Nanodrug Delivery Systems in Antitumor Immunotherapy.

Cancer has become one of the most important factors threatening human health, and the global cancer burden has been increasing rapidly. Immunotherapy has become another clinical research hotspot after surgery, chemotherapy, and radiotherapy because of its high efficiency and tumor metastasis prevention. However, problems such as lower immune response rate and immune-related adverse reaction in the clinical application of immunotherapy need to be urgently solved. With the development of nanodrug delivery systems, various nanocarrier materials have been used in the research of antitumor immunotherapy with encouraging therapeutic results. In this review, we mainly summarized the combination of nanodrug delivery systems and immunotherapy from the following 4 aspects: (a) nanodrug delivery systems combined with cytokine therapy to improve cytokines delivery in vivo; (b) nanodrug delivery systems provided a suitable platform for the combination of immune checkpoint blockade therapy with other tumor treatments; (c) nanodrug delivery systems helped deliver antigens and adjuvants for tumor vaccines to enhance immune effects; and (d) nanodrug delivery systems improved tumor treatment efficiency and reduced toxicity for adoptive cell therapy. Nanomaterials chosen by researchers to construct nanodrug delivery systems and their function were also introduced in detail. Finally, we discussed the current challenges and future prospects in combining nanodrug delivery systems with immunotherapy.

Anticancer Mechanisms and Potential Anticancer Applications of Antimicrobial Peptides and Their Nano Agents.

Traditional chemotherapy is one of the main methods of cancer treatment, which is largely limited by severe side effects and frequent development of multi-drug resistance by cancer cells. Antimicrobial peptides (AMPs) with high efficiency and low toxicity, as one of the most promising new drugs to replace chemoradiotherapy, have become a current research hotspot, attracting the attention of worldwide researchers. AMPs are natural-source small peptides from the innate immune system, and certain AMPs can selectively kill a broad spectrum of cancer cells while exhibiting less damage to normal cells. Although it involves intracellular mechanisms, AMPs exert their anti-cancer effects mainly through membrane destruction effect; thus, AMPs also hold unique advantages in fighting drug-resistant cancer cells. However, the poor stability and hemolytic toxicity of peptides limit their clinical application. Fortunately, functionalized nanoparticles have many possibilities in overcoming the shortcomings of AMPs, which provides a huge prospect for better application of AMPs. In this paper, we briefly introduce the characteristics and different sources of AMPs, review and summarize the mechanisms of action and the research status of AMPs used as an anticancer therapy, and finally focus on the further use of AMPs nano agents in the anti-cancer direction.

MMP-2 Responsive Peptide Hydrogel-Based Nanoplatform for Multimodal Tumor Therapy.

Introduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release. Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed. Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy. Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.

Study of the skin-penetration promoting effect and mechanism of combined system of curcumin liposomes prepared by microfluidic chip and skin penetrating peptides TD-1 for topical treatment of primary melanoma.

The transdermal drug delivery system (TDDS) is an effective strategy for the treatment of melanoma with fewer side effects and good biocompatible, but the skin penetration of drugs should be further promoted. Here, we proposed a new system that combined curcumin liposomes (Cur-Lips) with skin-penetrating peptides to promote skin penetration ability. However, the preparation of Cur-Lips has drawbacks of instability and low entrapment efficiency by the traditional methods. We thus innovatively designed and applied a microfluidic chip to optimize the preparation of Cur-Lips. Cur-Lips exhibited a particle size of 106.22 ± 4.94 nm with a low polydispersity index (＜0.3) and high entrapment efficiency of 99.33 ± 1.05 %, which were prepared by the microfluidic chip. The Cur-Lips increased the skin penetration capability of Cur by 2.76 times compared to its solution in vitro skin penetration experiment. With the help of skin-penetrating peptide TD-1, the combined system further promoted the skin penetration capability by 4.48 times. The (TD-1 + Cur-Lips) system also exhibited a superior inhibition effect of the tumor to B16F10 in vitro. Furthermore, the topical application of (TD-1 + Cur-Lips) gel suppressed melanoma growth in vivo, and induced tumor cell apoptosis in tumor tissues. The skin-penetration promotion mechanism of the system was investigated. It was proved that the system could interact with the lipids and keratin on the stratum corneum to promote the Cur distribute into the stratum corneum through hair follicles and sweat glands. We proved that the microfluidic chips had unique advantages for the preparation of liposomes. The innovative combined system of liposomes and biological transdermal enhancers can effectively promote the skin penetration effect of drugs and have great potential for the prevention and treatment of melanoma.

Zi-Su-Zi decoction improves airway hyperresponsiveness in cough-variant asthma rat model through PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cough-variant asthma (CVA) is one of the most common causes of chronic cough. Its pathogenesis is closely related to chronic airway inflammation and airway hyperresponsiveness. CVA belongs to the category of "wind cough" in Traditional Chinese medicine (TCM). Zi-Su-Zi decoction (ZSD) is a Chinese herbal formula that is clinically used for the treatment of cough and asthma, especially CVA. However, the mechanism of action remains unclear. AIM OF THE STUDY: In this study, we aimed to explore the potential mechanism by which ZSD improves CVA airway hyperresponsiveness. MATERIALS AND METHODS: The targets of ZSD in CVA were studied using a Network pharmacology. The main chemical components of ZSD were detected and analyzed using ultra-high-pressure liquid chromatography (UHPLC-MS/MS). In animal experiments, the rat model of CVA was established using Ovalbumin (OVA)/Aluminum hydroxide (AL(OH)3) sensitization. Moreover, the experiment also evaluated cough symptoms, percentage of eosinophils (EOS%), pulmonary function tests, histopathological sections, blood cytokine levels, mRNA and protein levels. RESULTS: The results showed that Network pharmacology suggested 276 targets of ZSD and CVA and found that ZSD treatment with CVA was closely related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. UHPLC-MS/MS revealed that ZSD contained 52 main chemical components. Compared with the model group, the cough symptoms of the rats in the different ZSD concentration groups were relieved, the EOS% index was lowered, and body weight was increased. HE staining showed that ZSD reduced airway inflammation, edema and hyperplasia, thereby improving the pathological structure of lung tissue, and the effect of high-dose ZSD was especially significant. Our most important finding was that ZSD blocked the entry of hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription-3 (STAT3) and nuclear factor kappa-B (NF-κB) into the nucleus by interfering with PI3K/AKT1/mechanistic target of rapamycin (mTOR), and janus kinase 2 (JAK2) signaling factors. Consequently, inhibiting the release of cytokines and immunoglobulin-E, thereby reducing airway hyperresponsiveness (AHR) and partially reverses airway remodeling. CONCLUSIONS: This study showed that ZSD can improve airway hyperresponsiveness and partially reverse airway remodeling by inhibiting the PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways. Therefore, ZSD is an effective prescription for the treatment of CVA.

Stimulus-responsive nano lipidosome for enhancing the anti-tumour effect of a novel peptide Dermaseptin-PP.

OBJECTIVE: Dermaseptin-PP is a newly discovered anticancer peptide with a unique antitumour mechanism and remarkable effect. However, this α-helix anticancer peptide risks haemolysis when used at high doses, which limits its further application. This study aims to prepare a pH-responsive liposome, Der-loaded-pHSL, using nanotechnology to avoid the haemolysis risk of Dermaseptin-PP and increase its accumulation in tumour sites to enhance efficacy and reduce toxicity. METHODS: The characterisation of Der-loaded-pHSL was carried out employing preparation. The effect of haemolysis and tumour inhibition were investigated by in vitro haemolysis assay and cytotoxicity assay. The cell uptake under different pH conditions was investigated by flow cytometry, and the effect of pH on tumour cell selectivity was evaluated. In order to evaluate the in vivo targeting and antitumour effect of Der-loaded-pHSL, the in vivo distribution experiment and the pharmacodynamic experiment were performed using the nude mouse tumour model. RESULTS: The preparation method of the Der-loaded-pHSL is simple, and the liposome has good nanoparticle characteristics. When Dermaseptin-PP was prepared as liposome, haemolysis was significantly decreased, and tumour cell inhibition was significantly enhanced. Compared with ordinary liposomes, this change was more significant in Der-loaded-pHSL. The uptake of pH-sensitive liposomes was higher in the simulated acidic tumour microenvironment, and the uptake showed a specific acid dependence. In vivo experiments showed that Der-loaded-pHSL had a significant tumour-targeting effect and could significantly enhance the antitumour effect of Dermaseptin-PP. CONCLUSION: Der-loaded-pHSL designed in this study is a liposome with a quick, simple, effective preparation method, which can significantly reduce the haemolytic toxicity of Dermaseptin-PP and enhance its antitumour effect by increasing the tumour accumulation and cell intake. It provides a new idea for applying Dermaseptin-PP and other anticancer peptides with α-helical structure.

[Application of traditional Chinese medicine theory in modern traditional Chinese medicine nano-preparation: taking tumor treatment as an example].

With Zang-Fu organs, meridians, Qi and blood, and body fluid as the physiological and pathological basis, traditional Chinese medicine(TCM) theory is guided by the holistic concept and characterized by syndrome differentiation. It has made significant contributions to human health maintenance and disease prevention. Modern TCM preparation is developed on the basis of inheriting and developing TCM preparations using modern science and technology under the guidance of TCM theory. At present, the incidence and mortality of common tumors are increasing. TCM has rich clinical experience in the treatment of tumors. However, in the current stage, some TCM preparations have a tendency to deviate from the guidance of TCM theory. With the modernization of TCM, it is worth considering how TCM theory guides modern TCM preparations. Taking tumor treatment as an example, this paper introduced the development of TCM nano-preparation under the influence of modern nanotechnology, summarized the research on the development of modern TCM nano-preparation from the aspects of TCM holistic concept, TCM treatment principles, and TCM theory application, and discussed the application prospect of TCM nano-preparation in overall therapy, drug pairing, carrier selection, and targeted substance selection under the guidance of TCM theory. This paper provides new references for further developing the combination of tradition and modernization of TCM nano-preparation.

Combined Thermosensitive Gel Co-Loaded with Dermaseptin-PP and PTX Liposomes for Effective Local Chemotherapy.

Introduction: Chemotherapeutic drugs are often ineffective due to the delivery. Local chemotherapy, which has high drug concentration, low systemic toxicity, and long duration, has shown excellent potential. Cationic antimicrobial peptides have been proved to enhance the tumor cells' uptake of chemotherapeutic drugs through the membrane-breaking effect. In this study, we designed and developed a thermosensitive gel co-loaded with Dermaseptin-PP and paclitaxel liposomes to increase local chemotherapy. Methods: The paclitaxel liposomes were prepared. Then, it was co-loaded with Dermaseptin-PP in a poloxamer-based thermosensitive gel to obtain Dermaseptin-PP/paclitaxel liposomes gel. The thermosensitivity of gels was investigated by test tube inversion method. The rheology was tested by rheometer. The in vitro cytotoxicity and the permeation in tumor of gels were examined by H157 cells and the 3D cell model, respectively. The retention in tumor and antitumor activity of gels were evaluated by H157 tumor-bearing nude mice. Results: The particle size of paclitaxel liposomes was 148.97 ± 0.21 nm. The encapsulation rate was 86.1%, and the drug loading capacity was 19.4%. The gels had slow-release and temperature-sensitive properties. The porous 3D network structure of the gels could ensure that the drug was fixed into the tumor. In vitro and in vivo distribution studies showed that Dermaseptin-PP promoted the permeation of the gels in H157 multicellular tumor spheres and achieved longer retention in tumor. In vitro and in vivo antitumor studies demonstrated that Dermaseptin-PP/paclitaxel liposomes gel significantly inhibited the growth of tumors for local chemotherapy with good biosafety. Conclusion: This study provided a promising nanomedicine platform for combining antimicrobial peptides and chemotherapeutic drugs for local chemotherapy.

Combined Chemo-Immuno-Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform.

Tumor metastasis and recurrence are recognized to be the main causes of failure in cancer treatment. To address these issues, an "all in one" and "one for all" nanoplatform was established for combined "chemo-immuno-photothermal" therapy with the expectation to improve the antitumor efficacy. Herein, Docetaxel (DTX, a chemo-agent) and cynomorium songaricum polysaccharide (CSP, an immunomodulator) were loaded into zein nanoparticles coated by a green tea polyphenols/iron coordination complex (GTP/FeIII, a photothermal agent). From the result, the obtained nanoplatform denoted as DTX-loaded Zein/CSP-GTP/FeIII NPs was spherical in morphology with an average particle size of 274 nm, and achieved pH-responsive drug release. Moreover, the nanoplatform exhibited excellent photothermal effect both in vitro and in vivo. It was also observed that the nanoparticles could be effectively up take by tumor cells and inhibited their migration. From the results of the in vivo experiment, this nanoplatform could completely eliminate the primary tumors, prevent tumor relapses on LLC (Lewis lung cancer) tumor models, and significantly inhibit metastasis on 4T1 (murine breast cancer) tumor models. The underlying mechanism was also explored. It was discovered that this nanoplatform could induce a strong ICD effect and promote the release of damage-associated molecular patterns (DAMPs) including CRT, ATP, and HMGB1 by the dying tumor cells. And the CSP could assist the DAMPs in inducing the maturation of dendritic cells (DCs) and facilitate the intratumoral infiltration of T lymphocytes to clear up the residual or disseminated tumor cells. In summary, this study demonstrated that the DTX-loaded Zein/CSP-GTP/FeIII is a promising nanoplatform to completely inhibit tumor metastasis and recurrence.

Studies of Mucosal Irritation and Cellular Uptake Mechanisms of Xingnaojing Nanoemulsion

Abstract Xingnaojing (XNJ) injection was used to treat pneumonia and stroke in clinic in China, but with poor patient compliance. Xingnaojing nanoemulsion for intranasal delivery was developed to improve it. This article tried to evaluate the mucosal irritation of Xingnaojing nanoemulsion and investigate cellular uptake mechanism of its encapsulated lipophilic drugs. The toad palate model and rat nasal mucosa model were used to study the nasal ciliotoxicity and nasal mucosal irritation of nanoemulsion to evaluate its safety intranasally. The cellular uptake mechanism was studied by Calu-3 cell model. Coumarin 6 was encapsulated in nanoemulsion and the endocytic pathways were studied by cellular uptake experiments after being treated with different inhibitors. In toad palate model, the cilia movement of Xingnaojing nanoemulsion group last for 467.40 ± 39.02 min, which was obviously longer than deoxycholate group (90.60 ± 15.40 min). Studies on rats showed that the damage caused by nanemulsion is capable of being recovered. Nanoemulsion uptake was reduced obviously when cells were treated with wortmannin, and it also decreased about 13% when the temperature reduced from 37ºC to 4ºC. Mucosal irritation caused by nanoemulsion is low and the damage is recoverable. The cellular uptake of Xingnaojing nanoemulsion is energy-dependent, and macropinocytosis was the most important pathway for cellular uptake.

Study on the Mechanism of Baimai Ointment in the Treatment of Osteoarthritis Based on Network Pharmacology and Molecular Docking with Experimental Verification.

Purpose: The external preparation of the Tibetan medicine formula, Baimai ointment (BMO), has great therapeutic effects on osteoarthritis (OA). However, its molecular mechanism remains almost elusive. Here, a comprehensive strategy combining network pharmacology and molecular docking with pharmacological experiments was adopted to reveal the molecular mechanism of BMO against OA. Methods: The traditional Chinese medicine for systems pharmacology (TCMSP) database and analysis platform, traditional Chinese medicine integrated database (TCMID), GeneCards database, and DisGeNET database were used to screen the active components and targets of BMO in treating OA. A component-target (C-T) network was built with the help of Cytoscape, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment through STRING. Autodock Tools which was used to dock the key components and key target proteins was analyzed. Animal experiments were performed to verify the key targets of BMO. Hematoxylin-eosin and toluidine blue staining were used to observe the pathology of joints. Protein expression was determined using enzyme-linked immunosorbent assay. Results: Bioactive compounds and targets of BMO and OA were screened. The network analysis revealed that 17-ß-estradiol, curcumin, licochalone A, quercetin, and glycyrrhizic acid were the candidate key components, and IL6, tumor necrosis factor (TNF), MAPK1, VEGFA, CXCL8, and IL1B were the candidate key targets in treating OA. The KEGG indicated that the TNF signaling pathway, NF-κB signaling pathway, and HIF-1 signaling pathway were the potential pathways. Molecular docking implied a strong combination between key components and key targets. The pathology and animal experiments showed BMO had great effects on OA via regulating IL6, TNF, MAPK1, VEGFA, CXCL8, and IL1B targets. These findings were consistent with the results obtained from the network pharmacology approach. Conclusion: This study preliminarily illustrated the candidate key components, key targets, and potential pathways of BMO against OA. It also provided a promising method to study the Tibetan medicine formula or external preparations.

[Puerarin-Chuanxiong oil submicron emulsion combining medicine and adjuvant].

This study was mainly based on the compatibility of Puerariae Lobatae Radix and Chuanxiong Rhizoma to prepare submicron emulsion and evaluated its physical and pharmaceutical properties. Firstly, pseudo-ternary phase diagrams were drawn by dripping method which took Chuanxiong oil as the oil phase and the area of microemulsion region as the index. On this basis, suitable emulsifier and co-emulsifier were screened for the preparation of Chuanxiong oil submicron emulsion. Then, the formula realizing the largest oil loading was selected. Finally, puerarin substituted part of emulsifier and co-emulsifier to lower their content, so as to form puerarin-Chuanxiong oil submicron emulsion featuring the combination of medicine and adjuvant. Its particle size, zeta potential, centrifugal stability and storage stability were determined, and the in vitro drug release behavior was investigated by dialysis bag method, based on which the quality of the as-prepared submicron emulsion was evaluated comprehensively. The proposed method was proved feasible for the preparation of Chuanxiong oil submicron emulsion, which adopted polyoxyethylene castor oil(EL-40) as the emulsifier and was free from co-emulsifier. The formula of the maximum oil loading was found as Chuanxiong oil∶EL-40∶water 3∶7∶90. Further, puera-rin successfully replaced up to 10% of the emulsifier in submicron emulsion. Eventually, the optimal drug-loading formula was determined as puerarin∶Chuanxiong oil∶EL-40∶water 7∶30∶63∶900. The quality evaluation results of the as-prepared submicron emulsion demonstrated that the average emulsion droplet size was 333.9 nm, the PDI 0.26, and the zeta potential-10.12 mV. The submicron emulsion had a good centrifugal stability and did not present any instable phenomena such as delamination and precipitation during its standing still for 50 days. The evaluation of in vitro drug release behavior indicated that the submicron emulsion was capable of releasing the drug completely. The puerarin-chuanxiong oil submicron emulsion prepared in this study possessed a stable quality and to some extent increased the solubility of puerarin along with a sustained-release effect. This study provided ideas for the clinical application of puerarin.

Combined photothermal-immunotherapy via poly-tannic acid coated PLGA nanoparticles for cancer treatment.

Photothermal therapy (PTT) is able to ablate tumors via hyperthermia, while immunotherapy could prevent tumor recurrence and metastasis by activating the host immune responses. Therefore, the combination of PTT and immunotherapy offers great advantages for the treatment of cancer. To achieve this goal, poly tannic acid (pTA) coated PLGA nanoparticles (PLGA-pTA NPs) were synthesized for combined photothermal-immunotherapy. pTA was a coordination complex formed by TA and Fe3+ and it could be easily coated on PLGA NPs within seconds with a coating rate of 5.89%. As a photothermal agent, PLGA-pTA revealed high photothermal conversion efficiency and excellent photo-stability upon 808 nm laser irradiation. It also exhibited strong photothermal cytotoxicity against 4T1 cells. Moreover, PLGA-pTA based PTT could effectively trigger DC maturation since it could induce the release of DAMPs. The result of animal experiments showed that PLGA-pTA plus laser irradiation raised the tumor temperature up to ca. 60 °C and effectively suppressed the growth of primary tumors. What's more, the progression of distant tumors as well as lung metastasis was also significantly inhibited due to the activation of anti-tumor responses by PLGA-pTA mediated PTT. When further combined with anti-PD-L1 antibody (a-PD-L1), the tumor growth and metastasis were almost completely inhibited. Our study provided a versatile platform to achieve combined photothermal-immunotherapy with enhanced therapeutic efficacy.

Recent strategies for nano-based PTT combined with immunotherapy: from a biomaterial point of view.

Cancer has been a great threat to humans for decades. Due to the limitations of monotherapy, combinational therapies such as photothermal therapy (PTT) and immunotherapy have gained increasing attention with expectation to overcome the shortfalls of each other and obtain satisfactory therapeutic outcomes. PTT can inhibit primary tumors by thermal ablation but usually fails to achieve complete eradication and cannot prevent metastasis and recurrence. Meanwhile, the efficacy of immunotherapy is usually attenuated by the weak immunogenicity of tumor and the immunosuppressive tumor microenvironment (ITM). Therefore, many recent studies have attempted to synergize PTT with immunotherapy in order to enhance the therapeutic efficacy. In this review, we aim to summarize the cutting-edge strategies in combining nano-based PTT with immunotherapy for cancer treatment. Herein, the combination strategies were mainly classified into four categories, including 1) nano-based PTT combined with antigens to induce host immune responses; 2) nano-based PTT in combination with immune adjuvants acting as in situ vaccines; 3) nano-based PTT synergized with immune checkpoint blockade or other regulators to relieve the ITM; 4) nano-based PTT combined with CAR-T therapy or cytokine therapy for tumor treatment. The characteristics of various photothermal agents and nanoplatforms as well as the immunological mechanisms for the synergism were also introduced in detail. Finally, we discussed the existing challenges and future prospects in combined PTT and immunotherapy.

In vitro activities of a novel antimicrobial peptide isolated from phyllomedusa tomopterna.

Because of the abuse of antibiotics, clinical strains began to become more drug-resistant. Their evolution has long surpassed the speed of us looking for a new generation of antibacterial drugs. Therefore, it is urgent to discover a new antimicrobial substance to alleviate the pressure on conventional antibiotics. Antimicrobial peptides (AMP) are known for their significant activity towards a broad spectrum of bacteria, protozoa, yeasts, filamentous fungi. Here, we report a novel AMP named Dermaseptin-TO. Results demonstrate that Dermaseptin-TO can quickly exhibit antimicrobial activity to bacteria and yeast in a dose-related way. The highest minimum inhibit concentration (MIC) was observed in the E.faecalis group (128 µM). Also, haemolytic outcomes showed no more than 10.65% of red blood cells were affected when in the same concentrations or below. Besides, Dermaseptin-TO also showed anticancer activity at a higher concentration. From the above, evidence proved that Phyllomedusine frog skin secretion is still a rich source that contains novel AMP and Dermaseptin-TO is competent to become an antimicrobial agent, its anticancer activity may broaden the way in basic cancer research. Also, following the same templates in molecular cloning may acquire new AMP classes with potent antimicrobial effects that could widen drug design in new anti-infective drugs.

Poly-tannic acid coated paclitaxel nanocrystals for combinational photothermal-chemotherapy.

Combinational photothermal-chemotherapy offers great advantages for the treatment of cancer. To achieve this goal, the poly-tannic acid (pTA) coated paclitaxel nanocrystals (PNC) were prepared, which was denoted as PNC-pTA. Herein, paclitaxel (PTX) was prepared as nanocrystals acting as chemo-agent for chemotherapy. And the tannic acid formed a pTA layer coated on PNC in the presence of Fe3+ serving as a potential agent for photothermal therapy (PTT). PNC-pTA was around 470 nm in rod shape and the pTA content was determined to be 11.50 ± 0.48 wt% by mass ratio. pTA exhibited photothermal effect upon laser irradiation of 808 nm, and this effect could be strengthened with the increased amount of Fe3+ in pTA. Moreover, pTA showed excellent photostability under repeated laser irradiation. And with the aid of pTA, the cellular uptake of PNC-pTA was greatly enhanced for different cancerous cell lines. PNC-pTA plus laser irradiation showed much stronger cytotoxicity against the 4T1 cell line compared with that without laser irradiation. And the result of animal experiments showed that PNC-pTA exhibited mild photothermal effect in vivo and the strongest tumor inhibition effect upon laser irradiation compared with single photothermal therapy or chemotherapy. These results confirmed the combinational chemo-photothermal effect of PNC-pTA. Our study provided a versatile platform to achieve combined photothermal-chemotherapy with enhanced therapeutic efficacy.

Albumin coated trimethyl chitosan-based targeting delivery platform for photothermal/chemo-synergistic cancer therapy.

Current metastatic breast cancer therapies are not only affected by limited drug delivery options, but also restricted to the monotherapies. Here, we synthesized trimethyl chitosan (TMC), loaded it with photosensitizer IR780 or bufalin by ionic gelation, and coated it with human serum albumin (HSA) by electrostatic absorption (designated TIH or TBH, respectively). The near-spherical nanoparticles had a size of approximately 30 nm, exerted strong photothermal effects, and enhanced cellular mitochondrion colocation and phototoxicity. Tumor microenvironments were disrupted by TIH-mediated photothermal effects, which enhanced the accumulation of a second TBH dose in the tumor that promoted deep penetration in the whole tumor mass. After laser irradiation our nanoplatform enhanced cancer tissue accessibility and substantially suppressed tumor growth, and causing a 98.46 % inhibition of lung metastasis. Thus HSA-masked TMC represents a promising tumor-targeted drug delivery strategy with synergistic modality that may improve the therapeutic outcome of metastatic breast cancer.

Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study.

Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.

Focus on Notoginsenoside R1 in Metabolism and Prevention Against Human Diseases.

Notoginsenoside (NG)-R1 is one of the main bioactive compounds from Panax notoginseng (PN) root, which is well known in the prescription for mediating the micro-circulatory hemostasis in human. In this article, we mainly discuss NG-R1 in metabolism and the biological activities, including cardiovascular protection, neuro-protection, anti-diabetes, liver protection, gastrointestinal protection, lung protection, bone metabolism regulation, renal protection, and anti-cancer. The metabolites produced by deglycosylation of NG-R1 exhibit higher permeability and bioavailability. It has been extensively verified that NG-R1 may ameliorate ischemia-reperfusion (IR)-induced injury in cardiovascular and neuronal systems mainly by upregulating the activity of estrogen receptor α-dependent phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor erythroid-2-related factor 2 (NRF2) pathways and downregulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. However, no specific targets for NG-R1 have been identified. Expectedly, NG-R1 has been used as a main bioactive compound in many Traditional Chinese Medicines clinically, such as Xuesaitong, Naodesheng, XueShuanTong, ShenMai, and QSYQ. These suggest that NG-R1 exhibits a significant potency in drug development.

Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer.

Purpose: Maytansine (DM1) is a potent anticancer drug and limited in clinical application due to its poor water solubility and toxic side effects. Zein is widely used in nano drug delivery systems due to its good biocompatibility. In this study, we prepared DM1-loaded zein nanoparticles (ZNPs) to achieve tumor targeting and reduce toxic side effects of DM1. Methods: ZNPs were prepared by phase separation and Box-Behnken design was used to optimize the formulation. Then, confocal fluorescence microscope and flow cytometry were used to determine cellular uptake of ZNPs. A549 cells were cultured in vitro to study cytotoxicity and used to establish tumor xenografts in nude mice. Biodistribution and antitumor activity of ZNPs were performed in vivo experiments. In addition, we also performed histological and immunohistochemical examinations on tumors and viscera. Results: The optimal prescription was obtained by using 120 µL zein added to 2 mL water under stirring in 300 rpm. The encapsulation efficiency and drug loading were 82.97 ± 0.80% and 3.32 ± 0.03%, respectively. We found that DM1-loaded ZNPs have a strong inhibitory effect on A549 cells, which stemmed from the ability of ZNPs to enhance cellular uptake. Furthermore, we demonstrated that DM1-loaded ZNPs exhibits a better antitumor efficacy than DM1, which tumor inhibition rate were 97.3% and 92.7%, respectively. The biodistribution revealed that ZNPs could targeted to tumor. Finally, we confirmed by histological that DM1-loaded ZNPs are nontoxic. Conclusion: DM1-loaded ZNPs have considerable antitumor activity. Thus, DM1-loaded ZNPs are a promising treatment of non-small cell lung cancer.