Lipoplex-loaded microbubbles for gene delivery: A Trojan horse controlled by ultrasound

Cationic poly(ethylene glycol)ylated (PEGylated) liposomes are one of the most important gene transfer reagents in non-viral gene therapy. However, the low transfection efficiencies of highly PEGylated lipoplexes currently hamper their clinical use. Recently, ultrasound has been used in combination with microbubbles to enhance the uptake of genes in different cell types. However, the gene transfer efficiency still remains low in these experiments. To overcome the limitations of both techniques, we present the attachment of PEGylated lipoplexes to microbubbles via biotin-avidin-biotin linkages. Exposure of these lipoplex-loaded microbubbles to ultrasound results in the release of unaltered lipoplexes. Furthermore, these lipoplex-loaded microbubbles exhibit much higher transfection efficiencies than "free" PEGylated lipoplexes or naked plasmid DNA (pDNA) when combined with microbubbles and ultrasound. Interestingly, the lipoplex-loaded microbubbles only transfect cells when exposed to ultrasound, which is promising for space- and time-controlled gene transfer. Finally, this novel Trojan-horse-like concept can also be exploited to achieve the ultrasound- triggered release of nanoparticles containing other therapeutic agents such as anticancer drugs

DNA vaccination for prostate cancer: key concepts and considerations

While locally confined prostate cancer is associated with a low five year mortality rate, advanced or metastatic disease remains a major challenge for healthcare professionals to treat and is usually terminal. As such, there is a need for the development of new, efficacious therapies for prostate cancer. Immunotherapy represents a promising approach where the host’s immune system is harnessed to mount an anti-tumour effect, and the licensing of the first prostate cancer specific immunotherapy in 2010 has opened the door for other immunotherapies to gain regulatory approval. Among these strategies DNA vaccines are an attractive option in terms of their ability to elicit a highly specific, potent and wide-sweeping immune response. Several DNA vaccines have been tested for prostate cancer and while they have demonstrated a good safety profile they have faced problems with low efficacy and immunogenicity compared to other immunotherapeutic approaches. This review focuses on the positive aspects of DNA vaccines for prostate cancer that have been assessed in preclinical and clinical trials thus far and examines the key considerations that must be employed to improve the efficacy and immunogenicity of these vaccines

Continuous delivery of endogenous inhibitors from poly(lactic-co-glycolic acid) polymeric microspheres inhibits glioma tumor growth

There is an urgent need for modalities that can localize and prolong the administration of the antitumor agents, particularly antiangiogenic, to achieve long-term tumor inhibition. However, one of the major obstacles is designing a device in which the biological activity of sensitive endogenous inhibitors is retained. We have designed a biodegradable polymeric device, which provides a unique and practical means of localizing and continuously delivering hemopexin (PEX) or platelet factor 4 fragment (PF-4/CTF) at the tumor site while maintaining their biological activity. The potential and efficacy of this system is shown in vitro and in vivo in a human glioma mouse model

Continuous delivery of endogenous inhibitors from poly (lactic-co-glycolic acid) polymeric microspheres inhibits glioma tumor growth

Purpose: There is an urgent need for modalities that can localize and prolong the administration of the antitumor agents, particularly antiangiogenic, to achieve long-term tumor inhibition. However, one of the major obstacles is designing a device in which the biological activity of sensitive endogenous inhibitors is retained. We have designed a biodegradable polymeric device, which provides a unique and practical means of localizing and continuously delivering hemopexin (PEX) or platelet factor 4 fragment (PF-4/CTF) at the tumor site while maintaining their biological activity. The potential and efficacy of this system is shown in vitro and in vivo in a human glioma mouse model. Experimental Design: Polymeric microspheres made of poly(lactic-co-glycolic acid) (PLGA) were loaded with very low amounts of PEX and PF-4/CTF. The release profiles of these factors from PLGA and their biological activity were confirmed in vitro using proliferation assays done on endothelial and tumor cells. Tumor inhibition using this system was studied in nude mice bearing a human s.c. glioma. Results: PEX and PF-4/CTF released in vitro from PLGA microspheres were biologically active and significantly inhibited the proliferation of human umbilical vein endothelial cells, bovine capillary endothelial cells, and U87-MG cells. A single local s.c. injection of PLGA microspheres loaded with low amounts of PEX or PF-4/CTF resulted in an 88% and 95% reduction in glioma tumor volume 30 days post-treatment. Immunohistochemical analysis of the treated tumors showed a marked decrease in tumor vessel density compared with untreated tumors. Conclusion: Our findings show that polymeric microspheres are a very promising approach to locally and efficiently deliver endogenous inhibitors to the tumor site leading to a significant inhibition of the tumor