* transitions in DNA, which occurred from 1.01 to 0.76 and 1.26–0.19 following drug (MSN‐AP‐Cap‐Ti) interaction.

Glycosidase-activated H2S donorsto enhance chemotherapy efficacy

Hydrogen sulfide (H2S) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (H2S) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, H2S was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. H2S release was also detected by H2S probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated H2S donors were evaluated against HepG2 by MTT assay. Among them, Man1 and Man2 exhibited an obvious reduction of cell viability in HepG2 cells, with cell viability as 37.6 % for 80 μM of Man. Consistently, significant apoptosis was observed in HepG2 cells after treatment with Man1 and Man2. Finally, We evaluated the potential of Man1 for combination therapy with doxorubicin. A synergistic effect was observed between Man1 and Doxorubicin in HepG2 and Hela cells. All these results indicated glycosidase-activated H2S donorshave promising potential for cancer therapy.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

Enhancing photothermal therapy of tumors with image-guided thermal control of gene-expressing bacteria.

Purpose: Bacteria-mediated tumor therapy has showed promising potential for cancer therapy. However, the efficacy of bacterial monotherapy treatment which can express and release therapeutic proteins in tumors has been found to be unsatisfactory. To date, synergistic therapy has emerged as a promising approach to achieve stronger therapeutic outcomes compared to bacterial monotherapy. It is a challenge to visualize these tumor-homing bacteria in vivo and guide them to express and release in situ therapeutic proteins. Procedure: We have developed a kind of engineered bacteria (named CGB@ICG) genetically incorporating acoustic reporter proteins and thermo-inducible ClyA expression gene circuit and chemically modified with indocyanine green on the bacterial surface. The presence of acoustic reporter proteins and indocyanine green facilitates the visualization of CGB@ICG via contrast-enhanced ultrasound imaging and optical imaging, making it possible to guide the sound wave or laser to irradiate precisely these bacteria for inducing the expression of ClyA protein via acoustic- or photothermal effects. The expression and secretion of ClyA protein in the tumor, combined with photothermal therapy, greatly enhanced the anti-tumor efficacy of the engineered bacteria and improved their biosafety. Results: We successfully performed multimodal imaging of CGB@ICG in vivo resulting in remoting control the expression of ClyA protein in tumor. In vivo experiments showed that bacteria-mediated therapy combined photothermal therapy exhibited a rapid decrease in tumor volume compared to other groups, while the tumor volume of the combination therapy group continued to decrease and even achieved complete healing. Thus, combination therapy not only reduced the rate of tumor growth but also prevented the proliferation of tumor cells for an extended period. Conclusion: Our study demonstrated that CGB@ICG serves as an efficacious imaging agent and delivery vector to combine engineered bacteria with photothermal therapy, holding great promise for tumor treatment.

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity

BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 μM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 μM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

In Vitro/In Vivo Preparation and Evaluation of cRGDyK Peptide-Modified Polydopamine-Bridged Paclitaxel-Loaded Nanoparticles.

Cancer remains a disease with one of the highest mortality rates worldwide. The poor water solubility and tissue selectivity of commonly used chemotherapeutic agents contribute to their poor efficacy and serious adverse effects. This study proposes an alternative to the traditional physicochemically combined modifications used to develop targeted drug delivery systems, involving a simpler surface modification strategy. cRGDyK peptide (RGD)-modified PLGA nanoparticles (NPs) loaded with paclitaxel were constructed by coating the NP surfaces with polydopamine (PD). The average particle size of the produced NPs was 137.6 ± 2.9 nm, with an encapsulation rate of over 80%. In vitro release tests showed that the NPs had pH-responsive drug release properties. Cellular uptake experiments showed that the uptake of modified NPs by tumor cells was significantly better than that of unmodified NPs. A tumor cytotoxicity assay demonstrated that the modified NPs had a lower IC50 and greater cytotoxicity than those of unmodified NPs and commercially available paclitaxel formulations. An in vitro cytotoxicity study indicated good biosafety. A tumor model in female BALB/c rats was established using murine-derived breast cancer 4T1 cells. RGD-modified NPs had the highest tumor-weight suppression rate, which was higher than that of the commercially available formulation. PTX-PD-RGD-NPs can overcome the limitations of antitumor drugs, reduce drug toxicity, and increase efficacy, showing promising potential in cancer therapy.

Bismuth Oxide (Bi2O3) Nanoparticles Cause Selective Toxicity in a Human Endothelial (HUVE) Cell Line Compared to Epithelial Cells.

A review of recent literature suggests that bismuth oxide (Bi2O3, referred to as B in this article) nanoparticles (NPs) elicit an appreciable response only after a concentration above 40-50 µg/mL in different cells all having an epithelial origin, to the best of our knowledge. Here, we report the toxicological profile of Bi2O3 NPs (or BNPs) (71 ± 20 nm) in a human endothelial cell (HUVE cell line) in which BNPs exerted much steeper cytotoxicity. In contrast to a high concentration of BNPs (40-50 µg/mL) required to stimulate an appreciable toxicity in epithelial cells, BNPs induced 50% cytotoxicity in HUVE cells at a very low concentration (6.7 µg/mL) when treated for 24 h. BNPs induced reactive oxygen species (ROS), lipid peroxidation (LPO), and depletion of the intracellular antioxidant glutathione (GSH). BNPs also induced nitric oxide (NO,) which can result in the formation of more harmful species in a fast reaction that occurs with superoxide (O2•-). Exogenously applied antioxidants revealed that NAC (intracellular GSH precursor) was more effective than Tiron (a preferential scavenger of mitochondrial O2•-) in preventing the toxicity, indicating ROS production is extra-mitochondrial. Mitochondrial membrane potential (MMP) loss mediated by BNPs was significantly less than that of exogenously applied oxidant H2O2, and MMP loss was not as intensely reduced by either of the antioxidants (NAC and Tiron), again suggesting BNP-mediated toxicity in HUVE cells is extra-mitochondrial. When we compared the inhibitory capacities of the two antioxidants on different parameters of this study, ROS, LPO, and GSH were among the strongly inhibited biomarkers, whereas MMP and NO were the least inhibited group. This study warrants further research regarding BNPs, which may have promising potential in cancer therapy, especially via angiogenesis modulation.

Comparative and Functional Analyses Reveal Conserved and Variable Regulatory Systems That Control Lasalocid Biosynthesis in Different Streptomyces Species.

Lasalocid, a representative polyether ionophore, has been successfully applied in veterinary medicine and animal husbandry and also displays promising potential for cancer therapy. Nevertheless, the regulatory system governing lasalocid biosynthesis remains obscure. Here, we identified two conserved (lodR2 and lodR3) and one variable (lodR1, found only in Streptomyces sp. strain FXJ1.172) putative regulatory genes through a comparison of the lasalocid biosynthetic gene cluster (lod) from Streptomyces sp. FXJ1.172 with those (las and lsd) from Streptomyces lasalocidi. Gene disruption experiments demonstrated that both lodR1 and lodR3 positively regulate lasalocid biosynthesis in Streptomyces sp. FXJ1.172, while lodR2 plays a negative regulatory role. To unravel the regulatory mechanism, transcriptional analysis and electrophoretic mobility shift assays (EMSAs) along with footprinting experiments were performed. The results revealed that LodR1 and LodR2 could bind to the intergenic regions of lodR1-lodAB and lodR2-lodED, respectively, thereby repressing the transcription of the lodAB and lodED operons, respectively. The repression of lodAB-lodC by LodR1 likely boosts lasalocid biosynthesis. Furthermore, LodR2 and LodE constitute a repressor-activator system that senses changes in intracellular lasalocid concentrations and coordinates its biosynthesis. LodR3 could directly activate the transcription of key structural genes. Comparative and parallel functional analyses of the homologous genes in S. lasalocidi ATCC 31180T confirmed the conserved roles of lodR2, lodE, and lodR3 in controlling lasalocid biosynthesis. Intriguingly, the variable gene locus lodR1-lodC from Streptomyces sp. FXJ1.172 seems functionally conserved when introduced into S. lasalocidi ATCC 31180T. Overall, our findings demonstrate that lasalocid biosynthesis is tightly controlled by both conserved and variable regulators, providing valuable guidance for further improving lasalocid production. IMPORTANCE Compared to its elaborated biosynthetic pathway, the regulation of lasalocid biosynthesis remains obscure. Here, we characterize the roles of regulatory genes in lasalocid biosynthetic gene clusters of two distinct Streptomyces species and identify a conserved repressor-activator system, LodR2-LodE, which could sense changes in the concentration of lasalocid and coordinate its biosynthesis with self-resistance. Furthermore, in parallel, we verify that the regulatory system identified in a new Streptomyces isolate is valid in the industrial lasalocid producer and thus applicable for the construction of high-yield strains. These findings deepen our understanding of regulatory mechanisms involved in the production of polyether ionophores and provide novel clues for the rational design of industrial strains for scaled-up production.

Trienzyme-like Co3O4@TiO2-x nanozymes for heterojunction-enhanced nanocatalytic-sonodynamic tumor therapy

Nanozymes have shown promising potential in cancer therapy owing to the advantages of low-cost, excellent stability, and high reproducibility. However, the inherent low catalytic activity of nanozymes and highly complex tumor microenvironment (TME) severely restricted the clinical applications of nanocatalytic therapy. Herein, we first reported a heterojunction (HJ)-enhanced nanocatalytic-sonodynamic therapy platform based on Co3O4@TiO2-x Z-scheme HJs by depositing Co3O4 nanoparticles (NPs) onto TiO2-x nanosheets (NSs). Co3O4@TiO2-x HJs not only exhibited excellent ultrasound (US)-triggered reactive oxygen species (ROS) generation ability, but also possessed triple enzyme-mimic activities (peroxidase-mimic, catalase-mimic, and GSH depletion activities) to realize the amplification of ROS levels and relieve tumor hypoxia. More importantly, the triple enzyme-mimic activities and sonodynamic properties of single-component Co3O4 or TiO2-x were greatly enhanced by the construction of Z-scheme HJs owing to the accelerate carrier transfer process and improved spatial separation dynamics of US-generated electron-hole pairs. The synergetic therapeutic effect of Co3O4@TiO2-x through HJ-enhanced nanocatalytic-sonodynamic therapy could achieve complete tumor eradication without recurrence. Our work will open up a promising approach to engineer semiconductor HJs with both sonodynamic and enzyme-mimic activities for enhanced nanocatalytic-sonodynamic combination therapy.

Influence of chain length on the anticancer activity of the antimicrobial peptide CAMEL with fatty acid modification

Antimicrobial peptides (AMPs) display promising potential in cancer therapy. Modification with fatty acids is a simple and effective approach to improve the activity of AMPs. In the present study, we investigated the effects of fatty acid chain lengths on the anticancer activity, self-assembly and mechanism of action of CAMEL (CM15, KWKLFKKIGAVLKVL-NH2), an amphipathic AMP with 15 amino acids. Conjugation of fatty acids could obviously improve the in vitro anticancer activity of CAMEL. Among the tested peptides, C12-CAMEL showed the highest anticancer activity, while C16-CAMEL killed cancer cells with the slowest kinetics. This may be related to the self-assembly of C12-CAMEL and C16-CAMEL, which could form spherical nanoparticles and tightened nanofibers, respectively. In addition, necrosis and necroptosis rather than apoptosis were the major mechanisms underlying the anticancer activity of CAMEL, C12-CAMEL and C16-CAMEL, implying that modification with fatty acids did not obviously alter the mechanism of action of CAMEL. Notably, C12-CAMEL, with high and rapid cell-killing activity, exhibited significantly stronger in vivo anticancer activity than CAMEL and C16-CAMEL. Overall, the present work suggests that the choice of a suitable fatty acid for structural modification is necessary for improving the anticancer activity of AMPs.

A site-oriented nanosystem for active transcellular chemo-immunotherapy to prevent tumor growth and metastasis

Immunotherapy has shown promising potential in cancer therapy; however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapy-enhanced immunotherapy. When arriving at the tumor site, the matrix metallopeptidase 2 (MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and site-oriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues, recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.

Albumin Nanostructures for Nucleic Acid Delivery in Cancer: Current Trend, Emerging Issues, and Possible Solutions.

Simple SummaryNucleic acids are showing tremendous potential in cancer therapy. However, their successful delivery to tumor sites is still a challenge. Herein, we report on the use of albumin-based nanocarriers for the delivery of nucleic acids because of their biosafety, ease of surface modification, and tumor targeting. In addition, we discuss various surface modification strategies to improve the internalization, efficacy, and specific tumor targeting of the albumin nanocarriers. Cancer is one of the major health problems worldwide, and hence, suitable therapies with enhanced efficacy and reduced side effects are desired. Gene therapy, involving plasmids, small interfering RNAs, and antisense oligonucleotides have been showing promising potential in cancer therapy. In recent years, the preparation of various carriers for nucleic acid delivery to the tumor sites is gaining attention since intracellular and extracellular barriers impart major challenges in the delivery of naked nucleic acids. Albumin is a versatile protein being used widely for developing carriers for nucleic acids. It provides biocompatibility, tumor specificity, the possibility for surface modification, and reduces toxicity. In this review, the advantages of using nucleic acids in cancer therapy and the challenges associated with their delivery are presented. The focus of this article is on the different types of albumin nanocarriers, such as nanoparticles, polyplexes, and nanoconjugates, employed to overcome the limitations of the direct use of nucleic acids in vivo. This review also highlights various approaches for the modification of the surface of albumin to enhance its transfection efficiency and targeted delivery in the tumor sites.

In vivo toxicity and antitumor activity of newly green synthesized reduced graphene oxide/silver nanocomposites

A novel biosynthesis of dual reduced graphene oxide/silver nanocomposites (rGO/AgNC) using the crude metabolite of Escherichia coli D8 (MF06257) strain and sunlight is introduced in this work. Physicochemical analysis of these rGO/AgNC revealed that they are sheet-like structures having spherically shaped silver nanoparticles (AgNPs) with an average particle size of 8 to 17 nm, and their absorption peak ranged from 350 to 450 nm. The biosynthesized rGO/AgNC were characterized by UV–vis and FT-IR spectra, X-ray diffraction, Zeta potential and transmission electron microscopy. After the injection of these nanocomposites to mice, their uptake by the kidney and liver has been proven by the ultrastructural observation and estimation of the hepatic and renal silver content. These nanocomposites caused a moderate toxicity for both organs. Changes in the liver and kidney functions and histopathological effects had been observed. The rGO/AgNC revealed a remarkable antitumor effect. They showed a dose-dependent cytotoxic effect on Ehrlich ascites carcinoma (EAC) cells in vitro. Treatment of mice bearing EAC tumors intraperitoneally with 10 mg/kg rGO/AgNC showed an antiproliferative effect on EAC cells, reduced ascites volume, and maintained mice survival. The results indicate that this green synergy of silver nanoparticles with reduced graphene oxide may have a promising potential in cancer therapy.

Developing natural killer cells producing hypoxia-inducible cytokines for effective immunotherapy against solid tumors.

Abstract Natural Killer (NK) cells are a promising means for adoptive immunotherapy for cancers. NK cell therapies against hematological cancers such as acute myeloid leukemia have demonstrated good efficacy. However, the poor effector function of tumor-infiltrating NK cells limits the potential of NK cells against solid tumors. Accumulating data suggests that hypoxia in the tumor microenvironment (TME) suppresses the effector function of NK cells. One of the immunosuppressive features of hypoxia is the generation of adenosine, a metabolite that highly suppresses NK cell cytotoxicity and proliferation. Although engineering NK cells to overexpress stimulatory cytokines before the adoptive immunotherapy has demonstrated promising potential for cancer therapy, it raises a concern that high systemic levels of cytokines may lead to cytokine-mediated pathology. Therefore, we hypothesize that driving overexpression of the potent stimulatory cytokines exclusively in the TME would circumvent systemic toxicity. An attractive strategy to achieve this goal is to take advantage of the hypoxic condition, a key characteristic of the TME. Hypoxia-inducible factor 1 alpha (HIF1-α) plays a pivotal role in expressing hypoxia-responsive genes by associating with promoters containing hypoxia response element (HRE). By mimicking the biological system, HRE-induced cytokine expression vectors were generated and tested in NK cells. The expression was inducible under hypoxic conditions and was reversible upon re-oxygenated conditions. Our results suggest that the hypoxia-inducible vector system can be beneficial to trigger TME specific cytokine expressions in NK cells and provide insight into efficient immunotherapy against solid tumors.

A Red Light‐Triggered Drug Release System Based on One‐Photon Upconversion‐Like Photolysis

Photoresponsive drug release systems can enhance drug accumulation at the sites where light is applied. Nowadays, the photocleavable groups used in the systems usually require ultraviolet or blue light irradiation, which limits tissue penetration depth and is harmful to normal cells and living bodies. A one-photon upconversion-like photolysis strategy, which can cleave green light-activatable prodrugs with red light at the presence of a red light-excitable photosensitizer in organic solvents, is developed. However, both the prodrug and photosensitizer are hydrophobic and their energy transfer process is sensitive to oxygen molecules. Here, a simple strategy to address these problems by loading the two components in biocompatible and biodegradable polymeric micelles, is presented. The developed low-irradiance red light-triggered drug release system has a size around 40nm and exhibits good stability in aqueous solutions. The micellar encapsulation protects the photolysis reaction from oxygen quenching in normoxia aqueous solutions. The therapeutic effect of the system enhanced by the redlight irradiation is demonstrated through in vitro and in vivo studies, indicating promising potential in cancer therapy. The study provides the first example and also an important reference for applying one-photon upconversion-like photolysis in biomedical applications.