Figure - available from: Pharmacogenomics and Personalized Medicine
This content is subject to copyright. Terms and conditions apply.
Source publication
Among the gynecological malignancies, ovarian cancer is the leading cause of mortality in developed countries. Treatment of ovarian cancer is based on surgery integrated with chemotherapy. Platinum-based drugs (cisplatin and carboplatin) comprise the core of first-line chemotherapy for patients with advanced ovarian cancer. Platinum-resistant ovari...
Similar publications
Purpose
Cervical cancer is one of the most common causes of death among women globally. Combinations of cisplatin, paclitaxel, bevacizumab, carboplatin, topotecan, and gemcitabine are recommended as first-line therapies.
Methods
This study focuses on the development of folate-decorated, pH-sensitive lipid-polymer hybrid nanoparticles (LPNs). Loadi...
Purpose:
To develop an externally triggered rapid-release targeted system for treating ovarian cancer, gemcitabine (GMC) was entrapped into sonosensitive (SoS) folate (Fo)-modified liposomes (LPs).
Methods:
GMC-loaded LPs (GMC LPs), GMC-loaded Fo-targeted LPs (GMC-Fo LPs), and GMC-loaded Fo-targeted SoS LPs (GMC-SoS Fo LPs) were prepared utilizi...
This study attempted to prepare polyethylene-glycol modified (PEGylated) and folate-PEGylated liposomes containing paclitaxel (Ptx) in order to reduce the toxicity and improve the bioavailability and biocompatibility by targeting drugs to the lymphatics using cancer cell specific ligand folate to prevent metastasis via the lymphatic system. Liposom...
Non-targeted combination chemotherapy is a major clinical challenge for drug resistant ovarian cancer treatment. Lack of the specificity, adverse effect, low survival rate etc limit the chemotherapeutic treatment efficacy of drug resistance cancer. To overcome these obstacles, researchers have focused on nanotechnology based dual targeted therapies...
Citations
... cisplatin and carboplatin) are the core of first-line chemotherapeutics for patients with advanced breast ovarian cancer and have also been combined with taxanes for women with advanced ovarian cancer. 3,6 Taxanes are a class of diterpenes with anticancer properties, with paclitaxel (Taxol) being a commonly used drug in combination with carboplatin for platinum-sensitive patients. 6 Liposomal doxorubicin (Doxil ® or Caelyx ® ) 7 and gemcitabine 8 are also used. ...
This thesis provides novel insights into strategies for the formation of ligand conjugated glycol chitosan nanoparticles for active tumour targeting. The low molecular weight folic acid is chosen as initial model ligand. First, the synthesis of quaternary ammonium palmitoyl glycol chitosan (GCPQ), an amphiphilic derivative of chitosan with drug carrier potential, is explored. Then, the modification of GCPQ with thiol groups is outlined in detail, including optimisation of the feed of Traut’s reagent. Active targeting is generally achieved by conjugation of specific ligands to NP surface that specifically bind to overexpressed receptors at the tumour site with high affinity and avidity to improve the delivery of chemotherapeutics. In this work, the functionalisation of GCPQ with PEG-folic acid is systematically investigated, via thiol maleimide coupling or NHS chemistry, highlighting the potential of GCPQ to act as a platform for ligand multiplexing through these different chemistries. In-depth chemical characterisation of the conjugates is discussed, as well as physicochemical characterisation of the formed nanoparticles. In particular, the thesis explores the self-assembly of mono-functional polymers to provide multi-functional nanoparticles with targeting as well as fluorescent groups. In vitro uptake studies show preferential uptake in folate receptor positive cells compared to cells that do not overexpress folate receptors. In vivo biodistribution pilot study was carried out in six female Balb/c mice after inoculation with 4T1 mouse xenograft tumours, followed by dissociation of the tumours, livers, and spleens. Flow cytometric analysis was used to quantify the nanoparticle distribution. The results of this study show promise towards developing a synthetic strategy for the modification of GCPQ with multiple ligands, to allow it to perform as a multiplex nano-platform for the active targeting of chemotherapeutics.
... The form of Folate-drug binds to FRα and enters the cell with endocytosis [99]. Preliminary clinical evidence suggests that vintafoto may have an anti-tumor effect in women with advanced ovarian cancer [104]. Phase II of the Open-label II PRECEDENT preliminary (NCT00722592) examined the effects of vintafelius supplementation on PLD in patients with recurrent ovarian disease. ...
– Epithelial ovarian disease is often diagnosed in the advanced stage. The current state of the art of surgical and chemotherapy brings high incidence of complete remission; in any case, the recurrence rate is also high. In many patients, the disease eventually turns into a continuation of the symptoms of free time and recurrence episodes. Differential treatment-based approaches to adjacent therapies, now in use, provide assurance that we will turn ovarian malignancy into a manageable, chronic disease. In this review, we examine the prevalence of ovarian cancer treatment, the apparent late-term research into new forms of traditional medicine, and new approaches to rehabilitation, such as late investigations and early treatment issues. The latter include angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, growth factor signaling inhibitors, or folate receptor inhibitors, immunotherapeutic methods. We are also talking about the low cost
... FRs are also known to have at least four isoforms (FRα, FRβ, FRγ, and FRδ). Each isoform of FR has cancer precise tissue with dissimilar folate binding potential and unidirectional distribution (Ledermann et al., 2015;Serpe et al., 2014). FRα binds to folic acid with high affinity and transports folate into cells by receptorfacilitated endocytosis process. ...
Enhanced cancer treatment remains as one of the focused areas for researchers
around the world. Hence, the progress in this direction will be a challenge and an
opportunity in, inter-disciplinary field to mitigate the suffering of millions in the
upcoming decades. As we see, cancer death rate has also progressively increased
despite the current impressive treatment regimens but also due to the nonavailability
of vaccines and the re-occurring of cancer in substantially recovered
patients. Currently, numerous treatment strategies like surgical removal of solid
tumors followed by radiation with a combination of immunotherapy/chemotherapy
by the researchers and clinicians are routinely being followed. However, recurrence
and distant metastasis often occur following radiation therapy, commonly due to the
generation of radio-resistance through deregulation of the cell cycle, cell death, and
inhibition of DNA damage repair mechanisms. Thus, chemotherapeutic/immunotherapeutic
treatment systems have progressed remarkably in the latest years owing to
destroying tumors, noninvasive, and affordable charge of therapy. But, traditional
chemotherapeutic approaches target the DNA of mutated and normal healthy cells,
resulting in a significantly increased risk of toxicity and drug resistance. Thus, many
receptors targeted therapies are in the developmental phase of discovery. Cancer
cells have a specialized set of surface receptors that provide potential targets for cancer
therapeutics. Cell surface receptor-dependent endocytosis is well a known major
mechanism for the internalization of macromolecular drugs. This review emphasizes
the recent development of several surface receptors mediated cancer-targeting
approaches for the effective delivery of various therapeutic formulations.
... Another notable imaging agent is 99m Tc-etarfolatide, a peptide derivative of folic acid designed to coordinate 99m Tc. This radioisotope is more cost-effective and has a much shorter half-life (*6 h) than 111 In [123]. In preclinical studies, 99m Tcetarfolatide predominantly accumulated in FRa-positive tumor and kidney tissues. ...
RNA interference (RNAi) applications have evolved from experimental tools to study gene function to the development of a novel class of gene-silencing therapeutics. Despite decades of research, it was not until August 2018 that the US FDA approved the first-ever RNAi drug, marking a new era for RNAi therapeutics. Although there are many limitations associated with the inherent structure of RNA, delivery to target cells and tissues remains the most challenging. RNAs are unable to diffuse across cellular membranes due to their large size and polyanionic backbone and, therefore, require a delivery vector. RNAi molecules can be conjugated to a targeting ligand or packaged into a delivery vehicle. Alnylam has used both strategies in their FDA-approved formulations to achieve efficient delivery to the liver. To harness the full potential of RNAi therapeutics, however, we must be able to target additional cells and tissues. One promising target is the folate receptor α, which is overexpressed in a variety of tumors despite having limited expression and distribution in normal tissues. Folate can be conjugated directly to the RNAi molecule or used to functionalize delivery vehicles. In this review, we compare both delivery strategies and discuss the current state of research in the area of folate-mediated delivery of RNAi molecules.
... As such, the application of FR is extensively studied within the field of oncology as folate dysregulation can result in the disruption of many cell growth-related processes. FR has been found to overexpressed in a variety of malignancies, including breast, pancreatic, ovarian, colorectal, brain, and lung cancers [9]. ...
... The low affinity and high capacity reduced folate carrier (RFC) normally mediates folate intake and is distinct from folate receptors, as well as the proton-coupled folate transporter (PCFT) [11]. The main route of transportation of folate is mediated by the RFC, which is responsible for the uptake of dietary folate but is unable to take up anything conjugated with folate [9]. Furthermore, FR expression in normal tissues is limited to the luminal surface, confined to the apical surface of the epithelium, out of direct contact to any circulating folate or folate receptor targeting agents [10]. ...
The development of a highly specific drug delivery system (DDS) for anti-cancer therapeutics is an area of intense research focus. Chemical engineering of a “smart” DDS to specifically target tumor cells has gained interest, designed for safer, more efficient, and effective use of chemotherapeutics for the treatment of cancer. However, the selective targeting and choosing the critical cancer surface biomarker are essential for targeted treatments to work. The folic acid receptor alpha (FRalpha) has gained popularity as a potential target in triple-negative breast cancer (TNBC). We have previously reported on a functionalized folic acid (FA)-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) that has the essential features for efficient “smart” DDS. This biocompatible DDS self-assembles in a pH-dependent manner, providing stimuli-responsive, active targeting, extended-release of hydrophobic chemotherapeutic agents, and can effectively penetrate the inner core of 3-dimensional cancer spheroid models. The empty FA-DABA-SMA decreased spheroid volume, revealing a previously unknown mechanism of action. Upon further investigation, a size- and shape-dependent interaction FA-DABA-SMA with FR reduced the expression of p53, the product of the highly mutated TP53 gene, and additional oncogenic c-Myc and STAT3 proteins. Here, we investigated how this copolymer influences FR behavior and disrupting the receptor’s functions. Results indicate that FA-DABA-SMA increases FR expression levels in breast MDA MB-231 cancer cells and disrupting FR signaling by the reduction in HES1 and NOTCH1 protein expression levels. Also, FA-DABA-SMA induces apoptosis and further causes a change in the morphology of the MDA MB-231 cells, as well as significantly reduces their ability to migrate in a Scratch wound assay. Collectively, these findings provide a novel insight into the functionalized FA-DABA-SMA copolymer. The 350 kDa and 20 kDa copolymers actively target FRα to initialize internationalization. However, only the large size and sheet-shaped 350 kDa copolymers disrupt FRα signaling. The significance of these novel findings reveals the intracellular activity of the copolymer that is critically dependent on the size and structural shape. This report offers novel therapeutic insight into a dual mechanism of FA-DABA-SMA copolymer for its therapeutic potential for the treatment of cancer.
... Various cancers are known to over-express FRA and have a greater affinity for Folic Acid [12][13][14] than do normal cells, due to their rapid and constitutive proliferation. Because of this higher FRA expression and affinity for Folic Acid in cancer cells versus normal tissues, (excluding kidney), Folic Acid conjugates have become applicable treatment strategies for targeting ovarian, endometrial, colorectal, kidney, lung and breast cancers with covalent florescent tags [15], in addition to 99m Tcetarfolatide [16,17] to enhance metastasized ovarian surgical cancer treatment. More recently a folatedrug conjugate of Vinblastine, Vintafolide, showed promising preclinical activity in Triple Negative Breast Cancer (TNBC) xenograft models [18] and was taken through Phase 3 clinical trials for treating human ovarian cancer where it eventually failed because it did not demonstrate efficacy on the prespecified outcome of progression-free survival (PFS) in women with platinum-resistant ovarian cancer [19]. ...
Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•−) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.
... The expression levels of FR were characterized in the prostate (DU-145), pancreatic (PANC-1) and breast (MDA-MB-231) cancer cells. It is well established in the literature that MDA-MB-231 and, to a lesser degree, PANC-1 cells overexpress FR, while DU-145 cells have minimal expression levels [13,14]. In Figure 1a, the immunocytochemistry staining of the FR using the anti-FR antibody showed varying expression levels of the FR on the different cancer cell lines (Figure 1b). ...
Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the loading drugs and overcoming multidrug resistance. The role of nanopolymer size and structural shape on the internalization process and subsequent intracellular toxicity is limited. Here, the size and shape dependent mechanism of a functionalized copolymer was investigated using folic acid (FA) covalently bonded to the copolymer poly (styrene-alt-maleic anhydride) (SMA) on its hydrophilic exterior via a biological linker 2,4-diaminobutyric acid (DABA) to target folic acid receptors (FR) overly expressed on cancer cells actively. We recently reported that unloaded FA-DABA-SMA copolymers significantly reduced cancer cell viability, suggesting a secondary therapeutic mechanism of action of the copolymer carrier post-internalization. Here, we investigated the size and shape dependent secondary mechanism of unloaded 350 kDa and 20 kDa FA-DABA-SMA. The 350 kDa and 20 kDa copolymers actively target folic acid receptors (FR) to initialize internationalization, but only the large size and sheet shaped copolymer disables cell division by intracellular disruptions of essential oncogenic proteins including p53, STAT-3 and c-Myc. Furthermore, the 350 kDa FA-DABA-SMA activates early and late apoptotic events in both PANC-1 and MDA-MB-231 cancer cells. These findings indicate that the large size and structural sheet shape of the 350 kDa FA-DABA-SMA copolymer facilitate multimodal tumor targeting mechanisms together with the ability to internalize hydrophobic chemotherapeutics to disable critical oncogenic proteins controlling cell division and to induce apoptosis. The significance of these novel findings reveals copolymer secondary cellular targets and therapeutic actions that extend beyond the direct delivery of chemotherapeutics. This report offers novel therapeutic insight into the intracellular activity of copolymers critically dependent on the size and structural shape of the nanopolymers.
... Previously, we have shown the successful internalization of FMSP-nanoparticles (300-400 nm) inside cancer cells, which induced the cancer cell death [27]. There are several reports of internalization of nanoparticles [33,34,35] which led to cell death. It would be interesting to study the how PMMA enters the cancer cells and induce the cell death by using in vitro and animal models. ...
Poly (methyl methacrylate) (PMMA) is basically biocompatible polyester with high resistance to chemical hydrolysis, and high drug permeability and the most important characteristics of PMMA is that it does not produce any toxicity. There is not much information about PMMA action on the colon cancer cells. In the present study, we have synthesized PMMA nanoparticles. The distribution pattern of PMMA particles was analysed by Zeta sizer and the size of the particles was calculated by using quasi elastic light scattering (QELS). The surface structure and the morphology of PMMA were characterized by transmission electron microscope (TEM) and scanning electron microscope (SEM), respectively. We have also analysed their effects on cancerous cells (human colorectal carcinoma cells, HCT-116) and normal, healthy cells (human embryonic kidney cells, HEK-293) by using morphometric, MTT, DAPI and wound healing methods. We report that PMMA particles inhibited the cancer cell viability in a dose-dependent manner. The lower dose (1.0 lg/ml) showed a moderate decrease in cancer cell viability, whereas higher dosages (2.5 lg/ml, 5.0 lg/mL and 7.5 lg/mL) showed steadily decrease in the cancer cell viability. We also report that PMMA is highly selective to cancerous cells (HCT-116), as we did not find any action on the normal healthy cells (HEK-293). In conclusion, our results suggest PMMA particles are potential biomaterials to be used in the treatment of colon cancer.
... Previously, we have shown the successful internalization of FMSP-nanoparticles (300-400 nm) inside cancer cells, which induced the cancer cell death [27]. There are several reports of internalization of nanoparticles [33,34,35] which led to cell death. It would be interesting to study the how PMMA enters the cancer cells and induce the cell death by using in vitro and animal models. ...
Poly (methyl methacrylate) (PMMA) is basically biocompatible polyester with high resistance to chemical hydrolysis, and high drug permeability and the most important characteristics of PMMA is that it does not produce any toxicity. There is not much information about PMMA action on the colon cancer cells. In the present study, we have synthesized PMMA nanoparticles. The distribution pattern of PMMA particles was analysed by Zeta sizer and the size of the particles was calculated by using quasi elastic light scattering (QELS). The surface structure and the morphology of PMMA were characterized by transmission electron microscope (TEM) and scanning electron microscope (SEM), respectively. We have also analysed their effects on cancerous cells (human colorectal carcinoma cells, HCT-116) and normal, healthy cells (human embryonic kidney cells, HEK-293) by using morphometric, MTT, DAPI and wound healing methods. We report that PMMA particles inhibited the cancer cell viability in a dose-dependent manner. The lower dose (1.0 μg/ml) showed a moderate decrease in cancer cell viability, whereas higher dosages (2.5 μg/ml, 5.0 μg/mL and 7.5 μg/mL) showed steadily decrease in the cancer cell viability. We also report that PMMA is highly selective to cancerous cells (HCT-116), as we did not find any action on the normal healthy cells (HEK-293). In conclusion, our results suggest PMMA particles are potential biomaterials to be used in the treatment of colon cancer.
... While we do not know the mechanism of interaction of FMSP-nanoparticles with cancer cells, the possibility of cell internalization cannot be ruled out. There are several reports of internalization of nanoparticles studied in various cancerous cells [48][49][50] which led to cell death. ...
Nanoparticles have many advantages such as high biocompatibility, bioavailability and effective therapeutic capabilities. The aim of the present study is to examine whether fluorescent magnetic submicronic polymer nanoparticles (FMSP-nanoparticles) have any impact on human colorectal cancer cells. In the present study, we have tested FMSP-nanoparticles with an average size of 100–200 nm on human colorectal carcinoma cells (HCT-116) to check their cytotoxic and anti-cancer capabilities. The effects of FMSP-nanoparticles on cancer cells were observed after 6 h, 24 h and 48 h intervals. The response of FMSP-nanoparticles-treated cells was evaluated by Trypan Blue, 4lue-diamidino-2-phenylindole (DAPI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our MTT analysis results revealed that FMSP-nanoparticles produced dose-dependent effects on cancer cells, FMSP-nanoparticles with dose of 1.25 µg/mL did not decrease cell survivability, whereas dosages of 12.5 µg/mL and 50 µg/mL respectively showed 23.59% and 59.47% decrease in the cancer cell survivability. In conclusion, our results demonstrate FMSP-nanoparticles have a potential anti-cancer capability and hold a great promise for colon cancer treatments.
