Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells

The potential use of many promising novel drugs is limited by their inability to specifically reach their site of action after intravenous administration, without secondary effects on healthy tissues. In order to remediate this problem, the protein transferrin (Tf) has been extensively studied as a targeting molecule for the transport of drug and gene delivery systems to the brain and cancer cells. A wide range of delivery approaches have been developed to target the Tf receptor and they have already improved the specific delivery of Tf-bearing therapeutic agents to their site of action. This review provides a summary of the numerous delivery strategies used to target the Tf receptor and focuses on recent therapeutic advances

Therapeutic efficacy of intravenously administered transferrin-conjugated dendriplexes on prostate carcinomas

Aim: Improved treatments for prostate cancer are critically needed in order to overcome metastasis and lethal recurrence. Intravenously administered gene therapy would be an attractive anticancer treatment strategy; however, the lack of suitable carrier systems able to selectively deliver therapeutic genes to tumors has so far limited this investigation. Given that transferrin receptors are overexpressed on prostate cancer cells, the purpose of this study is to determine whether transferrin-conjugated dendriplexes encoding TNF-α, TNF-related apoptosis-inducing ligand and IL-12 would suppress the growth of prostate cancer cell lines in vitro and in vivo. Materials & methods: Transferrin-conjugated dendriplexes encoding TNF-α, TNF-related apoptosis-inducing ligand and IL-12 were intravenously administered to mice bearing subcutaneous PC-3 and DU145 tumors. Results: The administration of the transferrin-conjugated generation 3 diaminobutyric polypropylenimine dendriplex encoding TNF-α resulted in tumor suppression for 60% of PC-3 and 50% of DU145 prostate tumors. Conclusion: These dendriplexes hold great potential as a novel approach for prostate cancer therapy

Preparation and analysis of novel tumour-targeted delivery systems for prostate cancer therapy

This thesis was previously held under moratorium from 25th March 2015 until 25th March 2017.Cancer is a major public health problem worldwide. It is considered a major cause of death around the world. The World Health Organization estimates that 84 million people will die of cancer between 2005 and 2015, and the incidence is expected to increase continuously as the world population ages (Danhier et al., 2010). Prostate cancer is one of the most commonly diagnosed cancers in men and remains the second leading cause of cancer-related deaths in industrial countries. To date, there is still no efficacious treatment for patients with advanced prostate cancer with metastases. New treatments are therefore critically needed for these patients.Gene therapy holds great promise for the intravenous treatment of prostate cancer. Non-viral gene delivery is emerging as potential safer alternative to the use of viral vectors for the treatment of various gene related diseases including cancer. Although non-viral vectors may not be as effective as the viral ones, the continuous research on rationally designing multifunctional non-viral polymeric gene delivery carriers resulted in improved delivery.This study is carried out to prepare and evaluate the efficacy of tumour- targeted transferrin, lactoferrin and lactoferricin conjugated polypropylenimine dendrimer as a novel gene delivery system able to improve the delivery of the therapeutic gene to cancer cells, in a safe and targeted way. We demonstrated that new tumour-targeted therapeutic systems recognizing receptors specifically overexpressed on prostate tumours, were able to improve the in vitro therapeutic efficacy on PC-3, DU145 and LNCaP prostate cancer cells when compared to the non-targeted delivery system, by up to 100-fold in LNCaP cells. In vivo, the intravenous administration of the tumour-targeted therapeutic system encoding Tumour Necrosis Factor (TNF) α resulted in tumour suppression for 60% of PC-3 and 50% of DU145 tumours.The dendriplex encoding TRAIL led to tumour suppression of 10% of PC-3 tumours. IL-12 mediated gene therapy resulted in tumour regression of 20% of both types of prostate tumours. By contrast, all the tumours treated with DAB-Tf, naked DNA or left untreated were progressive for both tumour types. The treatment was well tolerated by the animals, with no apparent signs of toxicity.The treatment of cancer cells with lactoferrin- and lactoferricin-bearing dendriplexes in vitro, led to an anti-proliferative activity enhanced by up to 5-fold for lactoferricin-bearing DAB in T98G cancer cells compared to the unmodified dendriplex. In vivo, the conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumour while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumours and up to 50% of B16-F10 tumours over one month. The treatment was well tolerated by the animals, with no apparent signs of toxicity.To our knowledge, it is the first time that an intravenously administered non-viral gene therapeutic system led to growth inhibition and even complete tumour suppression for prostate tumours.In conclusion, these tumour-targeted therapeutic systems therefore hold great potential as a novel approach for the gene therapy of prostate cancer.Cancer is a major public health problem worldwide. It is considered a major cause of death around the world. The World Health Organization estimates that 84 million people will die of cancer between 2005 and 2015, and the incidence is expected to increase continuously as the world population ages (Danhier et al., 2010). Prostate cancer is one of the most commonly diagnosed cancers in men and remains the second leading cause of cancer-related deaths in industrial countries. To date, there is still no efficacious treatment for patients with advanced prostate cancer with metastases. New treatments are therefore critically needed for these patients.Gene therapy holds great promise for the intravenous treatment of prostate cancer. Non-viral gene delivery is emerging as potential safer alternative to the use of viral vectors for the treatment of various gene related diseases including cancer. Although non-viral vectors may not be as effective as the viral ones, the continuous research on rationally designing multifunctional non-viral polymeric gene delivery carriers resulted in improved delivery.This study is carried out to prepare and evaluate the efficacy of tumour- targeted transferrin, lactoferrin and lactoferricin conjugated polypropylenimine dendrimer as a novel gene delivery system able to improve the delivery of the therapeutic gene to cancer cells, in a safe and targeted way. We demonstrated that new tumour-targeted therapeutic systems recognizing receptors specifically overexpressed on prostate tumours, were able to improve the in vitro therapeutic efficacy on PC-3, DU145 and LNCaP prostate cancer cells when compared to the non-targeted delivery system, by up to 100-fold in LNCaP cells. In vivo, the intravenous administration of the tumour-targeted therapeutic system encoding Tumour Necrosis Factor (TNF) α resulted in tumour suppression for 60% of PC-3 and 50% of DU145 tumours.The dendriplex encoding TRAIL led to tumour suppression of 10% of PC-3 tumours. IL-12 mediated gene therapy resulted in tumour regression of 20% of both types of prostate tumours. By contrast, all the tumours treated with DAB-Tf, naked DNA or left untreated were progressive for both tumour types. The treatment was well tolerated by the animals, with no apparent signs of toxicity.The treatment of cancer cells with lactoferrin- and lactoferricin-bearing dendriplexes in vitro, led to an anti-proliferative activity enhanced by up to 5-fold for lactoferricin-bearing DAB in T98G cancer cells compared to the unmodified dendriplex. In vivo, the conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumour while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumours and up to 50% of B16-F10 tumours over one month. The treatment was well tolerated by the animals, with no apparent signs of toxicity.To our knowledge, it is the first time that an intravenously administered non-viral gene therapeutic system led to growth inhibition and even complete tumour suppression for prostate tumours.In conclusion, these tumour-targeted therapeutic systems therefore hold great potential as a novel approach for the gene therapy of prostate cancer

Isolation and characterization of four novel β-Sitosteryl esters from <i>Salvadora persica</i> Linn.

<p><i>Salvadora persica</i> is virtuous to have a variety of phytoconstituents responsible for many biological activities some of them identified particularly while some are still to be acknowledged. A number of steroidal, glycosidic, terpenoids, saponins and functional esters are reported till date. The present study deals with extraction, isolation, and characterisation of four novel steroidal esters by systematic cold extraction of <i>S. persica</i>. The extracted phytoconstituents were characterised by sophisticated spectral UV, IR, NMR and MS, techniques. The reported four new β-Sitosteryl esters SP-2, 3, 5 and 6 were extracted and reported for the first time.</p

Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

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 &gt; 13 days compared to controls administered with the drug solution only. This tumor-targeted, tocotrienol-based nanomedicine therefore significantly improved the therapeutic response in cancer treatment

Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes

The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy