Low Systemic Toxicity Research Articles

Comparison of tumor-derived total RNA and cell lysate on antitumor immune activity

Tumor-derived total RNA (TdRNA) and cell lysate (TCL), with almost all the relevant tumor antigens, represent attractive alternative sources of antigens in antitumor immunotherapy. However, the comparison of their capacity to elicit immune responses against breast cancer is still lacking. In this study, the antitumor immune effects of TdRNA and TCL were systematically compared. We isolated TdRNA and TCL from 4T1 mouse breast cancer cells, and found that both sources of antigens could stimulate the maturation of dendritic cells (DCs) at the cellular and in vivo levels, and induce robust cellular immune responses, as evidenced by the increased percentages of both CD4+ and CD8+ T cells in the inguinal lymph nodes and spleen. But TdRNA performed stronger immunoactivities than TCL on the increase of T cell population through DCs activation. Additionally, the synergistic antitumor efficacy of paclitaxel (PTX) with TdRNA and TCL respectively was further evaluated in the murine 4T1 tumor model. Compared with TCL, TdRNA could inhibit tumor growth more effectively with low systemic toxicity when combined with PTX, which was, at least in part, attributable to the improvement of systemic immune function and tumor immune infiltration. Overall, TdRNA outperforms TCL in antitumor immunity, and is expected to be a promising candidate for application as the source of tumor antigens.

Boosting Checkpoint Immunotherapy with Biomaterials.

The immune checkpoint blockade (ICB) therapy has revolutionized the field of cancer treatment, while low response rates and systemic toxicity limit its clinical outcomes. With the rapid advances in nanotechnology and materials science, various types of biomaterials have been developed to maximize therapeutic efficacy while minimizing side effects by increasing tumor antigenicity, reversing immunosuppressive microenvironment, amplifying antitumor immune response, and reducing extratumoral distribution of checkpoint inhibitors as well as enhancing their retention within target sites. In this review, we reviewed current design strategies for different types of biomaterials to augment ICB therapy effectively and then discussed present representative biomaterial-assisted immune modulation and targeted delivery of checkpoint inhibitors to boost ICB therapy. Current challenges and future development prospects for expanding the ICB with biomaterials were also summarized. We anticipate this review will be helpful for developing emerging biomaterials for ICB therapy and promoting the clinical application of ICB therapy.

Mitochondria-targeting sonosensitizer-loaded extracellular vesicles for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as an effective therapeutic modality as it employs ultrasound (US) to eradicate deep-seated tumors noninvasively. However, the therapeutic efficacy of SDT in clinical settings remains limited owing to the low aqueous stability and poor pharmacokinetic properties of sonosensitizers. In this study, extracellular vesicles (EVs), which have low systemic toxicity, were used as clinically available nanocarriers to effectively transfer a sonosensitizer to cancer cells. Chlorin e6 (Ce6), a sonosensitizer, was conjugated to a mitochondria-targeting triphenylphosphonium (TPP) moiety and loaded into EVs to enhance the efficacy of SDT, because mitochondria are critical subcellular organelles that regulate cell survival and death. Additionally, piperlongumine (PL), a pro-oxidant and cancer-specific chemotherapeutic agent, was co-encapsulated into EVs to achieve efficient and selective anticancer activity. The EVs substantially amplified the cellular internalization of TPP-conjugated Ce6 (TPP-Ce6), resulting in the enhanced generation of intracellular reactive oxygen species (ROS) in MCF-7 human breast cancer cells upon US exposure. Importantly, EVs encapsulating TPP-Ce6 effectively destroyed the mitochondria under irradiation with US, leading to efficient anticancer activity. The co-encapsulation of pro-oxidant PL into EVs significantly enhanced the SDT efficacy in MCF-7 cells through the excessive generation of ROS. Moreover, the EV co-encapsulating TPP-Ce6 and PL [EV(TPP-Ce6/PL)] exhibited cancer-specific cell death owing to the cancer-selective apoptosis triggered by PL. In vivo study using MCF-7 tumor-xenograft mice revealed that EV(TPP-Ce6/PL) effectively accumulated in tumors after intravenous injection. Notably, treatment with EV(TPP-Ce6/PL) and US inhibited tumor growth significantly without causing systemic toxicity. This study demonstrated the feasibility of using EV(TPP-Ce6/PL) for biocompatible and cancer-specific chemo-SDT.

Anti-Hypoxia Nanoplatforms for Enhanced Photosensitizer Uptake and Photodynamic Therapy Effects in Cancer Cells.

Photodynamic therapy (PDT) holds great promise in cancer eradication due to its target selectivity, non-invasiveness, and low systemic toxicity. However, due to the hypoxic nature of many native tumors, PDT is frequently limited in its therapeutic effect. Additionally, oxygen consumption during PDT may exacerbate the tumor's hypoxic condition, which stimulates tumor proliferation, metastasis, and invasion, resulting in poor treatment outcomes. Therefore, various strategies have been developed to combat hypoxia in PDT, such as oxygen carriers, reactive oxygen supplements, and the modulation of tumor microenvironments. However, most PDT-related studies are still conducted on two-dimensional (2D) cell cultures, which fail to accurately reflect tissue complexity. Thus, three-dimensional (3D) cell cultures are ideal models for drug screening, disease simulation and targeted cancer therapy, since they accurately replicate the tumor tissue architecture and microenvironment. This review summarizes recent advances in the development of strategies to overcome tumor hypoxia for enhanced PDT efficiency, with a particular focus on nanoparticle-based photosensitizer (PS) delivery systems, as well as the advantages of 3D cell cultures.

Preparation and characterization of cetuximab-loaded egg serum albumin nanoparticles and their uses as a drug delivery system against Caco-2 colon cancer cells

To avoid the harmful side effects of cetuximab and improve its therapeutic efficacy, egg serum albumin (ESA) was used as a targeting drug carrier moiety for cancer therapy against Caco-2 colon cancer cells. The simple improved desolvation method was used to synthesize ESA nanoparticles (ESA-NPs) and cetuximab-loaded albumin nanoparticles (CET-ANPs) with glutaraldehyde as a crosslinking agent. The ESA-NPs and CET-ANPs were spherically shaped, and their sizes and surface potentials were 100 and − 24 nm and 170 and − 20 nm, respectively, as determined using transmission electron microscopy (TEM) and a Zeta potential analyzer. The specific functional groups of the prepared nanoparticles were revealed by FTIR analysis. In the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, CET-ANPs exerted the highest antitumor activity after 24 h followed by CET, ESA-NPs, and pure ESA. Combination of CET + ESA-NPs at different IC50 concentrations at ratios of 1:1, 1:2, 2:1, 1:4, 4:1, 1:9, or 9:1 showed significant synergistic effects with a combination index (CI) > 1. Furthermore, the CET either loaded with ESA-NPs or administered in combination (CET + ESA NPs) caused significant apoptotic damage, as well as an S-phase or G2/M cell cycle arrest to the cancer cells, respectively. These were directly linked with a significant upregulation of mRNA expression of Caspase3 and Bax genes and an extreme downregulation of the mRNA expression of Bcl2, particularly in the combination treatment group, as compared to the untreated cells. Finally, ESA-NPs improved the effectiveness of cetuximab, strongly caused apoptotic and antiproliferative action with lower systemic toxicity, and could be suggested for the targeted administration of anticancer medications in various nanosystems.

Supramolecular Theranostic Nanomedicine for In Situ Self-Boosting Cancer Photochemotherapy.

Although traditional nanomedicines have enhanced the therapeutic efficacy and improved the survival quality of cancer patients, random drug release and drug resistance are deep-rooted problems hindering their clinical application. A precise nanoplatform combing chemotherapy and photodynamic therapy (PDT) is developing as a new therapeutic strategy to overcome the above challenges. Herein, a novel supramolecular nanomedicine is ingeniously constructed for in situ self-boosting cancer photochemotherapy. Hydrophilic polyethylene glycol (PEG) chains or β-cyclodextrin (β-CD) hosts are first conjugated onto tetraphenyl porphyrin (TCPP) to improve the solubility of TCPP and decrease their π-π stacking interactions, guaranteeing a high-efficiency PDT. Then, two camptothecin (CPT) molecules are linked together via a reactive oxygen species (ROS)-responsive thioketal bond, which averts the premature burst release of CPT and realizes in situ drug release at the tumor site where PDT is performed, resulting in an enhanced chemotherapy. Benefiting from the collaboration of host-guest complexation between β-CD and CPT, multiple intermolecular hydrogen bonds of β-CD, π-π stacking interactions among CPT and TCPP as well as PEG shell protection, a prolonged blood circulation time, and a selective tumor accumulation are acquired, which facilitate the synergistic photochemotherapy and bring a pre-eminent antitumor response with a low systemic toxicity.

Lipid Nanoparticles Functionalized with Antibodies for Anticancer Drug Therapy.

Nanotechnology takes the lead in providing new therapeutic options for cancer patients. In the last decades, lipid-based nanoparticles-solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, and lipid-polymer hybrid nanoparticles-have received particular interest in anticancer drug delivery to solid tumors. To improve selectivity for target cells and, thus, therapeutic efficacy, lipid nanoparticles have been functionalized with antibodies that bind to receptors overexpressed in angiogenic endothelial cells or cancer cells. Most papers dealing with the preclinical results of antibody-conjugated nanoparticles claim low systemic toxicity and effective tumor inhibition, which have not been successfully translated into clinical use yet. This review aims to summarize the current "state-of-the-art" in anticancer drug delivery using antibody-functionalized lipid-based nanoparticles. It includes an update on promising candidates that entered clinical trials and some explanations for low translation success.

RGD-decorated PLGA nanoparticles improved effectiveness and safety of cisplatin for lung cancer therapy

Upon extensive pharmaceutical and biomedical research to treat lung cancer indicates that lung cancer remains one of the deadliest diseases and the leading cause of death in men and women worldwide. Lung cancer remains untreated and has a high mortality rate due to the limited potential for effective treatment with existing therapies. This highlights the urgent need to develop an effective, precise and sustainable solutions to treat lung cancer. In this study, we developed RGD receptor-targeted PLGA nanoparticles for the controlled and targeted co-delivery of cisplatin (CDDP) and upconversion nanoparticles (UCNP) in lung cancer therapy. Pluronic F127-RGD conjugate was synthesized by carbodiimide chemistry method and the conjugation was confirmed by FTIR and 1HNMR spectroscopy techniques. PLGA nanoparticles were developed by the double emulsification method, then the surface of the prepared nanoparticles was decorated with Pluronic F127-RGD conjugate. The prepared formulations were characterized for their particle size, polydispersity index, zeta potential, surface morphology, drug encapsulation efficiency, and in vitro drug release and haemolysis studies. Pharmacokinetic studies and safety parameters in BAL fluid were assessed in rats. Histopathology of rat lung tissue was performed. The obtained results of particle sizes of the nanoparticle formulations were found 100–200 nm, indicating the homogeneity of dispersed colloidal nanoparticles formulations. Transmission Electron Microscopy (TEM) revealed the spherical shape of the prepared nanoparticles. The drug encapsulation efficiency of PLGA nanoparticles was found to range from 60% to 80% with different nanoparticles counterparts. RGD receptor-targeted PLGA nanoparticles showed controlled drug release for up to 72 h. Further, RGD receptor-targeted PLGA nanoparticles achieved higher cytotoxicity in compared to CFT, CFT, and Ciszest-50 (marketed CDDP injection). The pharmacokinetic study revealed that RGD receptor-targeted PLGA nanoparticles were 4.6-fold more effective than Ciszest-50. Furthermore, RGD receptor-targeted PLGA nanoparticles exhibited negligible damage to lung tissue, low systemic toxicity, and high biocompatible and safety in lung tissue. The results of RGD receptor-targeted PLGA nanoparticles indicated that it is a promising anticancer system that could further exploited as a potent therapeutic approach for lung cancer.

Construction of S-N-C bond for boosting bacteria-killing by synergistic effect of photocatalysis and nanozyme

Bacterial infection-related diseases are major public safety issues leads to millions of deaths annually. Herein, a porous sulfur doped graphitic carbon nitride (g-SCN) for ecofriendly, metal-free and low systemic toxicity were synthesized. Sulfur doping enables to broaden the absorption spectrum and promote the photocarriers separation for photocatalysis enhancement. Moreover, sulfur element will coordinate with nitrogen, changing the electronic state and endowing g-SCN with the property of nanozyme. More importantly, we established different models and confirmed that S-N-C coordination is the source of peroxidase (POD)-like activity through theory and experiment. The increased specific surface area of g-SCN, ascribing to the porous structure, makes it easier to trap bacteria. With the synergistic effect of photocatalysis and nanozyme, the prepared g-SCN has the ability to kill both gram-negative and gram-positive bacterium, with an antibacterial efficiency up to 100%. This work provides innovative synergistic strategy for constructing nanomaterials for highly efficient antibacterial therapy.

A Meta-analysis on the Effectiveness of Extracellular Vesicles as Nanosystems for Targeted Delivery of Anticancer Drugs.

While the efficacy of anticancer drugs is hampered by low bioavailability and systemic toxicity, the uncertainty remains whether encapsulation of these drugs into natural nanovesicles such as extracellular vesicles (EVs) could improve controlled drug release and efficacy for targeted tumor therapy. Thus, we performed a meta-analysis for studies reporting the efficacy of EVs as nanosystems to deliver drugs and nucleic acid, protein, and virus (NPV) to tumors using the random-effects model. The electronic search of articles was conducted through Cochrane, PubMed, Scopus, Science Direct, and Clinical Trials Registry from inception up till September 2022. The pooled summary estimate and 95% confidence interval of tumor growth inhibition, survival, and tumor targeting were obtained to assess the efficacy. The search yielded a total of 119 studies that met the inclusion criteria having only 1 clinical study. It was observed that the drug-loaded EV was more efficacious than the free drug in reducing tumor volume and weight with the standardized mean difference (SMD) of -1.99 (95% CI: -2.36, -1.63; p < 0.00001) and -2.12 (95% CI: -2.48, -1.77; p < 0.00001). Similarly, the mean estimate of tumor volume and weight for NPV were the following: SMD: -2.30, 95% CI: -3.03, -1.58; p < 0.00001 and SMD: -2.05, 95% CI: -2.79, -1.30; p < 0.00001. Treatment of tumors with EV-loaded anticancer agents also prolonged survival (HR: 0.15, 95% CI: 0.10, 0.22, p < 0.00001). Furthermore, EVs significantly delivered drugs to tumors as revealed by the higher concentration at the tumor site (SMD: -2.73, 95% CI: -3.77, -1.69; p < 0.00001). This meta-analysis revealed that EV-loaded drugs and NPV performed significantly better in tumor growth inhibition with improved survival than the free anticancer agents, suggesting EVs as safe nanoplatforms for targeted tumor therapy.

Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation.

The key properties and high versatility of metal nanoparticles have shed new perspectives on cancer therapy, with copper nanoparticles gaining great interest because of the ability to couple the intrinsic properties of metal nanoparticles with the biological activities of copper ions in cancer cells. Copper, indeed, is a cofactor involved in different metabolic pathways of many physiological and pathological processes. Literature data report on the use of copper in preclinical protocols for cancer treatment based on chemo-, photothermal-, or copper chelating-therapies. Copper nanoparticles exhibit anticancer activity via multiple routes, mainly involving the targeting of mitochondria, the modulation of oxidative stress, the induction of apoptosis and autophagy, and the modulation of immune response. Moreover, compared to other metal nanoparticles (e.g. gold, silver, palladium, and platinum), copper nanoparticles are rapidly cleared from organs with low systemic toxicity and benefit from the copper's low cost and wide availability. Within this review, we aim to explore the impact of copper in cancer research, focusing on glioma, the most common primary brain tumour. Glioma accounts for about 80% of all malignant brain tumours and shows a poor prognosis with the five-year survival rate being less than 5%. After introducing the glioma pathogenesis and the limitation of current therapeutic strategies, we will discuss the potential impact of copper therapy and present the key results of the most relevant literature to establish a reliable foundation for future development of copper-based approaches.

Drug-resistant Stem Cell Models for the Hormone-responsive Luminal A Breast Cancer

Background: Progression of early stage breast cancer to advanced stage metastatic disease represents a major cause of death in women. The Luminal A breast cancer subtype exhibits acceptable response to Chemo-endocrine and targeted therapy. However, these treatment options are associated with intrinsic/acquired therapy resistance and emergence chemo-resistant cancer initiating stem cell population, and resultant progression to advanced stage metastatic disease. These limitations emphasize an unmet need for the development of reliable models for cancer stem cells that facilitate identification of efficacious therapeutic alternatives. Documented human consumption, low systemic toxicity, preclinical cancer growth inhibitory efficacy and stem cell targeting efficacy of natural products, such as dietary phytochemicals and nutritional herbs, provide mechanistic leads for these agents as testable therapeutic alternatives. Objectives: The objectives of the present review are to i.) Provide a systematic discussion of published evidence relevant conceptual background of conventional/targeted therapy and nutritional herbs as testable alternatives, ii.) Growth inhibitory efficacy of nutritional herbs in a cellular model for the Luminal A breast cancer, iii.) Breast cancer stem cell biology and stem cell models for therapy-resistant breast cancer, and iv.) Future research directions. Conclusions: Collectively, all the elements discussed in the present review validate mechanism-based experimental approaches to identify and prioritize potential therapeutic alternatives. Future Research: This review provides a rationale for investigations on patient-derived tumor samples that may minimize extrapolation of the preclinical data for their clinical relevance and translatability.

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

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. 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. 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. This study provided a promising nanomedicine platform for combining antimicrobial peptides and chemotherapeutic drugs for local chemotherapy.

Effect of Isobaric Levobupivacaine and Fentanyl versus Isobaric Ropivacaine and Fentanyl as an Adjuvant in Patients Undergoing Transurethral Resection of the Prostate: A Randomised Clinical Study

Introduction: Ropivacaine is a newer local anaesthetic proven to have a lower systemic toxicity profile, particularly in terms of cardiac and Central Nervous System (CNS) toxicity, than the racemic and levorotatory isomers of bupivacaine, especially in elderly patients. Fentanyl, as an adjuvant, enhances analgesia and promotes early postoperative mobility. Aim: To assess and compare the efficacy and safety of isobaric levobupivacaine and fentanyl versus isobaric ropivacaine and fentanyl in patients undergoing Transurethral Resection of the Prostate (TURP) under Spinal Anaesthesia (SA). Materials and Methods: A randomised clinical study was conducted in the Department of Anaesthesia at SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India, from March 2021 to January 2023. A total of 60 patients ranging in age from 40 to 80 years, scheduled for elective TURP, were enrolled in the present study. The selected patients were randomly assigned into two groups, each consisting of 30 patients. Group A received a dosage of 2.6 cc of 0.75% isobaric ropivacaine (equivalent to 19.5 mg) along with 0.4 cc of fentanyl (equivalent to 20 micrograms). In contrast, group B received a dosage of 2.6 cc of 0.5% isobaric levobupivacaine (equivalent to 13 mg) and 0.4 cc of fentanyl (20 micrograms). The primary outcome measures were the onset of action, duration of sensory-motor block, and postoperative analgesia. Data were analysed using Epi Info version 7.2.1.0 statistical software. The quantitative data collected were summarised using the mean and Standard Deviation (SD). A p-value of less than or equal to 0.05 was considered statistically significant. Results: The majority of patients in the present study were elderly males in both groups. The mean age distribution in group A was 64.27±8.17, and in group B, it was 65.13±7.1. Both groups were comparable and not statistically significant (p=0.634). The mean weight of the two groups was similar, with group A at 64.9±7.49 kg and group B at 63.1±6.96 kg. Both groups were comparable and not statistically significant (p=0.334). The mean height of the patients was 165±4.85 cm in group A and 164±3.83 cm in group B, and it was comparable between the two groups without statistical significance (p=0.145). The duration of sensory block was 241.03±18.88 minutes in group A and 181.5±33.42 minutes in group B. The duration of motor block was 210.7±17.93 minutes in group A and 160±14.82 minutes in group B. Group A demonstrated a significant prolongation of sensory (p&lt;0.001) and motor (p&lt;0.001) block, as well as postoperative analgesia, when compared to 0.5% levobupivacaine with fentanyl. Conclusion: The requirement for rescue analgesia occurred earlier in the levobupivacaine group. Therefore, the use of ropivacaine with fentanyl for spinal anaesthesia in TURP cases is a superior alternative compared to levobupivacaine with fentanyl, as it provides satisfactory quality and duration of block, as well as a longer duration of postoperative analgesia, as assessed by the Visual Analogue Scale (VAS) score and Modified Bromage score.

Naringin@Metal–Organic Framework as a Multifunctional Bioplatform

Naringin, a natural product, can be used as a therapeutic agent due to its low systemic toxicity and negligible adverse effect. However, due to its hydrophobic nature and thereby low solubility, high-dose treatment is required when used for human therapy. Herein, we demonstrate the employment of a metal-organic framework (MOF) as a nontoxic loading carrier to encapsulate naringin, and the afforded nairngin@MOF composite can serve as a multifunctional bioplatform capable of treating Gram-positive bacteria and certain cancers by slowly and progressively releasing the encapsulated naringin as well as improving and modulating immune system functions through synergy between naringin and the MOF.

An “all in one” strategy to boost antibacterial phototherapy via porphyrin and boron dipyrromethenes based covalent organic framework

Bacterial drug resistant is considered as a major threat to human health. Antibacterial phototherapy (PT) including photodynamic and photothermal therapy has attracted increasing attention owing to spatiotemporal precision, no drug resistance, and low systemic toxicity. However, the efficacy of photodynamic or photothermal therapy alone is limited by low oxygen concentration and high sterilization temperature, respectively. Herein, an “all in one” strategy is proposed and a porphyrin and boron dipyrromethenes (bodipy) based covalent organic framework (COF), named as Tph-BDP-COF, is synthesized to manipulate the excitation energy dissipation pathway, and thus realizing excellent synergetic antibacterial phototherapy. The “all in one” hybrid exhibits a narrow optical bandgap (1.33 eV) and a fast energy and electron transfer compare with porphyrin-base COF-366, hence improving intersystem crossing process and photothermal conversion. Thus, Tph-BDP-COF showed superior ROS generation and excellent photothermal conversion ability, consequently giving an efficient “all in one” antibacterial activities (97 %) compared with the porphyrin-based COF-366 (54 %). These findings give inspiration for the “all in one” phototherapy materials design.

Research Progress on Ferroptosis as a Therapeutic Strategy in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common type of kidney cancer in adults and constitutes approximately 90% of all renal malignancies. Although advancements have been made in the treatment of RCC, the 5 -year survival rate is still low, and new treatment modalities are still required. Ferroptosis is an iron-dependent programmed cell death caused by the accumulation of lipid peroxide products. Recent studies revealed the involvement of ferroptosis metabolism, lipid peroxidation, and System XC-GSH-GPX4 shafts as major mechanisms closely related to RCC progression. Nanoparticles in combination with small molecular ferroptosis induction agents have the advantages of solubility, targeted enhancement, low systemic toxicity, controllable drug control, and synergy advantage in emerging combination therapies. In the future, it is possible to be used in nano treatment. The relationship between ferroptosis-related mechanisms and RCC progression and its role in the treatment could provide novel treatment strategies for patients with advance-stage RCC.

Ent-kaurenoic acid-enriched Mikania glomerata leaves-complexed β-cyclodextrin: Pharmaceutical development and in vivo antitumor activity in a sarcoma 180 mouse model

The extract obtained from Mikania glomerata leaves rich in ent-kaurenoic acid (ERKA) shows cytotoxic activity in vitro, but its hydrophobic nature and thermosensitivity are issues to be solved prior to in vivo antitumor studies. The purpose of this study was to investigate the antitumor activity of inclusion complexes formed between ERKA and β-cyclodextrin (ERKA:β-CD) in rodents. ERKA:β-CD complexes obtained by malaxation (MX) and co-evaporation (CE) methods were firstly characterized regarding their physical properties, encapsulation efficiency, and cytotoxicity againts L929 cells. The antitumor activity study was then performed in mice with sarcoma 180 treated with saline, 5-fluouracil (5FU) and ERKA:β-CD at 30, 100 and 300 µg/kg. The weight, volume, percentage of inhibition growth, gross and pathological features and positivity for TUNEL, ki67, NFκB and NRF2 in the tumors were assessed. Serum lactate-dehydrogenase activity (LDH), white blood cells count (WBC) and both gross and pathological features of the liver, kidneys and spleen were also evaluated. The formation of the inclusion complexes was confirmed by thermal analysis and FTIR, and they were non-toxic for L929 cells. The MX provided a better complexation efficiency. ERKA:β-CD300 promoted significant tumor growth inhibition, and attenuated the tumor mitotic activity and necrosis content, comparable to 5-fluorouracil. ERKA:β-CD300 also increased TUNEL-detected cell death, reduced Ki67 and NF-kB immunoexpression, and partially inhibited the serum LDH activity. No side effect was observed in ERKA:β-CD300-treated animals. The ERKA:β-CD inclusion complexes at 300 µg/kg displays antitumour activity in mice with low systemic toxicity, likely due to inhibition on the NF-kB signaling pathway and LDH activity.

Biointerfacial giant capsules with high paclitaxel loading and magnetic targeting for breast tumor therapy

High drug loading, targeted delivery, prolonged drug release, and low systemic toxicity are effective weapons for hydrophobic drug delivery systems to solve serious concerns in poor water-solubility and toxicity of paclitaxel (PTX). Herein, we reported that biointerfacial giant multilayer microcapsules (BGMs) with the feature of high-density drug loading and high-efficiency magnetic delivery were fabricated templated by PTX-liposome-microbubble complex using the layer-by-layer self-assembly (LbL) technique. The drug loading capacity of BGMs was improved by optimizing the structure of microbubbles and capsules to increase the PTX-contained layers, and the resultant BGMs exhibited high drug loading content (50.56 ± 0.09 %) and sustained drug release properties. The BGMs with an average diameter of 74.1 ± 12.1 µm and an average thickness of 275.5 ± 48.4 nm contained abundant magnetic nanoparticles (MNPs) in their cavity, which endowed these capsules with outstanding magnetic properties and fast magnetophoretic velocity in the blood (∼0.3 mm/s, ▽B = 1 T/mm). Moreover, both in vitro and in vivo studies demonstrated that the biocompatible PTX-loaded magnetic BGMs (Capsule@PLMPPL) caused notable death (71.3 ± 2.9 %) of 4 T1 breast cancer cells through PTX diffusion, capsules degradation, and subsequent endocytosis by cancer cells, and ultimately effectively inhibited tumor growth. In general, the developed BGM with good deformability and degradation was the first reported giant polyelectrolyte capsule to be used in tumor therapy, which could notably improve the therapeutic efficacy of PTX while reducing its side effects.

Epigenetic reprogramming of carrier free photodynamic modulator to activate tumor immunotherapy by EZH2 inhibition

Tumor cells are characterized by unlimited proliferation and escape of immune clearance, which are closely associated with the down regulation of surface antigens. In this work, a carrier free photodynamic modulator (CeTaz) is developed to improve immunosuppressive tumor microenvironment and promote the recognition of tumors by T cells by epigenetic reprogramming. Specifically, CeTaz is assembled by chlorine e6 (Ce6) and tazemetostat (Taz) through intermolecular interactions. Upon light irradiation, CeTaz is able to promote the generation of reactive oxygen species (ROS) for a robust photodynamic therapy (PDT) to inhibit localized tumor growth. Meanwhile, the PDT also induces immunogenic cell death (ICD) to initiate immune response, leading to the activation of effector T cells. More importantly, CeTaz could inhibit the epigenetic regulator of EZH2 to suppress the methylation of H3K27, which would promote tumor cells to express MHC-I and release CXCL10. Consequently, the epigenetically reprogrammed tumor cells are readily recognized by effector T cells to enhance the antitumor immunity. Results indicate that the PDT activated immunotherapy of CeTaz could simultaneously inhibit the growth of primary and distant tumors with a low system toxicity. This study would advance the development of carrier free nanomedicine for precise treatment of metastatic tumor.