Drug-induced liver injury associated with savolitinib: a novel case report and causality assessment.

BACKGROUND: Savolitinib, a small molecule inhibitor, has gained approval as the inaugural medication in China that specifically targets MET kinase. Patients with advanced non-small cell lung cancer (NSCLC) who show MET exon 14 skipping now have a new and innovative treatment option available. CASE REPORT: In this case report, we describe a patient who experienced drug-induced liver injury (DILI) due to the administration of savolitinib. After being prescribed with savolitinib (400 mg per day, oral), a 73-year-old male diagnosed with stage IV NSCLC with MET exon 14 skipping mutation experienced an increase in liver enzymes and bilirubin levels according to his laboratory tests conducted one month later. Following a 14-day course of hepatoprotective medication, the liver function reverted back to its normal state. After receiving savolitinib (200 mg per day, oral) for one week, the patient was once again diagnosed with severe liver impairment. Then savolitinib was discontinued and received treatment with hepatoprotective drugs for one week. Following the restoration of normal liver function, another attempt was made to administer a small amount of savolitinib (100 mg per day, oral). Thus far, the patient has been followed up and there has been no recurrence of liver damage. Additionally, the lung CT scan revealed ongoing tumor shrinkage with no apparent indications of spreading or metastasis. The Roussel Uclaf Causality Assessment Method (RUCAM) determined that savolitinib was "highly probable" cause of DILI. Moderate-severe was determined to be the extent of DILI severity. CONCLUSION: To the best of our understanding, this is the initial instance of DILI resulting from the use of savolitinib as a standalone treatment in a real-world setting. During the administration of savolitinib, healthcare professionals should carefully consider the potential occurrence of DILI. Administering the patient with a small amount of savolitinib resulted in a remarkable response against the tumor, leading us to speculate that the effectiveness of savolitinib might be associated with its plasma concentration. Studying the pharmacokinetics and pharmacodynamics (PK/PD) of savolitinib is beneficial for tailoring and accurately prescribing the medication to each individual.

Simultaneous Delivery of Doxorubicin and EZH2-Targeting siRNA by Vortex Magnetic Nanorods Synergistically Improved Anti-Tumor Efficacy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The present study reports an engineered magnetic nanodrug based on Fe3 O4 vortex nanorods coated with a macrophage membrane loaded with doxorubicin (DOX) and Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) siRNA. This novel nanodrug displays excellent tissue penetration and preferential tumor accumulation. More importantly, it significantly increases tumor suppression compared to chemotherapy, suggesting the synergistic activity of the combination of doxorubicin and EZH2-inhibition. Importantly, owing to tumor-targeted delivery, nanomedicine shows an excellent safety profile after systemic delivery, unlike conventional chemotherapy. In summary, chemotherapy and gene therapy are combined into a novel magnetic nanodrug carrying doxorubicin and EZH2 siRNA, which shows promising clinical application potential in TNBC therapy.

A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal cancer.

Exosomes have emerged as a promising drug carrier with low immunogenicity, high biocompatibility and delivery efficiency. Here in, we isolated exosomes from A33-positive LIM1215 cells (A33-Exo) and loaded them with doxorubicin (Dox). Furthermore, we coated surface-carboxyl superparamagnetic iron oxide nanoparticles (US) with A33 antibodies (A33Ab-US), expecting that these A33 antibodies on the surface of the nanoparticles could bind to A33-positive exosomes and form a complex (A33Ab-US-Exo/Dox) to target A33-positive colon cancer cells. The results showed that A33Ab-US-Exo/Dox had good binding affinity and antiproliferative effect in LIM1215 cells, as shown by increased uptake of the complex. In vivo study showed that A33Ab-US-Exo/Dox had an excellent tumor targeting ability, and was able to inhibit tumor growth and prolong the survival of the mice with reduced cardiotoxicity. In summary, exosomes functionalized by targeting ligands through coating with high-density antibodies may prove to be a novel delivery system for targeted drugs against human cancers.

Efficacy and Mechanism of a Biomimetic Nanosystem Carrying Doxorubicin and an IDO Inhibitor for Treatment of Advanced Triple-Negative Breast Cancer.

Introduction: Chemotherapy is still the treatment of choice for advanced triple-negative breast cancer. Chemotherapy combined with immunotherapy is being tried in patients with triple-negative breast cancer. As a kind of "cold tumor", triple-negative breast cancer has a bottleneck in immunotherapy. Indoleamine 2, 3-dioxygenase-1 inhibitors can reverse the immunosuppressive state and enhance the immune response. Methods: In this study, mesoporous silica nanoparticles were coated with the chemotherapeutic drug doxorubicin and indoleamine 2, 3-dioxygenase 1 inhibitor 1-Methyl-DL-tryptophan (1-MT), and then encapsulate the surfaces of a triple-negative breast cancer cell membrane to construct the tumor dual-targeted delivery system CDIMSN for chemotherapy and immunotherapy, and to investigate the immunogenic death effect of CDIMSN. Results and discussion: The CDIMSN could target the tumor microenvironment. Doxorubicin induced tumor immunogenic death, while 1-MT reversed immunosuppression. In vivo findings showed that the tumor size in the CDIMSN group was 2.66-fold and 1.56-fold smaller than that in DOX and DIMSN groups, respectively. CDIMSN group was better than naked DIMSN in stimulating CD8+T cells, CD4+T cells and promoting Dendritic Cells(DC) maturation. In addition, blood analysis, biochemical analysis and Hematoxylin staining analysis of mice showed that the bionic nanoparticles had good biological safety.

Co-delivery of the autophagy inhibitor si-Beclin1 and the doxorubicin nano-delivery system for advanced prostate cancer treatment.

Resistance to apoptosis is a key mechanism underlying how cancer cells evade tumor therapy. Autophagy can prevent anticancer drug-induced apoptosis and promote tumor resistance. The purpose of this study was to improve the sensitivity and efficacy of chemotherapeutic drugs through the inhibition of autophagy. Hydrophobic doxorubicin-hydrazone-caproyl-maleimide (DOX-EMCH) and autophagy-inhibiting si-Beclin1 were simultaneously delivered via the amphiphilic peptide micelle system (Co-PMs) using poly(L-arginine)-poly(L-histidine)-DOX-EMCH as the copolymer building unit. The constructed micelle system promoted the escape of si-Beclin1 from endosomes and the release of DOX into the nucleus. The Co-PMs exhibited 2.7-fold higher cytotoxicity and proapoptotic ability in PC3 cells than DOX treatment alone, demonstrating that si-Beclin1 could inhibit the autophagic activity of prostate cancer (PCa) cells by targeting the type III PI3K pathway and enhance the sensitivity of the cells to the chemotherapeutic drug DOX. In addition, the peptide micelles successfully passively targeted DOX and si-Beclin1 to the tumor tissue. Compared with DOX or si-Beclin1 treatment alone, the Co-PMs showed a 3.4-fold greater tumor inhibitory potential in vivo, indicative of a significant antiproliferative effect. Our results suggested that the Co-PMs developed in this study have the potential to combine autophagy inhibition and chemotherapy in cancer treatment, especially for PCa.

Tumor Microenvironment Multiple Responsive Nanoparticles for Targeted Delivery of Doxorubicin and CpG Against Triple-Negative Breast Cancer.

Introduction: Currently, the main treatment for advanced breast cancer is still chemotherapy. Immunological and chemical combination therapy has a coordinated therapeutic effect and achieves some efficacy. However, the immunosuppressive tumor microenvironment is a major cause for the failure of immunotherapy in breast cancer. CpG oligodeoxynucleotides can activate the tumor immune microenvironment to reverse the failure of immunotherapy. Methods: In this study, we designed an amphiphilic peptide micelle system (Co-LMs), which can targeted delivery of the immune adjuvant CpG and the chemotherapeutic drug doxorubicin to breast cancer tumors simultaneously. The peptide micelle system achieved tumor microenvironment pH and redox-sensitive drug release. Results and Discussion: Co-LMs showed 2.3 times the antitumor efficacy of chemotherapy alone and 5.1 times the antitumor efficacy of immunotherapy alone in triple-negative breast cancer mice. Co-LMs activated cytotoxic CD8+ T lymphocytes and CD4+ T cells in mice to a greater extent than single treatments. We also found that Co-LMs inhibited the metastasis of circulating tumor cells in the bloodstream to some extent. These results indicate that the Co-LMs offer a promising therapeutic strategy against triple-negative breast cancer.

Aptamer-conjugated multi-walled carbon nanotubes as a new targeted ultrasound contrast agent for the diagnosis of prostate cancer.

Early diagnosis is primarily important for the therapeutic and prognostic outcomes of malignancies including prostate cancer (PCa). However, the visuality and veracity of ultrasound imaging for the diagnosis and prognostic prediction of PCa remains poor at present. In this study, we developed a new nanoultrasound contrast agent by modifying multi-walled carbon nanotubes (MWCNTs) with polyethylene glycol (PEG) and anti-PSMA aptamer. The result showed that the modified MWCNTs offered better visuality and veracity and were able to target PCa cells more effectively as compared with the traditional contrast agent. The zeta potential was about - 38 mv. The length of this contrast agent was about 400 nm and the diameter of it was about 30 nm. The zeta potential, TEM, and FT-IR all proved the successful preparation of the agent. The vitro cytological study revealed good cell uptake and biocompatibility of the new contrast agent. The minimum detection concentration in vitro is 10 µg/ml. The earliest stage of the detection was under the parameters of frequency = 6.0 MHz and medical index = 0.06. Both in vitro and in vivo ultrasound imaging demonstrated that the new nanoultrasound contrast agent had a good development effect, distribution, and metabolism, and may prove to be a good targeted ultrasound contrast agent, especially for PCa.

Functionalized Multi-Walled Carbon Nanotubes for Targeting Delivery of Immunostimulatory CpG Oligonucleotides Against Prostate Cancer.

Immuno-based oncotherapy has been successfully implemented for cancer treatment. In the present study, we developed a Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs (CpG ODNs) nano-delivery system based on Multi-walled carbon nanotubes (MWCNTs) conjugated with H3R6 polypeptide (MHR-CpG) for prostate cancer immunotherapy. The in vitro and in vivo toxicity data revealed that the prepared MHR showed high biocompatibility. Confocal laser scanning microscopy confirmed that MHR-CpG could specifically target the endosomal TLR9. In addition, the use of MHR enhanced the immunogenicity of CpG in both humoral and cellular immune pathways, as evidenced by the increased expression of CD4+ T-cells, CD8+ T-cells, TNF-α, and IL-6. The in vivo anti-cancer efficacy study on RM-1 tumor-bearing mice demonstrated that MHR-CpG could deliver the immunotherapeutics to the tumor site and the tumor-draining lymph node to suppress tumor growth. These results suggested that MHR-CpG was a promising multifunctional nano system for prostate cancer immunotherapy.

Co-delivery of autophagy inhibitor ATG7 siRNA and docetaxel for breast cancer treatment.

The lysosomal degradation pathway of autophagy has a crucial role in protecting cancer cells from multiple endogenous and exogenous stresses, particularly during the pathogenesis of cancer. Accordingly, agents that inhibit autophagy may have broad therapeutic applications. We have developed a novel strategy based on co-delivery of an autophagy related 7 (ATG7) siRNA and docetaxel (DTX) in a crosslinked, reducible, peptide-based micellar system for breast cancer treatment. Our results show that DTX and siATG7 co-treatment exhibited 2.5- and 1.7-fold higher cytotoxicity and apoptosis, respectively, in MCF-7 cells than DTX treatment alone did, which demonstrates that siATG7 enhances the efficacy and apoptotic effect of DTX. Our study showed that breast cancer cell lines differ greatly in their dependency on autophagy under conditions of normal or stress. Furthermore, siATG7 delivery in a micellar system can effectively silence the ATG7 gene, suppress DTX-induced autophagy, and exhibit improved anticancer effects. In addition, DTX in a co-delivery system showed at least a 1.84-fold greater tumor inhibition compared to that of DTX-loaded micelles in vivo. Finally, a Cy5 indicator that was loaded into crosslinked micelles revealed a remarkably high accumulation in tumors, demonstrating excellent tumor targeting ability of the micellar system. Therefore, our research demonstrated the synergistic efficacy of the combination of autophagy inhibition and chemotherapy delivered by polypeptide micelles for breast cancer therapy.

Aptamer-mediated delivery of docetaxel to prostate cancer through polymeric nanoparticles for enhancement of antitumor efficacy.

Treatment of aggressive prostate cancer remains a great challenge due to inadequate drug distribution into the cancerous lesions after administration. This study aimed to develop aptamer-anchored nanoparticles (apt-NPs) for systemic delivery of docetaxel (DTX) and to evaluate the tumoricidal activity against the prostate cancer in vitro and in vivo. DTX-loaded apt-NPs (DTX-apt-NPs) were prepared by a solvent diffusion technique using functional PLGA-b-PEG and sodium oleate. DTX-apt-NPs were characterized by in vitro release, antitumor activity, cellular uptake and cytotoxic mechanisms. Pharmacokinetics and tissue distribution studies were performed in rats to investigate the biofate of DTX-apt-NPs. Finally, the in vivo antitumor efficacy was examined on the LNCaP cells xenograft tumor model. The resulting DTX-apt-NPs were 93.6nm in particle size with narrow distribution and possessed a high entrapment efficiency (97.62%) and acceptable drug loading (8.91%). DTX-apt-NPs demonstrated an enhanced in vitro antitumor effect and marked cellular uptake compared with the solution formulation or conventional nanoparticles. The intracellular trafficking of DTX-apt-NPs was shown to be an active transport process involving the clathrin-dependent endocytosis. Anti-PSMA aptamer-mediated delivery was assumed mainly responsible for the enhanced antitumor efficacy. DTX-apt-NPs that can target to PSMA-overexpressed prostate cancer provide a feasible approach for systemic delivery of DTX to the cancerous prostate to achieve a fine prognosis.

Synergistic effect of reduced polypeptide micelle for co-delivery of doxorubicin and TRAIL against drug-resistance in breast cancer.

Cationic peptides as a non-viral gene vector have become a hotspot of research because of their high transfection efficcacy and safety. Based on our previous study, we synthesized a cationic reduction-responsive vector based on disulfide cross-linked L-arginine, L-histidine and lipoic acid (LHRss) as the co-carrier of both doxorubicin (DOX) and the necrosis factor-related apoptosis-inducing ligand (pTRAIL). The LHRss/DOX/TRAIL construct has reduction-sensitive behavior and an enhanced endosomal escape ability to increase the cytotoxicity of DOX and the transfection efficiency. Further, the LHRss/DOX/TRAIL construct increased the accumulation of DOX and promoted the expression of pTRAIL, thus increasing cellular apoptosis by 83.7% in MCF-7/ADR cells. In addition, the in vivo biodistribution results showed that the LHRss/DOX/TRAIL construct could target tumors well. The in vivo anti-tumor effect study demonstrated that the LHRss/DOX/TRAIL construct inhibited tumor growth markedly, with a tumor inhibitory rate of 94.0%. The co-delivery system showed a significant synergistic anti-tumor effect. The LHRss/DOX/TRAIL construct may prove to be a promising co-delivery vector for the effective treatment of drug resistant breast cancer.

Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer.

In the present study, we developed a novel type of reduction-sensitive nanoparticles (NPs) for docetaxel (DTX) delivery based on cross-linked lipoic acid NPs (LANPs). The physicochemical properties, cellular uptake and in vitro cytotoxicity of DTX loaded LANPs (DTX-LANPs) on A549 cells were investigated. Furthermore, the in vivo distribution and in vivo efficacy of DTX-LANPs was evaluated. The results showed that DTX-LANPs had a particle size of 110 nm and a negative zeta potential of -35 mv with excellent colloidal stability. LANPs efficiently encapsulated DTX with a high drug loading of 4.51% ± 0.49% and showed remarkable reduction-sensitive drug release in vitro. Cellular uptake experiments demonstrated that LANPs significantly increased intracellular DTX uptake by about 10 fold as compared with free DTX. The cytotoxicity of DTX-LANPs showed significantly higher potency in inhibiting A549 cell growth than free DTX, while blank LANPs had a good biocompatibility. In addition, in vivo experiments demonstrated that DTX-LANPs could enhance tumour targeting and anti-tumour efficacy with low systemic toxicity. In conclusion, LANPs may prove to be a potential tumour microenvironment-responsive delivery system for cancer treatment, with the potential for commercialization due to the simple component, controllable synthesis, stability and economy.

Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy.

The co-delivery of chemotherapeutic drugs and microRNAs (miR) represents a promising strategy for tumor therapy due to the synergistic effect achieved. In the present study, hydrophobic doxorubicin (DOX) and negatively charged miR-34a were simultaneously delivered via a reducible self-assembling disulfide cross-linked stearyl-peptide-based micellar system (SHRss) using poly(l-arginine)-poly(l-histidine)-stearoyl as the copolymer building unit. The nanoscale SHRss micelles exhibited a low critical micelle concentration (CMC) with positive surface charge. In addition, the present micellar system facilitated the escape of miR-34a from the endosome and release of DOX into the cell nucleus, leading to the downregulation of silent information regulator 1 (SIRT1) expression and inhibition of DU145 and PC3 androgen-independent prostate cancer cell proliferation. In addition, DOX and miR-34a, delivered by SHRss micelles, passively targeted tumor tissue. Furthermore, a synergistic anti-proliferative effect was observed compared with DOX or miR-34a treatment alone in vivo. Our results demonstrate that the SHRss micelles developed in the present study represent a promising approach for combined delivery of gene agents and hydrophobic chemotherapeutic drugs in cancer therapy.