Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA (original) (raw)
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Tumor regression after systemic administration of tocotrienol entrapped in tumor-targeted vesicles
Journal of Controlled Release, 2009
The therapeutic potential of tocotrienol, an extract of vitamin E with anti-cancer properties, is hampered by its failure to specifically reach tumors after intravenous administration, without secondary effects on normal tissues. We hypothesize that the encapsulation of tocotrienol-rich fraction (TRF) within vesicles bearing transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumors after intravenous administration. The objectives of this study are therefore to prepare and characterize transferrintargeted vesicles encapsulating TRF, and to evaluate their therapeutic efficacy in vitro and in vivo. The entrapment of TRF in transferrin-bearing vesicles led to a 3-fold higher TRF uptake and more than 100-fold improved cytotoxicity in A431 (epidermoid carcinoma), T98G (glioblastoma) and A2780 (ovarian carcinoma) cell lines compared to TRF solution. The intravenous administration of TRF encapsulated in transferrin-bearing vesicles led to tumor regression and improvement of animal survival in a murine xenograft model, contrary to that observed with controls. The treatment was well tolerated by the animals. This work corresponds to the first preparation of a tumor-targeted delivery system able to encapsulate tocotrienol. Our findings show that TRF encapsulated in transferrin-bearing vesicles is a highly promising therapeutic system, leading to tumor regression after intravenous administration without visible toxicity.
Anti-cancer efficacy of intravenously administered tumor-targeted vesicles entrapping tocotrienol
Despite its potent in vitro anti-cancer activity, the vitamin E extract tocotrienol has its therapeutic potential hampered by its poor bioavailability and by its inability to reach tumors in a specific way after intravenous administration. One possibility to overcome this issue would be to entrap tocotrienol within vesicles bearing transferrin, whose receptors are present in abundance on many cancer cell types. In this study, we demonstrated that the systemic administration of tocotrienol entrapped within transferrin-bearing vesicles led to tumor suppression of 20% of A431 epidermoid carcinoma tumors and 50% of B16-F10 melanoma tumors at the end of the treatment. The survival of animals treated with these vesicles was improved by more than 20 days in comparison with the controls, for the two cancer models tested. Animals did not show any secondary effects following administration of the treatment.
Journal of controlled release : official journal of the Controlled Release Society, 2017
The therapeutic potential of tocotrienol, a member of the vitamin E family of compounds with potent in vitro anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a novel tumor-targeted vesicular formulation of tocotrienol would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo. In this work, we demonstrated that novel transferrin-bearing multilamellar vesicles entrapping α-T3 resulted in a dramatically improved (by at least 52-fold) therapeutic efficacy in vitro on A431 cell line, compared to the free drug. In addition, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles resulted in tumor suppression for 30% of A431 and 60% of B16-F10 tumors, without visible toxicity. Mouse survival was enhanced by >13days compared to controls administered with the drug solution only. This tumor-targeted, t...
Novel tocotrienol-entrapping vesicles can eradicate solid tumors after intravenous administration
Journal of Controlled …, 2011
The therapeutic potential of tocotrienol, a vitamin E extract with anti-cancer properties, is hampered by its failure to specifically reach tumors after intravenous administration. In this work, we demonstrated that novel transferrin-bearing, tocopheryl-based multilamellar vesicles entrapping tocotrienol significantly improved tocotrienol uptake by cancer cells overexpressing transferrin receptors. This led to a dramatically improved therapeutic efficacy in vitro, ranging from 17-fold to 72-fold improvement depending on the cell lines, compared to the free drug. In vivo, the intravenous administration of this novel tocotrienol formulation led to complete tumor eradication for 40% of B16-F10 murine melanoma tumors and 20% of A431 human epidermoid carcinoma tumors. Animal survival was improved by more than 20 days compared to controls, for the two tumor models tested. These therapeutic effects, together with the lack of toxicity, potentially make transferrin-bearing vesicles entrapping tocotrienol a highly promising therapeutic system as part as an anti-cancer therapeutic strategy.
Delivery of the vitamin E compound tocotrienol to cancer cells
Therapeutic delivery, 2011
Tocotrienol, a member of the vitamin E family of compounds, is currently receiving increased attention owing to its highly promising anticancer effects. However, its potential in cancer therapy is limited by its poor bioavailability and its inability to specifically reach tumors at therapeutic concentrations after intravenous administration. In order to address these problems, various delivery strategies have been proposed, such as the inclusion of tocotrienol in gamma-cyclodextrins, prodrugs and emulsions, and entrapment in lipid nanoparticles and vesicles. Among these approaches, we have demonstrated that the entrapment of tocotrienol within vesicles bearing transferrin, whose receptors are overexpressed on numerous cancer cells, significantly improved the uptake by cancer cells overexpressing transferrin receptors. Consequently, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles led to tumor regression and even complete tumor suppression in so...
Frontiers in Pharmacology
Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant, and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienols to tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLCs) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers, and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed toward effective clinical translation.
Anticancer drug delivery with transferrin targeted polymeric chitosan vesicles
Pharmaceutical …
Purpose. The study reports the initial biological evaluation of targeted polymeric glycol chitosan vesicles as carrier systems for doxorubicin (Dox). Methods. Transferrin (Tf) was covalently bound to the Dox-loaded palmitoylated glycol chitosan (GCP) vesicles using dimethylsuberimidate (DMSI). For comparison, glucose targeted niosomes were prepared using N-palmitoyl glucosamine. Biological properties were studied using confocal microscopy, flow cytometry, and cytotoxicity assays as well as a mouse xenograft model. Results. Tf vesicles were taken up rapidly with a plateau after 1-2 h and Dox reached the nucleus after 60-90 min. Uptake was not increased with the use of glucose ligands, but higher uptake and increased cytotoxicity were observed for Tf targeted as compared to GCP Dox alone. In the drug-resistant A2780AD cells and in A431 cells, the relative increase in activity was significantly higher for the Tf-GCP vesicles than would have been expected from the uptake studies. All vesicle formulations had a superior in vivo safety profile compared to the free drug. Conclusions. The in vitro advantage of targeted Tf vesicles did not translate into a therapeutic advantage in vivo. All vesicles reduced tumor size on day 2 but were overall less active than the free drug.
Pharmaceutics
The main advantage of extracellular vesicles (EVs) as a drug carrier system is their low immunogenicity and internalization by mammalian cells. EVs are often considered a cell-specific delivery system, but the production of preparative amounts of EVs for therapeutic applications is challenging due to their laborious isolation and purification procedures. Alternatively, mimetic vesicles prepared from the cellular plasma membrane can be used in the same way as natural EVs. For example, a cytoskeleton-destabilizing agent, such as cytochalasin B, allows the preparation of membrane vesicles by a series of centrifugations. Here, we prepared cytochalasin-B-inducible nanovesicles (CINVs) of various cellular origins and studied their tropism in different mammalian cells. We observed that CINVs derived from human endometrial mesenchymal stem cells exhibited an enhanced affinity to epithelial cancer cells compared to myeloid, lymphoid or neuroblastoma cancer cells. The dendritic cell-derived C...
Cationic lipid-based delivery system for systemic cancer gene therapy
Cancer Gene Therapy, 2000
A cationic lipid-based gene delivery system composed of N-[(1-(2,3-dioleyloxy)propyl)]-N-N-N-trimethylammonium chloride and cholesterol, at a 4:1 molar ratio, was developed for systemic administration. Plasmid biodistribution and expression were characterized in syngeneic mouse tumor model squamous cell carcinoma VII cells. A reporter gene expression plasmid was used for biodistribution of plasmid and expression. The results showed that lungs and primary tumors were transfected. Fluorescence microscopy showed that fluorescent-labeled transfection complexes were passively targeted to the tumor vasculature and that the endothelial cells internalized the plasmid. Transgene expression was characterized based on duration of expression and dosing schedule. In vivo gene transfer with an interleukin-12 expression plasmid yielded protein levels in blood, lungs, and primary tumor after intravenous administration. Efficacy studies showed that 15 g of interleukin-12 plasmid was sufficient to produce a gene-specific inhibition of primary tumor growth. These results characterize the vascularity of the tumor model, characterize the in vivo gene transfer properties of the plasmid-based gene delivery system, and show that the transgene expression level was sufficient to elicit a biological response by inhibiting tumor growth.
Strategies for the use of Extracellular Vesicles for the Delivery of Therapeutics
Journal of Neuroimmune Pharmacology, 2019
Extracellular vesicles (EVs) are nanosized, membrane-bound vesicles released from eukaryotic and prokaryotic cells that can transport cargo containing DNA, RNA, lipids and proteins, between cells as a means of intercellular communication. Although EVs were initially considered to be cellular debris deprived of any essential biological functions, emerging literature highlights the critical roles of EVs in the context of intercellular signaling, maintenance of tissue homeostasis, modulation of immune responses, inflammation, cancer progression, angiogenesis, and coagulation under both physiological and pathological states. Based on the ability of EVs to shuttle proteins, lipids, carbohydrates, mRNAs, long non-coding RNAs (lncRNAs), microRNAs, chromosomal DNA, and mitochondrial DNA into target cells, the presence and content of EVs in biofluids have been exploited for biomarker research in the context of diagnosis, prognosis and treatment strategies. Additionally, owing to the characteristics of EVs such as stability in circulation, biocompatibility as well as low immunogenicity and toxicity, these vesicles have become attractive systems for the delivery of therapeutics. More recently, EVs are increasingly being exploited as conduits for delivery of therapeutics for anticancer strategies, immunomodulation, targeted drug delivery, tissue regeneration, and vaccination. In this review, we highlight and discuss the multiple strategies that are employed for the use of EVs as delivery vehicles for therapeutic agents, including the potential advantages and challenges involved.