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Tumor is a kind of disease with high morbidity, high mortality and poor prognosis. Chemotherapy is the main treatment of tumor, but the problem of chemotherapy resistance is becoming increasingly prominent, so finding ways to overcome chemotherapy resistance and improve the therapeutic effect has become an urgent problem to be solved. At present, with the development of research, the anti-tumor effect of some traditional Chinese medicine has attracted extensive attention. Berberine, traditionally used in the treatment of digestive system diseases, has been proved to have the effect of anti-tumor and reversing tumor multi-drug resistance. This review summarizes the recent researches on the reversion multi-drug resistance in tumor by berberine, in order to explore the means to improve the therapeutic effect and prognosis of tumor drug resistance.
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Bladder cancer (BC) is one of the most common malignancies of the urinary tract. Surgery combined with chemoradiotherapy is the mainstay of treatment, but BC is markedly heterogeneous, leading to unsatisfactory outcomes. Antibody-drug conjugate (ADC), a new type of targeted drug, has achieved remarkable results in the treatment of tumors by coupling a chemical junction with a highly cytotoxic small molecule, which can exert anti-tumor effects while avoiding the impacts on normal cells. To date, several ADCs have been used in the treatment of BC at home and abroad, and play an increasingly important role in the field of BC therapy. This article briefly introduces the mechanism of ADC, the current application of ADC in BC treatment, and the problems and challenges faced, hoping to provide reference for clinical work.
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Hazardous environmental factors as well as occupational factors can lead to elevated incidence of diseases including tumors, and specific molecular biomarkers are needed to guide the diagnosis and treatment of diseases. In recent years, ubiquitin-specific protease 14 (USP14) has gradually attracted the attention of researchers. USP14 is widely expressed in various organs of human body and regulates the stability and degradation of important proteins in various signaling pathways. Studies have shown that its abnormal expression is highly correlated with tumors, neurodegenerative diseases, autophagy, immune response, and viral infections, and is involved in the regulation of various classic signaling pathways. It has been shown to play a key role in the development of various human diseases and can be used as a diagnostic and prognostic molecular biomarker and therapeutic target in the development of tumors. This paper reviewed the current status of research on the structure and regulation of USP14 and its function in physiological and pathological processes, with the aim of providing a reference for research on diseases or injuries caused by environmental and occupational factors.
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Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.
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Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.
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Background: Knowledge of newer and targeted drug delivery system is essential for applying pharmacology in treating various clinical conditions. Using appropriate dosage form considering patient抯 age, comorbidities, socioeconomic status, literacy, severity of clinical condition will enhance the effect of drug, decrease the adverse reactions and improve the patient抯 compliance. Learning is most effective when student involvement, participation, and interaction is maximized. Aim and Objectives: To evaluate improvement in knowledge of 2nd year MBBS students for availability, use and necessity of different dosage forms and newer and targeted drug delivery system by assignment based learning. Materials and Methods: The assignment-based activity was conducted for 2nd year MBBS students on different dosage forms and newer and targeted drug delivery system. Seventy students were divided into seven groups and assigned seven questions. Pre-test and post-test were conducted. Results: Post-test results were significantly higher than the pre-test results when compared by paired t-test. There was significant difference among the groups when Analysis of variance test was applied. Group 3, 4, 5 and 6 had gathered good information from e-resources about different drugs list of newer and targeted drug delivery system and Group 3 and 4 gathered details of liposomal and radio-pharmaceuticals based newer drug delivery system. Conclusion: Assignment based activities should be carried out for the critical topics where recent advances are going on, newer techniques for treatment are developing and newer dosage forms are marketed. Through this activity students with poor performance can be identified and guided personally and encouraged for better performance to be a competent physician.
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Aim Amyotrophic lateral sclerosis (Alii) is a neurodegenerative disease caused by the selective loss of upper and lower motor neurons.Its pathogenesis is complex and not yet fully understood.Accumulating evidences show that energy metabolism defieits and homeostasis imbalance lead to selective degeneration of motor neurons in ALS.Adenosine phosphate-activated protein kinase ( AMPK) and silent information regulator-1 (SIRT1) are known to sense energy metabolism at the cellular level, playing an essential part in regulating the energy homeostasis and autophagy by activating downstream pathways.AMPK activates SIRT1 to activate the deaeetylation and activation of downstream genes involved in energy metabolism such as peroxisome proliferator-aetivated receptor 7 ( PPAR-y) and eoaetivator la ( PGC-la) , thereby increasing the level of mitochondrial biosynthesis.Therefore, the mechanism by which AMPK/SIRT1 participates in the regulation of energy metabolism is highly likely to be a potential target for ALS treatment.Here we first review the important role of energy metabolism defects and mitochondrial abnormalities in the pathogenesis of ALS, and briefly address the therapeutic potential of AMPK/SIRT1/PGC-1 a pathway as a treatment target in ALS, and how targeted regulation of this signaling pathway makes it an effective therapeutic strategy for ALS.
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Liver transplantation is one of the main treatments of early hepatocellular carcinoma (HCC). The recurrence of HCC after liver transplantation severely affects the long-term survival rate of the recipients. Targeted therapy and immunotherapy play a critical role in HCC downstaging, preventing disease progression, reducing recurrence rate, prolonging the survival and improving the quality of life. However, no consensus has been reached on the application of targeted therapy and immunotherapy in recipients undergoing liver transplantation for HCC, including indications, timing and dosage. In this article, clinical research progresses on the indications and timing of targeted therapy and immunotherapy before and after liver transplantation for HCC were reviewed, aiming to provide reference for prolonging the survival of recipients after liver transplantation for HCC.
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OBJECTIVE To prepare and evalu ate doxorubicin-loaded red blood cell membrane chitosan-targeted nanoparticles of targeting tumor cell folate acid （FA）receptor（FA-RBC-DOX-CS-NPs）. METHODS Doxorubicin-loaded chitosan nanoparticles （DOX-CS-NPs） were prepared by ion cross-linking method. FA and amino polyethylene glycol phospholithin （NH2- PEG2000-DSPE）were covalently linked to modify the red blood cell membrane to construct FA-RBC-DOX-CS-NPS. FA-RBC- DOX-CS-NPs were characterized and investigated on in vitro drug release characteristics ，antitumor activity and endocytosis ability （investigation with human breast cancer MCF- 7 cells）. RESULTS Average particle size of FA-RBC-DOX-CS-NPs was （254.200± 2.651）nm，and polydispersity index was 0.199±0.031；Zeta potential was （－10.100±0.213）mV. FA-RBC-DOX-CS-NPs released fast in the tumor microenvironment （pH6.5）. Cellular experiments showed that ，the nanoparticles could inhibit the activity of MCF- 7 cell proliferation and improve the efficiency of endocytosis. CONCLUSIONS FA-RBC-DOX-CS-NPs are prepared successfully. The nanoparticles have good tumor cell targeting and endocytosis ability ，and can realize the enrichment of drugs in tumor cells.
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Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma (HNSCC) mortality. The overexpression of chemokine receptor 4 (CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4+ tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4+ HNSCC cells, achieving a high accumulation in CXCR4+ tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4+ cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted protein-only nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.
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Retinal pigment epithelial (RPE) is primarily impaired in age-related macular degeneration (AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization (CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor, rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages (termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.
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Objective To study the effects and mechanisms of molecular targeted drug combination on multi-driven proliferation hepatocellular carcinoma SK-Hep-1 cells. Methods Four molecular targeted drugs (HG6-64-1, Dasatinib, Crizotinib, and Sunitinib) were used to treat SK-Hep-1 cells, and the monophasic kinetic analysis curve and two-phase analysis curve were drawn. Western blot analysis was used to detect the effects of the above drugs on key signaling pathways in SK-Hep-1 cells. MTT assay was used to detect the effects of the above drugs and their combination on the proliferation of SK-Hep-1 cells. Results Compared with the monophasic kinetic analysis curve, the biphase analysis curve could better fit the effects of molecular targeted drugs on SK-Hep-1 cells, which predicted that the combination of HG6-64-1, Dasatinib, and MK-2206 could effectively inhibit the proliferation of SK-Hep-1 cells. Conclusion Two-phase kinetic analysis can quantitatively describe the response of multi-driven proliferation hepatocellular carcinoma SK-Hep-1 cells to molecular targeted therapy. The combination of HG6-64-1, Dasatinib, and MK-2206 is a potential drug combination for the treatment of hepatocellular carcinoma.
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Objective To analyze the clinical efficacy of different anti-tumor therapies for recurrence and metastasis after liver transplantation for primary liver cancer (liver cancer). Methods Clinical data of 145 recipients undergoing liver transplantation for liver cancer were retrospectively analyzed. The overall survival and recurrence and metastasis after liver transplantation for liver cancer were analyzed. The clinical efficacy of different anti-tumor therapies for recipients with recurrence and metastasis were compared. Results Sixty-five recipients (44.8%) developed recurrence and metastasis. The median recurrence time was 6 months. Among them, 1 case underwent secondary liver transplantation after recurrence and died of intestinal perforation. Twenty-four recipients (37%) received targeted drug therapy with a median tumor-bearing survival of 22 months. Eleven recipients (17%) received radiotherapy or chemotherapy with a median tumor-bearing survival of 11 months. Nine recipients (14%) received local treatment (surgical resection or radiofrequency ablation), and the median tumor-bearing survival was 8 months. Twenty recipients (31%) abandoned anti-tumor therapy, and the median tumor-bearing survival was 3 months. The tumor-bearing survival of recipients receiving anti-tumor therapy was significantly longer than that of recipients without anti-tumor therapy (P < 0.001). The tumor-bearing survival of recipients receiving targeted drug therapy was significantly longer than that of those receiving other anti-tumor therapies (P=0.03). The tumor-bearing survival of recipients receiving local treatment, radiotherapy and chemotherapy was considerably longer than that of those who abandoned anti-tumor therapy (P=0.004). Conclusions Surgical resection and radiofrequency ablation are the optimal therapies for recipients with recurrence and metastasis after liver transplantation for liver cancer. For recipients with multi-focal tumors who fail to receive local treatment, those receiving targeted drug therapy obtain the longest survival. In addition, radiotherapy and chemotherapy can also prolong the survival of recipients with recurrence and metastasis.
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Colorectal cancer is a common malignant tumor in the gastrointestinal tract, with the characteristics of high morbidity and mortality. Studies have shown that the occurrence and development of colorectal cancer is closely related to the abnormal activation of Wnt signaling pathway. Abnormal expression of β-catenin in Wnt pathway is found both in the cytoplasm and nucleus of tumor cells. Different drugs can target the Wnt signaling pathway and its upstream and downstream related factors to inhibit or suppress the development of colorectal cancer. We review the components of Wnt signaling pathway, and the correlation between Wnt signaling pathway and colorectal cancer. Then, we summarize the current status of drug research targeting the Wnt signaling pathway in colorectal cancer. Finally, the challenges and prospects of these methods and drugs were briefly summarized.
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Solid tumors are complex entities, comprising a wide variety of malignancies with very different molecular alterations. Despite this, they share a set of characteristics known as "hallmarks of cancer" that can be used as common therapeutic targets. Thus, every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates, and these adaptations lead to alterations in extra- and intracellular pH. These changes in pH are common to all solid tumors, and can be used either as therapeutic targets, blocking the cell proton transporters and reversing the pH changes, or as means to specifically deliver anticancer drugs. In this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic adaptations. We will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light exposure. Finally, we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery, describing how nanocarriers are being used to increase drug stability and specificity.
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In this study, exosomes were extracted from human malignant melanoma cell A375. Folic acid (FA) receptor was used as target and triptolide (TPL) was used as model drug to prepare exosome targeted drug delivery system, FA-Exo/TPL. The physicochemical properties and antitumor effect were evaluated in vivo and in vitro. Gradient centrifugation method was applied to collect exosomes. Then, exosome was modified with FA for loading TPL. The particle sizes of the FA-Exo/TPL were about 100 nm with a double-layer membrane structure like a tray. It is characteristic of high encapsulation efficiency and drug loading. In vitro experiments showed that FA-Exo/TPL could be effectively uptaken by A375 cells, thus significantly inhibiting proliferation and promoting apoptosis the cells. In vivo experiment results showed that FA-Exo/TPL could effectively inhibit the growth of tumor tissue, prolong the model mice life cycle, and significantly reduce the systemic toxicity of the free drug, playing a synergistic and toxic role. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of Fudan University Shanghai Cancer Center. This study provides a new strategies and methods for the preparation of TPL against malignant melanoma.
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The small size， moderate drug loading， and targeting properties of nano-preparations make them can be excellent delivery tools for drugs， genes or proteins crossing the cell or blood-brain barrier （BBB）. Currently， facilitating drug crossing BBB with innovative nano-drug delivery systems is considered as a strategic approach for the prevention， diagnosis and treatment of central nervous system （CNS） diseases. However， with the deepening of the research， the adverse reactions and toxicity of nanocarriers have gradually attracted the attention of researchers. Based on this， this paper summarized the situation of BBB-penetrating targeted nano-preparations at home and abroad in recent years from the perspective of classification of types and properties of nanocarriers， and analyzed the advantages and disadvantages of each carrier. The results showed that nano-preparations with active ingredients of traditional Chinese medicine （TCM） as carriers have become a promising way of cancer treatment， but the complexity and diversity of TCM components limited its application to a certain extent. Further studies should be strengthened to lay a foundation for the application and development of TCM nano-preparations in the field of CNS diseases.
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Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.
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Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents.Administration of these drugs with siRNA is an efficacious strategy in this battle.Here,the present study tried to incor-porate siRNA and paclitaxel(PTX)simultaneously into a novel nanocarrier.The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA)and glucose(Glu)onto its surface.The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCo-polyethyleneimine(FeCo-PEI)nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG)gene delivery system.Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA),FeCo-PEI-PLA-PEG-Glu(NPsB)and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB)nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay.Besides,siRNA-FAM internalization was investi-gated by fluorescence microscopy.The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations.Meanwhile,siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474cell lines.NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also,they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu.We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.
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Tumor has become the second most serious disease that threatens human health and life. Treating with chemical drugs (referred to as chemotherapy) is the most basic treatment, but most chemotherapeutic drugs cause damage to normal tissues. It is a difficult problem in the field of biomedical research that how to deliver anti-tumor drugs more efficiently, increase the concentration of drugs in tumor tissues, enhance the anti-tumor effect, and decrease the drug distribution in normal tissues to weaken the damage to normal tissues. In order to achieve the goals of accurate delivery of anti-tumor drugs and synergism and attenuation, the researchers used systematic evolution of ligands by exponential enrichment technology (SELEX technology) to screen aptamers that can specifically target tumor markers or tumor cells, and designed the novel liposome targeting drug delivery system with aptamers as targeting molecules (ligands). This paper briefly introduced nucleic acid aptamer technology and common tumor markers, and reviewed the research advances on the antitumor effect of aptamer-liposome drug delivery system. It will provide references for the selection of appropriate tumor markers as targets and the application of aptamer technology in the research and development of high-efficiency and low-toxicity liposome targeting agents of anti-tumor traditional Chinese medicine. Meanwhile, it is of great significance for promoting the application of aptamer technology in targeted drug delivery systems.