Chemo Drugs Research Articles

Abstract 3971: Genome-wide CRISPR/Cas9 screening reveals ATR as a therapeutic target that overcomes osteosarcoma chemoresistance

Abstract Osteosarcoma (OS) is the most common bone cancer in pediatric patients. Therapeutic target identification in OS has been extremely challenging due to the high degree of heterogeneity in its genetic profile and lack of specific oncogenic driver genes. Despite extensive research efforts, the treatment and survival outcomes for OS patients have stagnated over the past 30 years. OS remains a lethal cancer due to metastasis and development of resistance to current chemotherapies. Study of chemo-resistance mechanisms and identification of novel targets that can be used in combination therapy are therefore critical to improve OS treatment. The combination of gene essentiality concept and clustered, regularly interspaced, short palindromic repeats-associated nuclease Cas9 (CRISPR/Cas9) functional knockout screen is an ideal new strategy to address the genetic complexity and drug-resistance in OS. A gene is considered essential if it is critical for reproductive success in an organism under specified condition. The recent introduction of genome editing using the CRISPR/Cas9 system with pooled library of guided RNAs (gRNAs) makes it feasible to systematically identify the genes required for the proliferation. By comparing the fold change of gRNA abundance in the surviving population of cells relative to the initial population, the essential genes under different settings can be identified.As a novel therapeutic approach for identifying combination therapies for OS, we conducted genome-wide (GW) CRISPR/Cas9 screen in SaOS2 OS cell lines parallel with RNA-sequencing in different conditions (control, Cisplatin, Doxorubicin), followed by gene essentiality score calculation. Cisplatin (CIS) and Doxorubicin (DOX) combination is among those commonly used as first-line therapies for OS treatment. The objective of our studies is to bring forth new perspectives in target identification and chemo-resistance study for OS. The gene targets and pathways that become more essential for OS cell proliferation in the presence of chemo drugs were revealed. Drugs specific for some of these target could then be added to the established CIS or DOX regimen to overcome existing drug resistance. On the other hand, the genes that become less essential after treatment could provide additional chemo-resistant mechanisms. Multiple gene targets were identified in the screen. Among these, we’ve successfully identified and validated Berzosertib, an ataxia telangiectasia and Rad3-related protein kinase inhibitor (ATRi), as a synergistic lethality partner to Cisplatin in vitro for OS treatment. Efficacy and safety measurement of Berzosertib and Cisplatin combination therapy in an OS xenograft mouse model and in several OS patient-derived xenograft models is in progress. Citation Format: Shan Tang, Karen E. Pollok, Pankita H. Pandya, Ryan D. Roberts, Xue Wu, Lang Li. Genome-wide CRISPR/Cas9 screening reveals ATR as a therapeutic target that overcomes osteosarcoma chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3971.

Abstract 1108: Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression

Abstract Lung cancer is the leading cause of cancer-related death in the US. It is mainly divided in two types: small cell lung cancer and non-small cell lung cancer. About 85-90% of cases are classified as non-small cell lung cancer (NSCLC). Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers. Despite the advent of targeted therapies and chemotherapies, effective therapies for lung cancer are an unlikely outcome for most patients. SCLC is initially highly responsive to cisplatin and etoposide chemotherapy but, in almost every case, becomes rapidly chemo resistant. However, the mechanisms underlying initial sensitivity and subsequent resistance are not well investigated. Thus, alternative approaches and combination therapy is required for treating SCLCs. Recent studies in our lab show that NSCLC cells demonstrate elevated levels of heme via increased heme uptake and synthesis, and elevated oxidative phosphorylation (OXPHOS) and ATP generation which fuels NSCLC proliferation. Also, limiting heme via inhibition of heme uptake using heme sequestering peptides (HeSP2) can delay growth and progression of NSCLC tumors. This HeSP2 can also effectively inhibit angiogenesis, normalize tumor vasculature, and alleviate tumor hypoxia in NSCLC tumors and thereby inhibit lung tumor growth and progression. Tumor heterogeneity is critical for tumor growth, metastasis, and acquired therapeutic resistance. To understand if heme can effectively reduce tumor cell proliferation and growth and improve tumor microenvironment, we treated chemo resistant SCLCs with HeSP2 and in combination with commonly used chemo drugs cisplatin and etoposide. Our data shows that HesP2 can strongly inhibit cell proliferation and decreases oxygen consumption rate along with ATP generation in SCLCs. To gain insights into mechanism by which the heme sequestering peptides limit tumor growth and progression, we implanted subcutaneous or SCLC cell lines in NOD/SCID mice. Mice were treated with saline (control), HeSP2, HeSP2 and cisplatin, HeSP2 and etoposide. Tumor growth was monitored using caliper measurements. Tumors tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC) and histology experiments. These results indicate that heme sequestration can be a powerful strategy for suppressing lung tumors likely drug-resistant tumors that rely on oxidative phosphorylation for survival. Citation Format: Adnin Ashrafi, Narges Salamat, Li Zhang. Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1108.

Cisplatin Encapsulation Efficiency Profiles using Titania Nanotube Arrays Platform in Targeted Cancer Therapy

Titania nanotube arrays (TNA) nanosystem has been discussed widely in drug delivery applications that could provide advantages for sustaining chemo drug release in targeted cancer therapy. This study profiled the cisplatin chemo drug (CDDP) encapsulation efficiency on TNA (CDDP–TNA). Anatase TNA nanosystem used in this study present with diffraction angle 25 θ and 48 θ. The distribution and binding interaction of CDDP on TNA were identified using the primary functional marker amide I band (N–H), and the sustained release profile of CDDP from TNA was further captured. Furthermore, CDDP–TNA nanosystem is present with favorable hydrophilic properties that could facilitate the effective release of CDDP from TNA nanosystem. However, developing a controlled release model of CDDP -TNA nanosystem using polymer coating technology is needed to support the present finding, especially in targeted cancer therapy applications.

An immune-related lncRNA pairs signature to identify the prognosis and predict the immune landscape of laryngeal squamous cell carcinoma

BackgroundLaryngeal squamous cell carcinoma (LSCC) is the most common squamous cell carcinoma. Though significant effort has been focused on molecular pathogenesis, development, and recurrence of LSCC, little is known about its relationship with the immune-related long non-coding RNA (lncRNA) pairs.MethodsAfter obtaining the transcriptome profiling data sets and the corresponding clinical characteristics of LSCC patients and normal samples from The Cancer Genome Atlas (TCGA) database, a series of bioinformatic analysis was conducted to select the differently expressed immune-related lncRNAs and build a signature of immune-related lncRNA pairs. Then, the effectiveness of the signature was validated.ResultsA total of 111 LSCC patients and 12 normal samples’ transcriptome profiling data sets were retrieved from TCGA. 301 differently expressed immune-related lncRNAs were identified and 35,225 lncRNA pairs were established. After univariate Cox analysis, LASSO regression and multivariate Cox analysis, 7 lncRNA pairs were eventually selected to construct a signature. The riskscore was computed using the following formula: Riskscore = 0.95 × (AL133330.1|AC132872.3) + (-1.23) × (LINC01094|LINC02154) + 0.65 × (LINC02575|AC122685.1) + (-1.15) × (MIR9-3HG|LINC01748) + 1.45 × (AC092687.3|SNHG12) + (-0.87) × (AC090204.1|AL158166.1) + 0.64 × (LINC01063|Z82243.1). Patients were classified into the high-risk group (> 1.366) and the low-risk group (< 1.366) according to the cutoff value (1.366), which is based on the 5-year riskscore ROC curve. The survival analysis showed that the low-risk group had a better prognosis (P < 0.001). The riskscore was better than other clinical characteristics in prognostic prediction and the area under the curves (AUCs) for the 1-, 3-, and 5-year survivals were 0.796, 0.946, and 0.895, respectively. Combining age, gender, grade, stage, and riskscore, a nomograph was developed to predict survival probability in LSCC patients. Then, the riskscore was confirmed to be related with the content of tumor-infiltration immune cells and the model could serve as a potential predictor for chemosensitivity.ConclusionWe successfully established a more stable signature of 7 immune-related lncRNA pairs, which has demonstrated a better prognostic ability for LSCC patients and may assist clinicians to precisely prescribe chemo drugs.

Therapeutic Strategies for Ovarian Cancer in Point of HGF/c-MET Targeting.

Ovarian cancer is the fifth leading cause of cancer deaths in women and is regarded as one of the most difficult cancers to treat. Currently, studies are being conducted to develop therapeutic agents for effective treatment of ovarian cancer. In this review, we explain the properties of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) and how the signaling pathway of HGF/c-MET is activated in different cancers and involved in tumorigenesis and metastasis of ovarian cancer. We present the findings of clinical studies using small chemicals or antibodies targeting HGF/c-MET signaling in various cancer types, particularly in ovarian cancer. We also discuss that HGF/c-MET-targeted therapy, when combined with chemo drugs, could be an effective strategy for ovarian cancer therapeutics.

An in Vitro Model Study on the Effectiveness of Electrical Pulse Mediated Herbal Therapy on Breast Cancer

Background: Breast cancer is the most life-threatening cancer in women all over the world. Considering the detrimental side effects of standard chemo drugs, plant-based drugs can be used effectively. This work aims to investigate the effect of herbal extracts mediated by electrical pulses on breast cancer cell lines.Methods: Three different samples were chosen (Turmeric, Pepper, Neem), shade dried, and extracted using the soxhlet method, with ethanol as a solvent. These extracts were used as an anticancer drug against three breast cancer cell lines (MCF-10A, MCF-7, MDA-MB-231). Further, BTX ECM830 electroporator was used to generate electrical pulses of different parameters to enhance the uptake of extracts into the cancer cells. Realtime MT Assay was used to obtain the viability of breast cancer cell lines. A comparative study was conducted to assess the effect of each treatment on different breast cancer cell lines.Results: Treatments were more susceptive to cancerous cell lines than normal cells. Low intensity, high duration electrical pulses with herbal extracts showed a higher cytotoxic effect than other treatments. A notable increase in cell death was observed in combination treatments compared to single treatments. The lowest viability of 4% was obtained for synergetic treatment of electrical pulses and herbal extract. Conclusion: In the current study, we found for the first time that herbal extracts in combination with electrical pulses exhibited strong anticancer activity against breast cancer cell lines. This promising treatment can be used efficiently to treat breast cancer without any side effects.

Dual Effects of Titania Nanoparticle (TNP) Combination Treatment with a Chemodrug, Cisplatin Targeting for Nasopharyngeal Carcinoma

Standard treatment for progressive nasopharyngeal carcinoma (NPC) is chemo drug cisplatin (CDDP) as the sole treatment or adjuvant with chemoradiation. Integrating CDDP with the nanosystem has become a current research interest to enhance the effectiveness of chemo drug therapy for NPC. Nanoparticles such as titania nanoparticles (TNP) possessed higher adsorption properties into cells remarkably from the large surface area. Present work studied the combination treatment of TNP and CDDP towards nasopharyngeal carcinoma (NPC) cell lines models. The half-maximal inhibitory concentration (IC50) of CDDP and TNP were characterized on NPC cells, respectively. Further optimizations of the CDDP-TNP dual effect were studied, especially on the cytotoxic profile. The combined treatment of CDDP and TNP was more effective than a single treatment at inhibiting NPC cells by more than 60 %. On the other hand, this combined therapy had dual effects and was highly dependent on the dose of TNP exposed after 24-h exposure. This study suggested that the combination treatment of CDDP and TNP on NPC cells would improve the therapeutic outcomes even at lower concentrations of CDDP, thus could overcome the limitation of current cancer therapy in a future application.

Anticancer Biosurfactant-Loaded PLA-PEG Nanoparticles Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cells.

Despite various advancements in cancer therapies, treating cancer efficiently without side effects is still a major concern for researchers. Anticancer drugs from natural sources need to be explored as a replacement for chemo drugs to overcome their limitations. In our previous studies, isolation, characterization, and anticancer properties of a novel biosurfactant from Candida parapsilosis were reported. In this study, we report the cytotoxicity of the polymeric nanoparticles of this novel biosurfactant toward breast cancer cells. Biosurfactant-encapsulated polymeric nanoparticles of polylactic acid–poly(ethylene glycol) (PLA–PEG) copolymers were synthesized by the double emulsion solvent evaporation method. Folic acid (FA) was used as a targeting ligand to actively deliver the anticancer cargo to the cancer site. The encapsulation efficiency of nanoparticles was observed as 84.9%, and Fickian diffusion was observed as a kinetic model for the release of biosurfactant from nanoparticles. The controlled delivery of the biosurfactant was noticed when encapsulated in PLA–PEG copolymer nanoparticles. Additionally, it was observed that FA enhanced the uptake and cytotoxicity of biosurfactant-loaded nanoparticles in MDA-MB-231 cancer cells compared to biosurfactant-loaded plain nanoparticles. Induction of apoptosis was observed in cancer cells by these nanoparticles. We explore a potential anticancer agent that can be further analyzed for its efficiency and can be used as an alternative tool.

Identification of an Immune-Related BAT Signature for Predicting Adjuvant Chemotherapy Response and Overall Survival in Patients with Resected Ductal Adenocarcinoma of the Pancreas

BackgroundAdjuvant chemotherapy (ACT) is widely accepted in patients with pancreatic ductal adenocarcinoma (PDAC) after surgery; however, effective models for predicting ACT response are scarce. Thus, the objective of this study was to develop a novel signature for predicting its response and overall survival (OS) in resected PDAC patients. MethodsA total of 50 PDAC patients with the transcriptome expression profiles, information about chemotherapy, and relevant clinical data were retrieved from the Cancer Genome Atlas (TCGA), and twenty-nine patients with tissue specimens and clinical data from our hospital were included as a validation. A novel gene signature was developed using bioinformatic differentially expressed genes (DEGs) analysis, Lasso-penalized Cox regression, and multivariate Cox regression studies. ResultsBetween chemotherapy-resistant and chemotherapy-sensitive cohorts, 569 DEGs were identified, with 490 upregulated and 79 downregulated genes mainly specialized in the regulation of peptide/protein/hormone secretion, calcium ion homeostasis, and T cell activation regulation in biological processes. After Lasso-penalized Cox and multivariate Cox regression analysis, BAT (BCHE, ADH1A, and TNS4) signature was established to predict ACT response and OS. Moreover, BAT signature was verified as an independent risk factor for ACT response (p = 0.042) and OS (median OS: 17.5 months vs. 34.8 months, p = 0.040) and significantly associated with immune infiltrations (p < 0.05). Then, this signature was further validated as the independent risk factor for recurrence-free survival (RFS) in PDAC patients receiving postoperative ACT (median RFS: 9.0 months vs. not reached, p = 0.014), and tumor-infiltrating CD4+ and CD8+ T cells were further validated to be significantly decreased in tissues with higher BAT signature scores (p = 0.015 and 0.021, respectively). ConclusionThe BAT signature is a novel formulated and independent risk factor for predicting ACT response and long-term survival in patients with resected PDAC. This signature could comprehensively reflect local immune-related response, tumor purity, potential biological behavior, and chemo drug susceptibility.

Harnessing Focal Adhesions to Accelerate p53 Accumulation and Anoikis of A549 Cells Using Colloidal Self-Assembled Patterns (cSAPs).

Extracellular matrix (ECM) of the tumor microenvironment (TME), including topography and biological molecules, is crucial in cancer cell attachment, growth, and even the sensitivity to the chemo and cell drugs treatment. This study hypothesizes that mimic ECM structures can alter the attachment and drug sensitivity of cancer cells. A family of artificial ECM called colloidal self-assembled patterns (cSAPs) was fabricated to mimic tumor ECM structures. Cell adhesion, proliferation, and drug sensitivity of the A549 non-small cell lung cancer (NSCLC) cells were studied on 24 cSAPs, named cSAP#1-cSAP#24, where surface topography and wettability were distinct. The results showed that cell adhesion and cell spreading were generally reduced on cSAPs compared to the flat controls. In addition, the synergistic effect of cSAPs and several chemo drugs on cell survival was investigated. Interestingly, A549 cells were more sensitive to the combination of doxorubicin and cSAP#4. Under this condition, the focal adhesion kinase (FAK) signaling was downregulated while p53 signaling was upregulated, confirmed by real-time PCR and western blot analysis. It indicates that the specific surface structure could induce higher drug sensitivity and in vitro anoikis of A549 cells. A serum alternative, human platelet lysate (hPL), and different cSAPs were examined to verify our hypothesis. The result further confirmed that cell adhesion strongly affected the drug sensitivity of A549 cells. This study demonstrates that the tumor ECM is vital in cancer cell activity and drug sensitivity; therefore, it should be considered in drug discovery and therapeutic regimens.

Modulation of VEGF and TGF beta in 5-FU induced inflammation in MCF-7 using an herbal formulation

Acquired drug resistance is an increasing challenge in treating cancer with chemotherapy. One mechanism behind this resistance is the increased inflammation that supports the progression and development of cancer that arises because of the drug’s presence.&#x0D; Integrative oncology is the field that focuses on including natural products alongside traditional therapy to create a treatment that focuses on holistic patient well-being. In this in vitro study, we hypothesized that the use of an herbal formulation, consisting of turmeric and green tea, alongside a traditional chemotherapeutic drug, 5-fluorouracil (5-FU), can reduce the expression of two pro-cancer cytokines in breast cancer cells.&#x0D; Breast cancer cells were cultured and then treated with both 5-FU and the herbal formulation. We conducted enzyme-linked immunosorbent assays (ELISAs) to measure VEGF and TGFβ in the cell culture supernatant. The results clearly demonstrate that the use of the herbal formulation alongside the chemo drug significantly decreases the level of cytokines produced when compared to the levels produced when exposed solely to the chemo drug.&#x0D; Hence, we conclude that this combination of treatment, based on the principle of integrative oncology, shows potential for reducing the resistance against treatment conferred through increased inflammation. Consequently, this suggests a prospective way forward in improving the efficacy of cancer treatment.

Ultrathin tellurium nanosheets for simultaneous cancer thermo-chemotherapy

The emerging two-dimensional monoelemental materials (2D Xenes) have been commonly supposed as promising drug delivery carriers, photothermal and photodynamic therapeutic agents, biosensors, theranostics, and some other candidates for biomedical applications. Here, high-performance and bioactive ultrathin 2D Tellurium nanosheets (Te NSs) are prepared by a simple but efficient liquid-phase exfoliation approach. The as-obtained Te NSs possess a mean size of ∼90 nm and a mean thickness of ∼5.43 nm. The pegylation Te NSs (Te-PEG NSs) possess excellent biocompatibility and stability. The Te-PEG NSs could generate local hyperthermia with a remarkable photothermal conversion efficiency of about 55% under 808 nm laser irradiation. Additionally, Te-PEG NSs exhibit an extremely high loading capacity of chemo drug (∼162%) owing to their ultra-high surface area and tumor microenvironment-triggered drug release superiority. The results of in vivo experiments show that the Te-PEG NSs have higher tumor elimination efficiency via the combination of photothermal and chemotherapy, comparing to any other single therapeutic modalities. Therefore, our work not only highlights the promising potentials of tellurene as an ideal anti-cancer platform but also expands the application of 2D Te for cancer nanomedicine.

Quercetin potentiates the chemosensitivity of MCF-7 breast cancer cells to 5-fluorouracil.

Breast cancer is one of the leading causes of cancer mortality worldwide. 5-fluorouracil (5-FU) is one of the chemotherapy drugs to treat breast cancer, but it is associated with several side effects. Combination therapy is a way to increase the effectiveness of chemo drugs and decrease their usage dose. Quercetin (Quer) is one of the natural polyphenols with anti-cancer properties. This study investigated the apoptotic effect of 5-FU in combination with Quer compared with 5-FU alone on MCF-7 breast cancer cells. Different single and combined concentrations of 5-FU and Quer were applied to MCF 7 cells for 48h. Cell viability, apoptosis, gene expression of Bax, Bcl2, and p53, caspase activity, and colony number were assessed using MTT assay, flow cytometry, quantitative real-time PCR, enzyme-linked immunosorbent (ELISA), and Colony formation assay, respectively. The combination of 5-FU and Quer compared to 5-FU alone improved apoptosis by increasing the gene expression of Bax and p53 and caspase-9 activity and decreasing the Bcl2 gene expression. Colony formation in MCF-7 cells significantly decreased in the combined state compared to 5-FU alone. Quer potentiates the sensitivity of breast cancer to 5-FU so that this combination may be proposed as a treatment for breast cancer. Therefore, this combination can be suggested for future in vivo studies.

Proteomics-based prognostic signature and nomogram construction of hypoxia microenvironment on deteriorating glioblastoma (GBM) pathogenesis

The present study aimed to construct and evaluate a novel experiment-based hypoxia signature to help evaluations of GBM patient status. First, the 426 proteins, which were previously found to be differentially expressed between normal and hypoxia groups in glioblastoma cells with statistical significance, were converted into the corresponding genes, among which 212 genes were found annotated in TCGA. Second, after evaluated by single-variable Cox analysis, 19 different expressed genes (DEGs) with prognostic value were identified. Based on λ value by LASSO, a gene-based survival risk score model, named RiskScore, was built by 7 genes with LASSO coefficient, which were FKBP2, GLO1, IGFBP5, NSUN5, RBMX, TAGLN2 and UBE2V2. Kaplan–Meier (K–M) survival curve analysis and the area under the curve (AUC) were plotted to further estimate the efficacy of this risk score model. Furthermore, the survival curve analysis was also plotted based on the subtypes of age, IDH, radiotherapy and chemotherapy. Meanwhile, immune infiltration, GSVA, GSEA and chemo drug sensitivity of this risk score model were evaluated. Third, the 7 genes expression were evaluated by AUC, overall survival (OS) and IDH subtype in datasets, importantly, also experimentally verified in GBM cell lines exposed to hypoxic or normal oxygen condition, which showed significant higher expression in hypoxia than in normal group. Last, combing the hypoxia RiskScore with clinical and molecular features, a prognostic composite nomogram was generated, showing the good sensitivity and specificity by AUC and OS. Meanwhile, univariate analysis and multivariate analysis were used for performed to identify variables in nomogram that were significant in independently predicting duration of survival. It is a first time that we successfully established and validated an independent prognostic risk model based on hypoxia microenvironment from glioblastoma cells and public database. The 7 key genes may provide potential directions for future biochemical and pharmaco-therapeutic research.

Calcium phosphate-polymeric nanoparticle system for co-delivery of microRNA-21 inhibitor and doxorubicin

Targeted combination therapy has shown promise to achieve maximum therapeutic efficacy by overcoming drug resistance. MicroRNA-21 (miR-21) is frequently overexpressed in various cancer types including breast and non-small cell lung cancer and its functions can be inhibited by miR inhibitor (miR-21i). A combination of miR-21i and a chemo drug, doxorubicin (Dox), can provide synergistic effects. Here, we developed a calcium phosphate (CaP)-coated nanoparticle (NP) formulation to co-deliver miR-21i along with Dox. This NP design can be used to deliver the two agents with different physiochemical properties. The NP formulation was optimized for particle size, polydispersity, Dox loading, and miR-21i loading. The NP formulation was confirmed to downregulate miR-21 levels and upregulate tumor suppressor gene levels. The cytotoxic efficacy of the combined miR-21i and Dox-containing NPs was found to be higher than that of Dox. Therefore, the CaP-coated hybrid lipid-polymeric NPs hold potential for the delivery of miR-21i and Dox.

Self-Assembly Engineering Nanodrugs Composed of Paclitaxel and Curcumin for the Combined Treatment of Triple Negative Breast Cancer.

The clinical outcomes of triple-negative breast cancer (TNBC) chemotherapy are unsatisfactory. Water solubility and biosafety of chemo drugs are also major barriers for achieving satisfactory treatment effect. In this study, we have reported a combinational strategy by self-assembly engineering nanodrugs PC NDs, which were composed of paclitaxel (PTX) and curcumin (Cur), for effective and safe TNBC chemotherapy. PC NDs were prepared through reprecipitation method without using any additional carriers. The PC NDs were preferentially taken up by TNBC cells and we also observed pH-related drug release. Compared with free PTX and simple PTX/Cur mixture, PC NDs have shown higher therapeutic efficiency and better prognosis while the metastasis rate was significantly lower than that of either PTX or PTX/Cur mix group. Therefore, the self-assembly engineered PC NDs might be a promising nanodrugs for efficient and safe TNBC chemotherapy.

Responsive polymeric drug delivery systems for combination anticancer therapy: experimental design and computational insights

Combination therapy has been designed to overcome the setbacks of traditional chemotherapy in anticancer therapy. Since combination therapy comprises a combination of anticancer agents, the different pharmacokinetics and biodistribution properties of multiple drugs are the primary concern. Stimuli-responsive polymers can vary in structure with changes in environmental conditions. Therefore, the microenvironmental differences between tumor sites and normal tissues can be utilized to achieve controlled drug release within a specific time and location range. Thus, stimuli-responsive polymers have the ability to optimize combination drug administration. This present review addresses four different strategies for preparing a polymeric combination drug delivery system. Different types of payloads, including various chemo drugs, gene drugs, and photosensitizers, that have been explored in the experiment are crucial parts of the discussion in this review. In addition, the triggering conditions of stimuli-responsive polymers used in combination therapy in recent years are summarized. Moreover, due to the investigation of drug-carrier or drug-drug interactions at the molecular level, computational chemistry provides inspiration for the rational design of novel drug delivery systems. Thus, a series of simulations to calculate the thermodynamic and kinetic properties of drug carriers are also introduced. The challenges and perspectives of nanocarrier-based combination therapy have also been discussed.

Maculopapular erythema caused by previously used chemotherapy drugs after nivolumab treatment for malignant mesothelioma

Currently, an increasing number of cutaneous adverse reactions resulting from the use of programmed cell death protein 1 (PD-1) inhibitors have been described. We present a case in which drug eruption had not appeared before nivolumab therapy, but was induced by the same chemo drug after nivolumab therapy.

Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers

Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer.

Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.