Antitumor action of diphenyl diselenide nanocapsules: In vitro assessments and preclinical evidence in an animal model of glioblastoma multiforme (original) (raw)
Related papers
AAPS PharmSciTech, 2020
Diphenyl diselenide [(PhSe) 2 ] is a pleiotropic pharmacological agent, but it has low aqueous solubility. The nanoencapsulation of (PhSe) 2 allowed the preparation of an aqueous formulation as well as potentiated its in vitro antitumor effect and the effectiveness in a preclinical model of glioblastoma when administered by the intragastric route. Thus, aiming at maximizing the therapeutic potential of (PhSe) 2 , the present study designed a pegylated-formulation intending to intravenous administration of the (PhSe) 2 as a new approach for glioma therapy. The poly(-caprolactone) nanocapsules containing (PhSe) 2 were physically coated with polyethyleneglycol (PEG) using the preformed polymer interfacial deposition technique and evaluated through physicochemical, morphological, spectroscopic, and thermal characteristics. Hemocompatibility was determined by the in vitro hemolysis test and cytotoxicity assays were performed in astrocytes and glioma C6 cells (10-100 μM). The pegylated-nanocapsules had an average diameter of 218 ± 25 nm, polydispersity index of 0.164 ± 0.046, zeta potential of − 8.1 ± 1.6 mV, pH 6.0 ± 0.09, (PhSe) 2 content of 102.00 ± 3.57%, and encapsulation efficiency around 98%. Besides, the (PhSe) 2 pegylatednanocapsules were spherical, presented absence of chemical interaction among the constituents, and showed higher thermal stability than the non-encapsulated materials. PEG-coated nanocapsules did not cause hemolytic effect while formulations without PEG induced a hemolysis rate above 10%. Moreover, pegylated-nanocapsules had superior in vitro antiglioma effect in comparison to free compound (IC 50 : 24.10 μM and 74.83 μM, respectively). Therefore, the (PhSe) 2-loaded pegylated-nanocapsule suspensions can be considered a hemocompatible formulation for the glioma treatment by the intravenous route.
Nanoparticle based strategies for the treatment of Glioblastoma
2014
Glioblastoma is the most common and most biologically aggressive primary brain tumour in adults. In spite of tremendous investment into research which has led to the development and application of novel diagnostic and therapeutic measures in the management of glioblastoma, the prognosis is still dismal with median survival time of about 12 – 15 months. Also, the success of most cytotoxic drugs clinically employed in the treatment of glioblastoma is greatly limited by their dose-limiting toxicity which typically manifests as clinically significant reduction in blood cell counts. The aim of this study is to demonstrate that a high dose nanoparticle formulation of the cytotoxic drug lomustine using a self-assembling chitosan amphiphile, quaternary ammonium palmitoyl glycol chitosan would lead to improved survival outcomes without a commensurate increase in toxic effects. The novel nanoparticle based lomustine formulation employed in this study enabled the administration of a lomustine ...
Nanotechnology – New Trends in the Treatment of Brain Tumours
Acta Medica (Hradec Kralove, Czech Republic), 2015
High grade gliomas are some of the deadliest human tumours. Conventional treatments such as surgery, radiotherapy and chemotherapy have only a limited effect. Nowadays, resection is the common treatment of choice and although new approaches, such as perioperative magnetic resonance imaging or fluorescent microscopy have been developed, the survival rate of diagnosed patients is still very low. The inefficacy of conventional methods has led to the development of new strategies and the significant progress of nanotechnology in recent years. These platforms can be used either as novel imaging tools or to improve anticancer drug delivery into tumours while minimizing its distribution and toxicity in healthy tissues. Amongst the new nanotechnology platforms used for delivery into the brain tissue are: polymeric nanoparticles, liposomes, dendrimers, nanoshells, carbon nanotubes, superparamagnetic nanoparticles and nucleic acid based nanoparticles (DNA, RNA interference [RNAi] and antisens...
Nanomedicines in the treatment of brain tumors
Nanomedicine (London, England), 2018
Brain metastases & primary CNS tumors Brain metastases are the most frequently occurring neurologic complications of cancer in adults, with 9-17% of all cancers resulting in brain metastasis and brain metastasis occurring in 8-14 per 100,000 in the general population [1]. Primary brain tumors, on the other hand, are relatively rare, and comprise about 1.4% of cancers [2]. Brain metastases are associated with median survival times of about 3-25 months [3], and a 5-year survival rate of 1.8% [4]. Treatment modalities employed for brain metastases include: surgical resection, whole brain radiation therapy, radiosurgery and chemotherapy [5]. The choice of treatment would usually be based on several considerations. These include: histopathology of the primary tumor, status of systemic disease, patient's performance status (general well being and lifestyle activity level), age of the patient, number and sites and precise location of the brain metastases (such as proximity to sites of vital brain function), coexisting morbidities and symptoms [2,5]. Glioblastoma multiforme (WHO Classification astrocytoma Grade IV), a metastatic primary brain tumor, accounts for 12-15% of all brain tumors [6] and is the most common primary brain tumor in adults [7]. Glioblastoma is an aggressive metastatic astrocytoma with a median survival of 14 months and <5% of patients survive for 3 years [8]. This tumor is difficult to diagnose early as the tumor is usually asymptomatic or presents with symptoms which are difficult to associate with GBM, for example, symptoms associated with a high intracranial pressure (headaches, nausea, vomiting and cognitive impairment) [9]. A major contribution to the poor survival rates is the insufficient transport of therapeutic molecules across the blood-brain barrier (BBB) [10]. The current standard of care comprises surgical resection to the maximum possible extent, followed by concurrent radio chemotherapy and adjuvant chemotherapy with temozolomide [2]. This treatment regimen became the standard of care for newly diagnosed glioblastoma patients after the results of the 2004 European Organisation for Research and Treatment of Cancer 26981-22981/National Cancer Institute of Canada Clinical Trials Group CE3 randomized Phase III trial demonstrated a 20.7% improvement in the median survival as well as 27.2% 2-year survival rates in glioblastoma patients, who had received postsurgical concomitant and adjuvant temozolomide (known as the Stupp regimen) compared with 10.9% 2-year survival rates with postsurgical radiotherapy alone [11]. For recurrent glioblastoma on the other hand, there is currently no standard treatment regimen [12], and thus patients frequently receive investigational agents in clinical trials [13]. The blood-brain barrier The treatment of brain tumors (or more generally, CNS tumors) is particularly challenging, mainly because of their intracranial location [14]. Intracranial tumors are effectively 'shielded' from the effects of most systemically administered cytotoxic agents. The brain parenchyma and most (but not all) intracranial tumors are protected by the intact BBB, which maintains the brain microenvironment by serving as a physical and metabolic barrier
Review Article Nanotechnology – New Trends in the Treatment of Brain Tumours
2016
Summary: High grade gliomas are some of the deadliest human tumours. Conventional treatments such as surgery, radio-therapy and chemotherapy have only a limited effect. Nowadays, resection is the common treatment of choice and although new approaches, such as perioperative magnetic resonance imaging or fluorescent microscopy have been developed, the survival rate of diagnosed patients is still very low. The inefficacy of conventional methods has led to the development of new strategies and the significant progress of nanotechnology in recent years. These platforms can be used either as novel imaging tools or to improve anticancer drug delivery into tumours while minimizing its distribution and toxicity in healthy tissues. Amongst the new nanotechnology platforms used for delivery into the brain tissue are: polymeric nanoparticles, liposomes, dendrimers, nanoshells, carbon nanotubes, superparamagnetic nanoparticles and nucleic acid based nanopar-ticles (DNA, RNA interference [RNAi] a...
Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model
International Journal of Pharmaceutics, 2009
Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anticancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac ® to carry the drug, a dose-effect ranging from 0.005 to 2.5 mg of Fc-diOH per animal can be evidenced.
2019
Cancer treatment suffers with the failure of chemotherapeutic agents because of multi drug resistance. Investigation of new molecules involves huge expenditure and time. Present investigation aims at the dual loading of anticancer agent Imatinib Mesylate along with Piperine on to bovine serum albumin nanoparticles in order to overcome multi drug resistance and to achieve the maximum therapeutic effect. Desolvation method with the addition of acetone is used to prepare the nanoparticles. Drugs and polymer are subjected to differential scanning calorimetry. Nanoparticles are evaluated for encapsulation efficiency, particle size, zeta potential and drug release studies. In-vitro anticancer activity of the nanoparticles against Human Glioblastoma Multiforme (GBM) cell line T98G is determined. Results indicated compatibility in DSC, an encapsulation efficiency of 52.456%-88.254%, particle size of 208.3nm -497.3nm, zetapotential of -16.5mV to -63.2mV and drug release of 86.256% to 94.56% ...
Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles
International Journal of Cancer, 2004
Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5–8 glioblastoma-bearing rats (total n = 151) were subjected to 3 cycles of 1.5–2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate-containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma. © 2004 Wiley-Liss, Inc.
Local Controlled Delivery of Anti-Neoplastic RNAse to the Brain
Pharmaceutical Research, 2009
RNAse proteins, also known as Amphibinases, have been shown effective against various solid tumors but were found selectively neurotoxic to Purkinje cells in the cerebellum. This work describes the use of a waxy biodegradable poly(ricinoleic-co-sebacic acid) for the local controlled delivery of cytotoxic amphibinases in the parietal lobe of the brain in an attempt to overcome cerebellar neuronal toxicity while affecting glioma cells.