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Near-infrared-responsive GE11-CuS@Gal nanoparticles as an intelligent drug release system for targeting therapy against oral squamous cell carcinoma
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Introduction:
In lateralized oral squamous cell carcinoma (OSCC) with ipsilateral cervical lymph node metastasis (CLNM), the surgical management of the unsuspicious contralateral neck remains a matter of debate. The aim of this study was to analyze this cohort and to compare the outcomes of patients with and without contralateral elective neck dissection (END).
Material and methods:
A retrospective analysis of patients with lateralized OSCC, ipsilateral CLNM (pN+) and contralateral cN0-stage was performed. Patients were divided into two groups according to the surgical management of the contralateral neck: I: END; and II: no END performed. Adjuvant radiotherapy was applied bilaterally in both groups according to individual risk.
Results:
A total of 65 patients (group I: 16 (24.6%); group II: 49 (75.4%)) with a median follow-up of 28 months were included. Initially, there was no case of contralateral CLNM after surgery. During follow-up, 6 (9.2%) patients presented with recurrent CLNM. In 5 of these cases (7.7%), the contralateral neck (group I: 3/16 (18.8%); group II: 2/49 (4.1%)) was affected. Increased ipsilateral lymph node ratio was associated with contralateral CLNM (p = 0.07). END of the contralateral side showed no significant benefit regarding OS (p = 0.59) and RFS (p = 0.19).
Conclusions:
Overall, the risk for occult contralateral CLNM in patients with lateralized OSCC ipsilateral CLNM is low. Our data suggest that END should not be performed routinely in this cohort. Risk-adapted radiotherapy of the contralateral neck alone seems to be sufficient from the oncological point of view.
Polyphenols and their derivates, a kind of natural product distributed in herb plants, vegetables, and fruits, are the most abundant antioxidants in the human diet and have been found to display cancer-preventative effects in several epidemiological studies. The scientific community has also validated the anti-cancer bioactivities and low toxicities of polyphenolic compounds, including flavones, tannins, phenolic acids, and anthocyanins, through in vitro and in vivo studies. However, the low stability, weak targeting ability, poor solubility, and low bioavailability of pure polyphenolic agents have significantly impaired their treatment efficacy. Nowadays, nano-based technology has been applied to surmount these restrictions and maximize the treatment efficacy of polyphenols. In this review, we summarize the advantages and related mechanisms of polyphenols in cancer treatment. Moreover, aiming at the poor solubility and low bioavailability of pure polyphenols in vivo, the advantages of nano-based delivery systems and recent research developments are highlighted. Herein, particular emphasis is mainly placed on the most widely used nanomaterials in the delivery of natural products, including liposomes, micelles, and nanogels. Finally, we present an overview and the challenges of future implementations of nano-based delivery systems of polyphenolic compounds in the cancer therapeutic field.
Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity; however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established; both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 μM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.
Oral squamous cell carcinoma (OSCC) is the most common type of malignant tumor in the head and neck, with a poor prognosis mainly due to recurrence and metastasis. Classical treatment modalities for OSCC like surgery and radiotherapy have difficulties in dealing with metastatic tumors, and together with chemotherapy, they have major problems related to non-specific cell death. Molecular targeted therapies offer solutions to these problems through not only potentially maximizing the anticancer efficacy but also minimizing the treatment-related toxicity. Among them, the receptor-mediated targeted delivery of anticancer therapeutics remains the most promising one. As OSCC exhibits a heterogeneous nature, selecting the appropriate receptors for targeting is the prerequisite. Hence, we reviewed the OSCC-associated receptors previously used in targeted therapy, focused on their biochemical characteristics and expression patterns, and discussed the application potential in personalized targeted therapy of OSCC. We hope that a better comprehension of this subject will help to provide the fundamental information for OSCC personalized therapeutic planning.
Low dose non-toxic disulfide cross-linked micelle (DCM) encapsulated paclitaxel (PTX) was found to be highly efficacious as a radiosensitizer against oral cancer preclinical model. Intensity-modulated radiation therapy was locally administered for three consecutive days 24 h after intravascular injection of DCM-[PTX] NPs at 5 mg/kg PTX. DCM-[PTX] NPs combined with conventional radiotherapy (2 Gy) resulted in a 1.7-fold improvement in therapeutic efficacy compared to conventional PTX plus radiotherapy. Interestingly, we found that radiotherapy can decrease tight junctions and increase the accumulation of DCM-[PTX] in tumor sites. Stereotactic body radiotherapy (SBRT) given at 6 Gy was used to further investigate the synergistic anti-tumor effect. Tumor tissues were collected to analyze the relationship between the time interval after SBRT and the biodistribution of the nanomaterials. Compared to combination DCM-[PTX] with conventional radiation dose, combination DCM-PTX with SBRT was found to be more efficacious in inhibiting tumor growth.
Background
Glucose oxidase (GOx)-based starvation therapy is a new cancer treatment strategy. However, the characteristics such as limited curative effect and hypoxic tumor environment hinder its further application seriously.
Methods
Herein, doxorubicin (DOX) loaded in hollow mesoporous copper sulfide (HMCuS) nanoparticles assembled with manganese dioxide (HMMD) as nanoshell was prepared. We developed a targeted enhanced cancer treatment method to camouflage HMMD by GOx-functionalized platelet (PLT) membranes (HMMD@PG).
Results
GOx can be specially transported to the tumor site with PLT membrane for effective starvation treatment. Glucose and oxygen (O2) in the tumor were converted to H2O2 under the catalysis of GOx. HMMD can catalyze H2O2 to produce O2 and consume glutathione (GSH) in time, which regulates the tumor microenvironment (TME) and improves the adverse conditions of anti-tumor. In addition, DOX encapsulated in HMCuS-MnO2 release was accelerated from the nanoparticles after the “gatekeeper” MnO2 is consumed. The study of anti-tumor mechanism shows that the remarkable tumor suppressive ability of HMMD@PG comes from the three peaks synergy of starvation treatment, photothermal treatment (PTT), and chemotherapy. This nanoplatform disguised by PLT membrane has significant tumor inhibition ability, good biocompatibility and almost has no side effects in main organs.
Conclusion
This work broadens the application mode of GOx and shows the new development of a multi-mode collaborative processing system of nanoplatforms based on cell membrane camouflage.
Galangin, a flavonoid isolated from the rhizome of Alpinia officinarum (Hance), exerts anticancer activities against many cancer cells such as liver cancer, breast cancer, lung cancer and esophageal cancer. However, the effect, as well as the underlying molecular mechanism of galangin on gastric cancer remains to be elucidated. In the present study, galangin inhibited cell viability of MGC 803 cells but not normal gastric mucosal epithelial GES-1 cells. It suppressed cell proliferation accompanied by reduced Ki67 and PCNA expression, promoted apoptosis shown by decreased Bcl-2 and elevated cleaved caspase-3 and cleaved PARP. And, galangin significantly inactivated JAK2/STAT3 pathway. When STAT3 was overexpressed, the proliferation inhibition and apoptosis promotion induced by galangin were abrogated. Meanwhile, galangin increased ROS accumulation, and reduced Nrf2 and NQO-1, but elevated HO-1 in MGC 803 cells. NAC, a ROS scavenger, rescued ROS over-accumulation and proliferation inhibition of galangin. STAT3 overexpression also counteracted excessive ROS accumulation induced by galangin. Consistent with the in vitro experiments, in nude mice exnografted with MGC 803 cells, galangin inhibited tumor growth and reversed the abnormally expressed proteins, such as p-JAK2, p-STAT3, Bcl-2, cleaved caspase-3, cleaved PARP, and Ki67. Taken together, galangin was suggested to inhibit the growth of MGC 803 cells through inducing apoptosis and decreasing cell proliferation, which might be mediated by modulating STAT3/ROS axis. Our findings implicate a potential application of galangin for gastric cancer therapy possibly with low toxicity.
Oridonin (ORI) has been shown to inhibit tumor cell growth and proliferation in vitro, while its optimum anti-tumor activity in vivo is limited due to the poor aqueous solubility and bioavailability. In this study, to improve the bioavailability, we developed a nanoparticle-based drug delivery system to facilitate delivery of ORI to breast tumor. ORI was encapsulated in biodegradable nanoparticles (NPs) based on poly-lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG) to form ORI NPs (ORI-NPs). The resulting ORI-NPs exhibited a mean particle diameter of 100 nm and displayed an efficient cellular uptake by human breast cancer MCF-7 cells. Compared to free ORI that showed no effects on tumor cell proliferation, the ORI-NPs showed significant cytotoxicity and delayed endothelial cell migration, tube formation and angiogenesis. Pharmacokinetics studies showed that ORI-NPs significantly increased the half-life of ORI in the blood circulation. In the nude mouse xenograft model, ORI-NPs markedly inhibited tumor growth and angiogenesis, while ORI did not show any inhibitory effects on the growth of tumor xenografts. The mechanism experiments showed that the antitumor activity of ORI-NPs against breast cancer might be through ROS related Nrf2/HO-1 signaling pathway. Together, these results demonstrated that ORI-loaded PEG-PLGA NPs enhanced bioactivity and bioavailability in vivo over ORI, indicating that ORI-NPs may represent a promisingly effective candidate against breast cancer.
How to actively target tumor sites manipulating the controllable release of the encapsulated anticancer drugs and photosensitizers for synergistic anticancer therapy remains a big challenge. In this study, a cancer cell-targeted, near-infrared (NIR) light-triggered and anticancer drug loaded liposome system (LPs) was developed for synergistic cancer therapy. Photosensitizer indocyanine green (ICG) and chemotherapy drug Curcumin (CUR) were coencapsulated into the liposomes, followed by the surface conjugation of GE11 peptide for epidermal growth factor receptor (EGFR) targeting on the cancer cell surface. Strictly controlled by NIR light, GE11 peptide modified and CUR/ICG-loaded LPs (GE11-CUR/ICG-LPs) could introduce hyperthermia in EGFR overexpressed A549 cancer cells for photothermal therapy, which could also trigger the increased release of CUR for enhanced cancer cell inhibition. GE11-CUR/ICG-LPs synergized photochemotherapy could induce reactive oxygen species (ROS) generation and cytoskeleton disruption to activate stronger apoptotic signaling events than the photothermal therapy or chemotherapy alone by regulating Bax/Bcl-2 and PI3K/AKT pathways. This EGFR-targeted drug-delivery nanosystem with NIR sensitivity may potentially serve in more effective anticancer therapeutics with reduced off-target effects.
Oral cancers refer to malignant tumors associated with high morbidity and mortality, and oral squamous cell carcinoma accounts for the majority of cases. It is an important part of head and neck, and oral cancer is one of the six most common cancers in the world. At present, the traditional treatment methods for oral cancer include surgery, radiation therapy, and chemotherapy. However, these methods have many disadvantages. In recent years, nanomedicine, the delivery of drugs through nanoplatforms for the treatment of cancer, has become a promising substitutive therapy. The use of nanoplatforms can reduce the degradation of the drug in the body and accurately deliver it to the tumor site. This minimizes the distribution of the drug to other organs, thereby reducing its toxicity and allowing higher drug concentration at the tumor site. This review introduces polymer nanoparticles, lipid-based nanoparticles, metal nanoparticles, hydrogels, exosomes, and dendrimers for the treatment of oral cancer, and discusses how these nanoplatforms play an anti-cancer effect. Finally, the review gives a slight outlook on the future prospects of nanoplatforms for oral cancer treatment.
Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.
One of the key mechanisms of alcoholic liver disease is oxidative stress. Both Curcumin and Baicalin exert antioxidant effects, but the mechanism of their combined effects of ethanol‐induced liver injury is still unclear. This study was conducted to evaluate the dual antioxidant activity of Curcumin combined with Baicalin against ethanol‐induced liver injury in rats. Rats were divided into five groups, a control, ethanol, ethanol + Curcumin (50 mg/kg), ethanol + Baicalin (50 mg/kg), and ethanol + Curcumin +Baicalin group with ten rats per group. The effects of ethanol on liver enzymes, oxidative stress indicators and the levels of Nrf2/HO‐1 pathway related proteins and mRNA were observed along with liver histopathology in rats. Our results found that the serum ALT and AKP levels were increased in ethanol‐treated rats, which also showed a rising trend of 8‐OHdG and LPO levels while hydroxyl radical scavenging ability, T‐AOC, and the activities of SOD and GSH‐Px were decreased in liver. The mRNA levels of Nrf2 and HO‐1 , the ratio of p‐Nrf2/Nrf2, the protein level of HO‐1 were decreased while NQO1 mRNA level, Nrf2, p‐Nrf2, and NQO1 protein levels were increased in ethanol‐treated rats. Combination treatment of Curcumin and Baicalin significantly reversed the ethanol‐induced liver oxidative damage and further activate the Nrf2/HO‐1 pathway, which was more effective than each drug alone. In conclusion, evidence has shown for the first time in this study that Curcumin combined with Baicalin ameliorated ethanol‐induced liver oxidative damage in rats and revealed liver‐protection.
Practical applications
Many drugs for treating alcoholic liver disease are available commercially, but some adverse effects they have may cause secondary damage to the liver. At present, the combined treatment of different natural phytochemicals has attracted special attention in modern medicine. Curcumin, a kind of phytochemicals, is extracted from turmeric rhizome. Baicalin is one of the major active components of Scutellaria Baicalensis. The current research is to explore the antioxidant effect of Curcumin and Baicalin in ethanol‐induced liver injury in rats. Our research proves that Curcumin combined with Baicalin on ethanol‐induced liver oxidative damage is superior to single drug treatment. Therefore, the combination of Curcumin and Baicalin may provide a more prospective natural remedy to combat ethanol‐induced liver injury.
Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine and cocoa-based products are the main dietary sources of flavonoids. Flavonoids have been shown to possess a wide variety of anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis, autophagy, and suppress cancer cell proliferation and invasiveness. Flavonoids have dual action regarding ROS homeostasis—they act as antioxidants under normal conditions and are potent pro-oxidants in cancer cells triggering the apoptotic pathways and downregulating pro-inflammatory signaling pathways. This article reviews the biochemical properties and bioavailability of flavonoids, their anticancer activity and its mechanisms of action.
Traditional photothermal therapy requires high‐intensity laser excitation for cancer treatments due to the low photothermal conversion efficiency (PCE) of photothermal agents (PTAs). PTAs with ultra‐high PCEs can decrease the required excited light intensity, which allows safe and efficient therapy in deep tissues. In this work, a PTA is synthesized with high PCE of 88.3% based on a BODIPY scaffold, by introducing a CF3 “barrier‐free” rotor on the meso‐position (tfm‐BDP). In both the ground and excited state, the CF3 moiety in tfm‐BDP has no energy barrier to rotation, allowing it to efficiently dissipate absorbed (NIR) photons as heat. Importantly, the barrier‐free rotation of CF3 can be maintained after encapsulating tfm‐BDP into polymeric nanoparticles (NPs). Thus, laser irradiation with safe intensity (0.3 W cm−2, 808 nm) can lead to complete tumor ablation in tumor‐bearing mice after intravenous injection of tfm‐BDP NPs. This strategy of “barrier‐free rotation” provides a new platform for future design of PTT agents for clinical cancer treatment. A photothermal agent (PTA) with a “barrier‐free” group rotor based on BODIPY is synthesized that demonstrates an ultra‐high photothermal conversion efficiency of 88.3%. The PTA is encapsulated into biocompatible polymer nanoparticles, which can accumulate at tumor sites in a mouse model. Low‐intensity near‐infrared light activates the nanoparticles to efficiently generate heat, resulting in complete ablation of the tumor.
Galangin (3,5,7‑trihydroxyflavone), a natural flavonoid present in plants, has been reported to possess anticancer properties in various types of cancers comprising glioma. The underlying mechanism, however, has not been fully elucidated. CD44, a hall marker in glioma, has been reported to be associated with epithelial-mesenchymal transition (EMT) and angiogenesis, which play important roles in glioma progression. In this study, we aimed to investigate whether galangin can inhibit EMT, angiogenesis and CD44 expression in glioma. We observed that galangin inhibited the proliferation, migration, invasion and angiogenesis of glioma cells in a dose-dependent manner, suppressed the expression of CD44 and inhibited angiogenesis of glioma cells through downregulating vascular endothelial growth factor (VEGF) in HUVECs. In addition, the overexpression of CD44 in U87 and U251 cells partly abolished the effects of galangin on glioma cells. Moreover, galangin suppressed tumor growth in an intracranial glioma mouse model. These results indicate that galangin is a potential novel drug for glioblastoma treatment due to its ability to suppress of CD44, EMT and angiogenesis.
Objective: To investigate the underlying molecular mechanisms contributing to oral squamous cell carcinoma (OSCC) cell resistance to the epidermal growth factor receptor (EGFR) inhibitor. Materials and methods: OSCC cell lines HSC-2 and HSC-3 were assessed in vitro for drug treatment, cell viability, and gene expression and the online gene expression in OSCC tissues was analyzed for association with OSCC prognosis. Results: HSC-2 and HSC-3 cells expressed high EGFR levels, but hepatocyte growth factor (HGF) treatment induced cetuximab resistance, whereas the Met inhibitor PHA-665752 as well as Met siRNA was able to restore OSCC cell sensitivity to cetuximab. HGF treatment induced tumor cells to express p-Akt and p-ERK1/2. In contrast, the activity of Akt and ERK1/2 was suppressed by treatment with PHA-665752, Met siRNA, or their combination. Furthermore, Met was highly expressed in OSCC tissues and associated with a poor patient survival, while Met/HGF-activated Akt also was associated with a poor patient survival. Conclusions: This study demonstrates that Met/HGF expression results in OSCC resistance to cetuximab and tumor recurrence after cetuximab therapy; thus, inhibition of Met/HGF activity could restore OSCC sensitivity to cetuximab.
The present study describes the preparation of a dodecapeptide YHWYGYTPQNVI (GE11)‑conjugated liposome bound with polyethylene glycol to enhance the therapeutic effect of resveratrol (RSV) in head and neck cancer cells. The results indicated that (RSV)‑loaded GE11‑conjugated liposomes (RSV‑GL) exhibited a high entrapment efficiency of >95%, with an active drug loading level of 19.5% w/w. Release kinetics revealed that RSV was released in a slow and sustained manner from the RSV‑GL and RSV‑loaded liposome (RSV‑L) nanoparticulate systems. The epidermal growth factor receptor (EGFR)‑overexpressing squamous cell carcinoma HN cells specifically internalized GE11 surface‑conjugated liposome in a manner that was markedly increased compared with that of the non‑targeted carrier. Consistently, RSV‑GL exhibited a significantly increased cytotoxic effect compared with that of the non‑targeted nanoparticles. Notably, RSV‑GL induced significantly increased proportions of early (~60%) and late (~10%) apoptotic cells in head and neck cancer cell populations. To the best of our knowledge, the application and development of EGFR‑targeted peptide‑conjugated liposome system for RSV delivery has not been studied previously in the treatment of head and neck cancer. In addition, RSV‑GL exhibited the greatest antitumor efficacy compared with any other group. RSV‑GL exhibited a 2‑fold decrease in tumor volume compared with the free RSV and a 3‑fold decrease in volume compared with the control. Overall, the nanomedicine strategy described in the present study may potentially advance the chemotherapy‑based treatment of head and neck cancer, with promising applications in other EGFR‑overexpressing tumors.
Hepatocellular carcinoma (HCC) is one of the most common cancers and has a high mortality rate in less developed countries, especially in China. Galangin (GA), one of the most important and naturally active flavonoids, extracted primarily from the root of Alpinia officinarum Hance, has been demonstrated to be effective in the treatment of HCC. It is a substance with defensive actions and a broad range of biological properties, including inhibitory effects on bacteria, fungi, viruses, the control of hypertension and diabetes, and chemoprevention of several cancers. Experiments have shown that GA prevents HCC through multiple anti-cancer mechanisms, anti-genotoxic activity against environmental and dietary carcinogens; anti-proliferative effects through reversal of the Warburg effect in HCC; arrest of the cell cycle in the G0/G1 phase; induction of apoptosis via stimulation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and the mitochondrial-dependent apoptosis pathway; induction of autophagy; and inhibition of angiogenesis, metastasis, and multidrug resistance (MDR). In addition, synergistic effects with other chemotherapy drugs have been demonstrated. Therefore, this review is focused on the anti−HCC mechanisms of GA.
The aim of this research was to investigate the value of autofluorescence imaging of oral cancer across different stages of tumor growth, to assist in detecting tumors. A xenograft mouse model was created with human oral squamous cell carcinoma cell line HSC‐3 being subcutaneously inoculated into nude mice. Tumor imaging was performed with an autofluorescence imaging method (Illumiscan®) using the luminance ratio, which was defined as the luminance of the tumor site over the luminance of normal skin tissue normalized to a value of 1.0. This luminance ratio was continuously observed postinoculation. Tumor and normal skin tissues were harvested, and differences in the concentrations of flavin adenine dinucleotide and nicotinamide adenine dinucleotide were examined. The luminance ratio of the tumor sites was 0.85 ± 0.05, and there was no significant change in the ratio over time, even if the tumor proliferated and expanded. Furthermore, flavin adenine dinucleotide and nicotinamide adenine dinucleotide were significantly lower in tumor tissue than in normal skin tissue. A luminance ratio under 0.90 indicates a high possibility of tumor, irrespective of the tumor growth stage. However, this cutoff value was determined using a xenograft mouse model and therefore requires further validation before being used in clinical diagnosis.
A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i) Epidermal growth factor receptor (EGFR) structures and functions; (ii) GE11 structure and biologic activity; (iii) examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles.
Laryngeal cancers are mostly squamous cell carcinomas. Although targeting radio-resistant cancer cells is important for improving the treatmental efficiency, the signaling pathway- and therapeutic strategy-related to laryngeal carcinoma still require further study. Galangin is an active pharmacological ingredient, isolated from propolis and Alpinia officinarum Hance, and has been reported to have anticancer and anti-oxidative properties through regulation of cell cycle, resulting in angiogenesis, apoptosis, invasion and migration without triggering any toxicity in normal cells. PI3K/AKT and p38 are important signaling pathways to modulate cancer cell apoptosis and proliferation through caspase-3, NF-κB and mTOR signal pathways. Autophagy is also enhanced by activating LC3s and Beclin 1. In the present study, galangin was found to suppress laryngeal cancer cell proliferation. Also, flow cytometry, immunohistochemical and western blot analysis indicated that cell apoptosis was induced for galangin administration, promoting caspase-3 expression through regulating PI3K/AKT/NF-κB. Furthermore, galangin inhibited laryngeal cancer cell proliferation, related to p38 inactivation by galangin treatment. Additionally, mTOR activation regulated by PI3K/AKT was reduced by galangin, suppressing cancer cell transcription and proliferation. Our data also indicated that the tumor volume and weight in nude mice were reduced for galangin use in vivo accompanied by Ki-67 decrease and TUNEL increase in tumor tissues. Together, our data indicated that galangin has a potential role in suppressing human laryngeal cancer via inhibiting tumor cell proliferation, activating apoptosis and autophagy, which were regulated by p38 and AKT/NF-κB/mTOR pathways, providing a therapeutic strategy for human laryngeal cancer treatment.
Statement of significance:
In recent years, localized cancer treatment using different biomaterials has attracted increasing attention for effective inhibition of tumor growth. However, it is still challenging for this kind of system to achieve a high drug loading, overcome biological barriers from the site of injection to the site of action, and combine synergetic therapy with diagnosis without adversely affecting the formation process. This study provides a localized diffusion molecular retention (DMR) tumor targeting drug delivery system based on hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) entrapment of anticancer drug for the first time, which can achieve high drug loading, improve local drug accumulation and retention, accomplish synergistic combination of chemo-phototherapy, and finally enhance antitumor effect. In addition, HMCuS NPs also possesses the property suitable for photoacoustic imaging, which could offer us a theranostic platform.
The interaction as well as the formation of bioconjugate of Bovine Serum
Albumin (BSA) and Zinc Oxide nanoparticles (ZnO NPs) is investigated.
The surface binding along with reorganization of BSA on the surface of
ZnO NPs forms stable ``hard corona.'' The time constants for surface
binding and reorganization are found to be 1.10 min and 70.68 min,
respectively. The close proximity binding of BSA with ZnO NPs via
tryptophan is responsible for bioconjugate formation. Fibrillar
aggregated structure of BSA is observed due to conformational change of
BSA in interaction with ZnO NPs.
Oral cancer is a type of cancer that develops in the mouth and is one of the deadliest malignancies in the world. Currently surgical, radiation therapy, and chemotherapy are most common treatments. Better treatment and early detection strategies are required. Chemotherapeutic drugs fail frequently due to toxicity and poor tumor targeting. There are high chances of failure of chemotherapeutic drugs due to toxicity. Active, passive, and immunity-targeting techniques are devised for tumor-specific activity. Nanotechnology-based drug delivery systems are the best available solution and important for precise targeting. Nanoparticles, liposomes, exosomes, and cyclodextrins are nano-based carriers for drug delivery. Nanotechnology is being used to develop new techniques such as intratumoral injections, microbubble mediated ultrasonic therapy, phototherapies, and site-specific delivery. This systematic review delves into the details of such targeted and nano-based drug delivery systems in order to improve patient health and survival rates in oral cancer.
Multi-modal synergistic therapy, especially the integration of near-infrared laser phototherapies and chemotherapy, is often sought after owing to its minimal invasiveness, low side effects, and improved anticancer therapeutic efficacy. Herein, CuS nanoparticles were first coated with zinc phthalocyanine derivant (Pc)-functionalized mesoporous silica (mSiO2-Pc) to achieve a drug delivery system (CuS@mSiO2-Pc) with photothermal/photodynamic therapy. Chemical drug DOX was subsequently loaded for chemotherapy, and hyaluronic acid (HA) was employed as a covering material with cancer targeting. The as-obtained CuS@mSiO2-Pc(DOX)@HA nanoparticles were nano-sized with good biocompatibility, effective DOX loading, and controllable DOX releasing. Expectedly, this multifunctional nanoplatform exhibits effective generation of reactive oxygen species and hyperthermia upon the near-infrared laser irradiation. Most importantly, the nanoparticles were targeted into 4T1 cells and showed significantly remarkable cytotoxicity under near-infrared laser irradiation, proving their synergistic therapeutic efficacy. Therefore, this targeted drug system based on CuS with synergistic photothermal therapy/photodynamic therapy/chemotherapy has great application prospects in clinical anticancer treatment for triple negative breast cancer.
Nanotechnology-mediated drug delivery systems suffer from insufficient retention in tumor tissues and unreliable drug release at specific target sites. Herein, we developed an epidermal growth factor receptor-targeted multifunctional micellar nanoplatform (GE11-DOX+CEL-M) by encapsulating celecoxib into polymeric micelles based on the conjugate of GE11-poly(ethylene glycol)-b-poly(trimethylene carbonate) with doxorubicin to suppress tumor growth and metastasis. The polymeric micelles maintained stable nanostructures under physiological conditions but quickly disintegrated in a weakly acidic environment, which is conducive to controlled drug release. Importantly, GE11-DOX+CEL-M micelles effectively delivered the drug combination to tumor sites and enhanced tumor cell uptake through GE11-mediated active tumor targeting. Subsequently, GE11-DOX+CEL-M micelles dissociated in response to intracellular slightly acidic microenvironmental stimuli, resulting in rapid release of celecoxib and doxorubicin to synergistically inhibit the proliferation and migration of tumor cells. Systemic administration of GE11-DOX+CEL-M micelles into mice bearing subcutaneous 4T1 tumor models resulted in higher tumor growth suppression and decreased lung metastasis of tumor cells compared with micelles without GE11 decoration or delivering only doxorubicin. Furthermore, the micelles effectively reduced the systemic toxicity of the chemotherapy drugs. This nanotherapeutic system provides a promising strategy for safe and effective cancer therapy.
The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@[email protected] is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@[email protected] can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@[email protected] reshapes the immune microenvironments by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4⁺ and CD8⁺ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@[email protected]-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.
Abnormal regulation of cell signaling pathways on cell survival, proliferation and migration contributes to the development of malignant tumors. Among them, epidermal growth factor receptor (EGFR) is one of the most important biomarkers in many types of malignant solid tumors. Its over-expression and mutation status can be served as a biomarker to identify patients who can be benifit from EGFR tyrosine kinase inhibitors and anti-EGFR monocloncal antibody (mAb) therapy. For decades, researches on EGFR targeted ligands were actively carried out to identify potent candidates for cancer therapy. An ideal EGFR ligand can competitively inhibit the binding of endogenous growth factor, such as epidermal growth factor (EGF) and transforming growth factor-α(TGF-α) to EGFR, thus block EGFR signaling pathway and downregulate EGFR expression. Alternatively, conjugation of EGFR ligands on drug delivery systems (DDS) can facilitate targeting delivery of therapeutics or diagnostic agents to EGFR over-expression tumors via EGFR-mediated endocytosis. GE11 peptide is one of the potent EGFR ligand screened from a phage display peptide library. It is a dodecapeptide that can specifically binds to EGFR with high affinity and selectivity. GE11 has been widely used in the diagnosis and targeted delivery of drugs for radiotherapy, genetherapy and chemotherpy against EGFR positive tumors. In this review, the critical factors affecting the in vivo and in vitro targeting performance of GE11 peptide, including ligand-receptor intermolecular force, linker bond properties and physiochemical properties of carrier materials, are detailedly interpreted. This review provides a valuable vision for the rational design and optimization of GE11-based active targeting strategies for cancer treatment, and it will promote the translation studies of GE11 from lab research to clinical application.
Atherosclerosis is a global disease with an extremely high morbidity and fatality rate, so it is necessary to develop effective treatments to reduce its impact. In this work, we successfully prepared a multifunctional drug-loaded nano-delivery system with pH-responsive, CD44-targeted, and chemical-photothermal synergistic treatment. Dendritic mesoporous silica nanoparticles capped with copper sulfide (CuS) were synthesized via an oil-water biphase stratification reaction system; these served as the carrier material and encapsulated the anticoagulant drug heparin (Hep). The pH-sensitive Schiff base bond was used as a gatekeeper and targeting agent to modify hyaluronic acid (HA) on the surface of the nanocarrier. HA coating endowed the nanocomposite with the ability to respond to pH and target CD44-positive inflammatory macrophages. Based on this multifunctional nanocomposite, we achieved precise drug delivery, controlled drug release, and chemical-photothermal synergistic treatment of atherosclerosis. The in vitro drug release results showed that the nanocarriers exhibited excellent drug-controlled release properties, and could release drugs in the weakly acidic microenvironment of atherosclerotic inflammation. Cytotoxicity and cell uptake experiments indicated that nanocarriers had low cytotoxicity against RAW 264.7 cells. Modification of HA to nanocarriers can be effectively internalized by RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Combining CuS photothermal treatment with anti-atherosclerosis chemotherapy showed better effects than single treatment in vitro and in vivo. In summary, our research proved that H-CuS@DMSN-NC-HA has broad application prospects in anti-atherosclerosis.
Disulfiram (DSF) is an effective copper (Cu2+)-dependent antitumor agent. In the present study, we explored use of transferrin (Tf)-modified DSF/copper sulfide (CuS) nanocomplex (Tf-DSF/CuS) for glioma therapy. Tf was used as glioma targeting motifs, DSF as an anticancer agent, and CuS as a source of Cu2+ ions and a photothermal agent. DSF was loaded on CuS by metal-chelation, and released from the nanocomplex under acidic condition. The Tf-DSF/CuS complex exhibited high cytotoxic effect in vitro. Notably, cytotoxic activity was correlated with pH triggered release of Cu2+ which initiated non-toxicity to toxicity switch of DSF. Ultrasound-targeted microbubble destruction (UTMD) technique was used for highly selective accumulation of intravenous injected Tf-DSF/CuS in the glioma orthotopic tumor as compared with the free drugs and non-targeted DSF/CuS groups. Magnetic resonance imaging and pathological examinations showed that Tf-DSF/CuS effectively suppressed tumor growth, with an inhibition ratio of ∼85%. Additionally, DSF load did not compromise photothermal conversion ability of CuS nanoparticles. Efficacy of the photothermal ablation therapy of Tf-DSF/CuS was evaluated under 808 nm laser irradiation both in vitro and in vivo. These findings show that copper-sulfide based disulfiram nanoparticles are effective agents for anti-glioma therapy.
Oral cavity squamous cell carcinoma (OCSCC) is the most common malignancy of the oral cavity. The substantial risk factors for OCSCC are the consumption of tobacco products, alcohol, betel quid, areca nut, and genetic alteration. However, technological advancements have occurred in treatment, but the survival decreases with late diagnosis; therefore, new methods are continuously being investigated for treatment. In addition, the rate of secondary tumor formation is 3–7% yearly, which is incomparable to other malignancies and can lead to the disease reoccurrence. Oral cavity cancer (OCC) arises from genetic alterations, and a complete understanding of the molecular mechanism involved in OCC is essential to develop targeted treatments. This review aims to update the researcher on oral cavity cancer, risk factors, genetic alterations, molecular mechanism, classification, diagnostic approaches, and treatment.
Galangin, a non-toxic phytochemical is known to possess several therapeutic applications. Mounting evidences have demonstrated that galangin a naturally available flavonoid exerts anticancer effects via several mechanisms. The phytocompound induces apoptosis and renders antiangiogenic property. Additionally, galangin has demonstrated significate results in combating various cancer types when administered in combination with other phytocompounds or with gold nanoparticles (GNPs). The present article is a critical review of galangin for its treatment on different types of cancer and its usability as an alternative cancer therapeutics.
Despite advancements in synthetic chemistry, nature remains the primary source of drug discovery, and this never-ending task of finding novel and active drug molecules will continue. Flavonoids have been shown to possess highly significant therapeutic activities such as anti-inflammatory, anti-oxidant, anti-viral, anti-diabetic, anti-cancer, anti-aging, neuroprotective, and cardioprotective, etc., However, it has been found that orally administered flavonoids have a critical absorption disorder and, therefore, have low bioavailability and show fluctuating pharmacokinetic and pharmacodynamic responses. A detailed investigation is required to assess and analyze the variation in the bioavailability of flavonoids due to interactions with the intestinal barrier. This review will emphasize on the bioavailability and the pharmacological applications of flavonoids, key factors affecting their bioavailability, and strategies for enhancing bioavailability, which may lead to deeper understanding of the extent of flavonoids as a treatment and/or prevention for different diseases in clinics.
The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) for the treatment of melanoma lung metastasis. DMSA-conjugated APG-loaded NPs (DMSA-APG-NPs) administered by an oral route exhibited sustained APG release and showed considerable enhancement of plasma half-life, Cmax value, and bioavailability compared to APG-NPs both in plasma and the lungs. DMSA-conjugated APG-NPs showed comparably higher cellular internalization in B16F10 and A549 cell lines compared to that of plain NPs. Increased cytotoxicity was observed for DMSA-APG-NPs compared to APG-NPs in A549 cells. This difference between the two formulations was lower in B16F10 cells. Significant depolarization of mitochondrial transmembrane potential and an enhanced level of caspase activity were observed in B16F10 cells treated with DMSA-APG-NPs compared to APG-NPs as well. Western blot analysis of various proteins was performed to understand the mechanism of apoptosis as well as prevention of melanoma cell migration and invasion. DMSA conjugation substantially increased accumulation of DMSA-APG-NPs given by an intravenous route in the lungs compared to APG-NPs at 6 and 8 h. This was also corroborated by scintigraphic imaging studies with radiolabeled formulations administered by an intravenous route. Conjugation also allowed comparatively higher penetration as evident from an in vitro three-dimensional tumor spheroid model study. Finally, the potential therapeutic efficacy of the formulation was established in experimental B16F10 lung metastases, which suggested an improved bioavailability with enhanced antitumor and antimetastasis efficacy of DMSA-conjugated APG-NPs following oral administration.
Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proved to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent anti-tumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/[email protected]) to solubilize and stabilize DSF, and more importantly, achieve pH triggered Zn2+ release and subsequent synergistic anti-tumor activity. The prepared SF/[email protected] nanocomposites were spherical and had a high drug loading. Triggered by the lysosomal pH, SF/[email protected] could induce the rapid release of Zn2+ under the acidic conditions and caused nanoparticulate disassembly along with DSF release. In vitro experiments showed that cytotoxicity of DSF could be enhanced by the presence of Zn2+, and further amplified when encapsulated into SF/[email protected] nanocomposites. It was confirmed that the significantly amplified cytotoxicity of SF/[email protected] resulted from pH-triggered Zn2+ release, inhibited cell migration, and increased ROS production. In vivo study showed that SF/[email protected] nanocomposites significantly increased the tumor accumulation and prolonged the retention time there. In vivo anti-tumor experiments in the xenograft model showed that SF/[email protected] exerted the highest tumor-inhibition rate among all the drug treatments. Therefore, this exquisite study established silk fibroin-modified disulfiram/zinc oxide nanocomposites, SF/[email protected], where ZnO not only acted as a delivery carrier but also served as a metal ion reservoir to achieve synergistic antitumor efficacy. The established DSF nanoformulation displayed excellent therapeutic potential in future cancer treatment.
The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles ([email protected] NPs). The [email protected] NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles ([email protected]@DOX NPs). The [email protected]@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.
Background: The width of the surgical resection margin impacts recurrence and survival in oral cavity squamous cell carcinoma (OSCC). The most commonly used definition of a clear margin is one larger than 5 mm, although due to anatomical restrictions to e.g. bone or vessels, this size is not always feasible. Margins less than 5 mm affect postsurgical strategies and prognoses, and further knowledge of margins smaller than 5 mm is needed.
Aims/objectives: We aimed to systematically review the literature on the impact of surgical resection margins less than 5 mm addressing recurrence and survival in OSCC.
Methods/materials: A systematic literature search was performed in the PubMed and EMBASE databases identifying studies regardless of publication date that examined margin less than 5 mm, with or without a comparison to size of 5 mm or greater, in patients with OSCC. We assessed the impact on recurrence and survival.
Results: We identified six studies (n = 1514 patients); all studies, investigated recurrence, and three (n = 768 patients) evaluated survival. The studies had noteworthy variability in, e.g. follow-up times, anatomical sublocations, T- and N-stage classifications, and outcome measures. Five studies (n = 1387 patients) reported that margins smaller than 5 mm would be safe and would not affect survival or recurrence negatively compared to their own data on larger margins. One study reported that a clear resection margin greater than five mm was necessary to ensure optimal outcomes.
Conclusion/significance: The literature showed significant bias and risk issues. In five of the included studies with 1387 patients, we found in selected cases, where margins larger than 5 mm are not possible, a tendency regarding resection margins less than 5 mm to be sufficient for the surgical treatment of patients with primary OSCC. However, the data is insufficient to enable altered recommendations of resection margins in patients with primary OSCC.
Hepatocellular carcinoma (HCC) remains a leading malignancy with a high mortality and little improvement in treatments. Protein drugs though known for their extraordinary potency and specificity have rarely been investigated for HCC therapy owing to lack of appropriate delivery systems. Here, we designed GE11 peptide-installed chimaeric polymersomes (GE11-CPs) for high-efficiency EGFR-targeted protein therapy of orthotopic SMMC 7721 HCC-bearing nude mice. GE11-CPs were assembled from poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-poly(aspartic acid) (PEG-P(TMC-DTC)-PAsp) and GE11-functionalized PEG-P(TMC-DTC), which allowed efficient loading and protection of proteins in the watery interior and fine-tuning of GE11 densities at the surface. CPs with short PAsp segments (degree of polymerization (DP) = 5, 10 and 15) exhibited a protein loading efficiency of 60%-72% and glutathione-responsive protein release. Saporin-loaded GE11-CPs had a size of 36 - 62 nm depending on GE11 densities and DP of PAsp. Notably, GE11-CPs with 10% GE11 revealed greatly enhanced uptake in SMMC 7721 cells, boosting the anticancer potency of saporin for over 3-folds compared with non-targeted control (half-maximal inhibitory concentration (IC50) = 11.0 versus 36.3 nM). The biodistribution studies using Cy5-labeled cytochrome C as a model protein demonstrated about 3-fold higher accumulation of GE11-CPs formulation than CPs counterpart in both subcutaneous and orthotopic SMMC 7721 tumor models. Notably, saporin-loaded GE11-CPs revealed low toxicity, effective tumor inhibition and significant improvement of survival rate compared with PBS and non-targeted groups (median survival time: 99 versus 37 and 42 days). EGFR-targeted chimaeric polymersomes carrying proteins appear an interesting HCC treatment modality.
Light stimulus responsive therapies are based on a variety of low-toxic therapeutic agents and produce anti-tumor effects only under external light stimulation, thus greatly reducing system toxicity and improving the specificity of treatment. Moreover, light stimulus responsive drug delivery system (DDS) can combine various theranostics molecules to exert synergistic therapeutic effects of various treatments, which has played an important role in cancer treatment. In this review, we introduced the light stimulus responsive cancer therapies including photodynamic therapy (PDT), photothermal therapy (PTT) and light-triggered DDS applied in the treatment of OSCC, described considerable photosensitizers (PSs) and nanomaterials used for oral cancers, which will hope to better the clinic outcome of OSCC patients.
Background
In cancer chemotherapy, conventional drugs aim to target the rapidly growing and dividing cells at the early stages. However, at an advanced stage, cancer cells become less susceptible because of the multidrug resistance and the recruitment of alternative salvage pathways for their survival. Besides, owing to target non-selectivity, healthy proliferating cells also become vulnerable to the damage. The combination therapies offered using flavonoids to cure cancer not only exert an additive effect against cancer cells by targetting supplementary cell carnage pathways but also hampers the drug resistance mechanisms. Thus, the review aims to discuss the potential and pharmacokinetic limitations of flavonoids in cancer treatment. Further successful synergistic studies reported using flavonoids to treat cancer has been described along with potential drug delivery systems.
Methods
A literature search was done by searching various online databases like Pubmed, Scopus, and Google Scholar with the specific keywords like “Anticancer drugs,” “flavonoids,” “oncology research,” and “pharmacokinetics.”
Results
Dietary phytochemicals, mainly flavonoids, hinder cell signalling responsible for multidrug resistance and cancer progression, primarily targeting cancer cells sparing normal cells. Such properties establish flavonoids as a potential candidate for synergistic therapy. However, due to low absorption and high metabolism rates, the bioavailability of flavonoids becomes a challenge. Such challenges may be overcome using novel approaches like derivatization, and single or co-delivery nano-complexes of flavonoids with conventional drugs. These new approaches may improve the pharmacokinetic and pharmacodynamic of flavonoids.
Conclusion
This review highlights the application of flavonoids as a potential anticancer phytochemical class in combination with known anti-cancer drugs/nanoparticles. It also discusses flavonoid’s pharmacokinetics and pharmacodynamics issues and ways to overcome such issues. Moreover, it covers successful methodologies employed to establish flavonoids as a safe and effective phytochemical class for cancer treatment.
Background and objectives
Squamous cell carcinoma of head and neck (SCCHN) is the fifth most prevalent cancer worldwide. Because the anatomical complexity of this region, complete surgical resection is often not achievable and conventional chemotherapy would aid locoregional control and mitigate distant metastasis. Nonetheless, the nonspecific cytotoxicity and short in vivo half-life of conventional chemotherapeutic drugs limit their effects. Given the high frequency of overexpression of wild type epidermal growth factor receptor (EGFR), we exploit EGFR as a homing beacon for drug delivery system with cytotoxic payloads.
Materials and methods
We generated fully human anti-EGFR single chain variable fragment (scFv)-conjugated immunoliposomes (IL) containing doxorubicin and vinorelbine and tested their anti-neoplastic efficacy in vitro and in vivo.
Result
Our IL enhanced endocytosis and significantly reduced the half maximal inhibitory concentrations of the therapeutic payloads when compared to non-targeting liposomal counterparts in various cell lines of SCCHN. Furthermore, median survival time was significantly prolonged in subcutaneous and orthotopic SCCHN xenograft murine models treated with our IL formulations than those treated with non-targeting counterparts (94 days versus 60 days and 72 days versus 56 days, respectively) without evident increased systemic toxicity.
Conclusion
The therapeutic index of the chemotherapeutic payloads was augmented by our EFGR-targeting IL formulation and they are warranted for further development and preclinical trial.
Application of nanotechnologies to cancer therapy might increase solubility and/or bioavailability of bioactive compounds of natural or synthetic origin and offers other potential benefits in cancer therapy, including selective targeting. In the present review we aim to evaluate in vivo studies on the anticancer activity of nanoparticles (NPs) obtained from food-derived flavonoids. From a systematic search a total of 60 studies were identified. Most of the studies involved the flavanol epigallocatechin-3-O-gallate and the flavonol quercetin, in both delivery and co-delivery (with anti-cancer drugs) systems. Moreover, some studies investigated the effects of other flavonoids, such as anthocyanins aglycones anthocyanidins, flavanones, flavones and isoflavonoids. NPs inhibited tumor growth in both xenograft and chemical-induced animal models of cancerogenesis. Encapsulation improved bioavailability and/or reduced toxicity of both flavonoids and/or co-delivered drugs, such as doxorubicin, docetaxel, paclitaxel, honokiol and vincristine. Moreover, flavonoids have been successfully applied in molecular targeted nanosystems. Selectivity for cancer cells involves pH- and/or reactive oxygen species-mediated mechanisms. Furthermore, flavonoids are good candidates as drug delivery for anticancer drugs in green synthesis systems. In conclusion, although human studies are needed, NPs obtained from food-derived flavonoids have promising anticancer effects in vivo.
The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ErbB3 is kinase impaired. Surprisingly, the ErbB2–ErbB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (⁷⁴⁶ELREA⁷⁵⁰) or the exon-21 L858R substitution. Gefitinib and erlotinib are orally effective type I reversible EGFR mutant inhibitors; type I inhibitors bind to an active enzyme conformation. Unfortunately, secondary resistance to these drugs occurs within about one year owing to a T790M gatekeeper mutation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein. Resistance also develops to this and related type VI inhibitory drugs owing to a C797S mutation; the serine residue is unable to react with the drugs to form a covalent bond. Approximately 20% of breast cancer patients exhibit ErbB2/HER2 gene amplification on chromosome 17q. One of the earliest targeted treatments in cancer involved the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain ErbB2/HER2 causing its down regulation. Surgery, radiation therapy, chemotherapy with cytotoxic drugs, and hormonal modulation are the mainstays in the treatment of breast cancer. Moreover, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used in the treatment of selected breast cancer patients. Of the approximate three dozen FDA-approved small molecule protein kinase inhibitors, five are type VI irreversible inhibitors and four of them including afatinib, osimertinib, dacomitinib, and neratinib are directed against the ErbB family of receptors (ibrutinib is the fifth and it targets Bruton tyrosine kinase). Avitinib, olmutinib, and pelitinib are additional type VI inhibitors in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the norm, and devising and implementing strategies for minimizing or overcoming resistance is an important goal in cancer therapeutics.
A smart supramolecular nanosystem integrating targeting, chemotherapy and photothermal therapy, was constructed based on carboxylatopillar[5]arene (CP[5]A)-functionalized CuS nanoparticles (CuS@CP NPs). CuS@CP NPs with good monodispersibility and strong near-infrared absorption were synthesized in aqueous solution through a facile one-pot supramolecular capping method, followed by surface installation of a liver cancer-targeted galactose derivative through host-guest binding interaction. The resulting smart supramolecular nanosystem, namely CuS@CPG, exhibited excellent photothermal ablation capability to HepG2 cells upon irradiation with laser at 808 nm. Chemotherapeutic drug, doxorubicin hydrochloride (DOX), was further loaded on CuS@CPG via electrostatic interactions between positively charged DOX and negatively charged CP[5]A to give CuS@CPG-DOX with a high drug loading capacity up to 48.4%. The weakening of DOX-CP[5]A interactions in an acidic environment promoted the pH-responsive drug release from CuS@CPG-DOX. Significantly, this multifunctional supramolecular nanosystem showed a remarkably enhanced therapeutic effect through the combination of targeted chemotherapy and photothermal therapy upon in vitro cell study. Moreover, preliminary in vivo study demonstrated that CuS@CPG and CuS@CPG-DOX had good biocompatibility and excellent tumor-inhibition effects upon NIR laser irradiation.
Retinoblastoma is reported as a rare cancer that occurs during childhood. Although several treatments are available for retinoblastoma, there is a need for alternative new treatment modalities for retinoblastoma with better safety and efficacy profile. Galangin (3,5,7-trihydroxyflavone), is a flavonoid compound, which is found in high concentration in lesser galangal. Galangin has been reported to have various bioactivities, including anti-inflammation, anti-oxidative stress and anti-cancer through various pathways. The objective of our study was to explore the effects of galangin on the suppression of retinoblastoma in vitro and in vivo. Using MTT analysis, transwell-chamber migration analysis, colony-forming analysis, wound healing analysis, immunofluorescent assay of KI-67, we found that galangin exhibited a suppressive effect on human retinoblastoma cell proliferation and migration. Moreover, PTEN, a tumor-suppressor, was increased by galangin in cancer cells and in tumor tissues isolated from retinoblastoma xenograft models. Additionally, galangin reduced protein kinase B (Akt) phosphorylation, which was associated with PTEN up-regulation. Galangin-reduced Akt activation and cell proliferation was abolished by PTEN knockdown, which might be associated with the over-expression of phosphatidylinositol-3,4,5-triphosphate (PIP3)/diphosphate product (PIP2). Furthermore, flow cytometry, Hoechst 33258 staining and western blot assays indicated that galangin could induce apoptosis through promoting Caspase-3 pathway, which was, at least partly, dependent on PTEN expression. Our data illustrated that galangin treatment suppressed the growth of retinoblastoma tumor in vivo by anti-proliferative and apoptogenic mechanisms. Thus, galangin might be a safe and promising non-chemotherapeutic drug, which could be useful as an adjuvant against retinoblastoma.
The present study was designed to understand the anticancer property and molecular mechanisms associated with chemo preventive effects of galangin. The anticancer effect was evaluated in vitro using human cervical cancer cell line (HeLa). Galangin was found to be effective in inducing cell death and inhibiting proliferation & migration significantly. The inhibitory effect of galangin could be correlated with the increase in ROS production & induction of apoptosis. Besides this the activity of glyoxalase-1, an enzyme important for the detoxification of cytotoxic metabolite methy glyoxal and Nrf-2 (a trascription factor), involved in redox signalling was also found to be decreased. We concluded that galangin exerts its chemo preventive effect via redox signalling by inhibiting glyoxalase-1 & increasing oxidative & carbonyl stress.
Plasmonic nanostructures show important properties for biotechnological applications, but they have to be guided on the target for exploiting their potentialities. Antibodies are the natural molecules for targeting. However, their possible adverse immunogenic activity and their cost have suggested finding other valid substitutes. Small molecules like peptides can be an alternative source of targeting agents, even if, as single molecules, their binding affinity is usually not very good. GE11 is a small dodecapeptide with specific binding to the epidermal growth factor receptor (EGFR) and low immunogenicity. The present work shows that thousands of polyethylene glycol (PEG) chains modified with lysines and functionalized with GE11 on clusters of naked gold nanoparticles, obtained by laser ablation in water, achieves a better targeting activity than that recorded with nanoparticles decorated with the specific anti-EGFR antibody Cetuximab (C225). The insertion of the cationic spacer between the polymeric part of the ligand and the targeting peptide allows for a proper presentation of GE11 on the surface of the nanosystems. Surface enhanced resonance Raman scattering signals of the plasmonic gold nanoparticles are used for quantifying the targeting activity. Molecular dynamic calculations suggest that subtle differences in the exposition of the peptide on the PEG sea are important for the targeting activity.
Multifunctional nanoprobes that provide diagnosis and treatment features have attracted great interests in precision medicine. Near-infrared (NIR) persistent luminescence nanoparticles (PLNP) are optimal materials due to no in situ excitation needed, deep tissue penetration, and high signal-to-noise ratio while activatable optical probes can further enhance signal-to-noise ratio for the signal turn-on nature. Here, we show the design of an activatable multifunctional PLNP/copper sulfide (CuS) based nanoprobe for luminescence imaging-guided photothermal therapy in vivo. Matrix metalloproteinases (MMP)-specific peptide substrate (H2N-GPLGVRGC-SH) was used to connect PLNP and CuS to build a MMP activatable system. The nanoprobe not only possesses ultralow-background for in vivo luminescence imaging due to the absence of autofluorescence and optical activatable nature, but also offers effective photothermal therapy from CuS nanoparticles. Further bioconjugation of c(RGDyK) enables the nanoprobe for cancer-targeted luminescence imaging-guided photothermal therapy. The good biocompatibility and the multiple functions of highly sensitive tumor-targeting luminescence imaging and effective photothermal therapy make the nanoprobe promising for theranostic application.
Statement of significance:
Until now, chemotherapy is still the major therapeutic approach applied in oncology. Despite their pharmacologically efficacy in cancer treatments, most chemotherapeutic agents without tumor-specific targeting ability have brought out serious toxicities to normal tissues. This study provides a promising near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanopaticles (HMCuS NPs) with capping of multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety to address the above problem. After the nanoplatform (DOX/HMCuS-HA) pinpointed breast cancer cells via CD44 receptor-mediated endocytosis pathway, intracellular multi-stimuli responsive controlled drug release would take place with remarkable spatial/temporal resolution. Then photoacoustic tomography (PAT) and synergistic combination of chemo-phototherapy would be simultaneously driven by the same NIR irradiation in a coordinated way, which brought out an outstanding theranostic effect. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system.