Lipoplex-based targeted gene therapy for the suppression of tumours with VEGFR expression by producing anti-angiogenic molecules

Abstract

Background: The anti-angiogenic fusion protein RBDV-IgG1 Fc (RBDV), which comprises the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A), has shown antitumour effects by reducing angiogenesis in vivo. This study used the cationic lipoplex lipo-PEG-PEI-complex (LPPC) to simultaneously encapsulate both the RBDV targeting protein and the RBDV plasmid (pRBDV) without covalent bonds to assess VEGFR targeting gene therapy in mice with melanoma in vivo. Results: LPPC protected the therapeutic transgene from degradation by DNase, and the LPPC/RBDV complexes could specifically target VEGFR-positive B16-F10 cells both in vitro and in vivo. With or without RBDV protein-targeting direction, the pRBDV-expressing RBDV proteins were expressed and reached a maximal concentration on the 7th day in the sera after transfection in vivo and significantly elicited growth suppression against B16-F10 melanoma but not IgG1 control proteins. In particular, LPPC/pRBDV/RBDV treatment with the targeting molecules dramatically inhibited B16-F10 tumour growth in vivo to provide better therapeutic efficacy than the treatments with gene therapy with IgG1 protein targeting or administration of a protein drug with RBDV. Conclusions: The simultaneous combination of the LPPC complex with pRBDV gene therapy and RBDV protein targeting might be a potential tool to conveniently administer targeted gene therapy for cancer therapy.

A flexible liposomal polymer complex as a platform of specific and regulable immune regulation for individual cancer immunotherapy

“…This study showed that LPPC combined DC MP and mAbs could be a good tool for regulating an individual’s immune responses by turning specific immune responses on or off. In addition, our previous results showed LPPC complexes could be safe in vivo because no obvious side effects were found in vivo treatment by histopathologic assay [ 15 , 17 , 21 ]. Moreover, to resolve the diversity and variation of MHC molecules and antigens in human population, LPPC/MP/Ab complexes showed remarkable potential and technological advances in human diseases such as cancers or autoimmune diseases for personalized precision immunotherapy.…”

“…As described previously [ 21 ], the organs or tissues of the mice were formalin-fixed, paraffin-embedded and subsequently stained by using histochemical techniques. The tissue slides were observed under a light microscope.…”

“…In terms of its applicability for unusual in vivo delivery routes, LPPC was applied to protein intercellular delivery for enzyme-defect therapy [ 17 ], efficient drug delivery across the BBB for brain tumor suppression and transdermal drug delivery for breast cancer inhibition [ 18 , 19 ]. Based on such characteristics, the LPPC complex could efficiently target tumors by targeting antibodies and deliver therapeutic drugs or transgenes, resulting in dramatic therapeutic efficacy, even achieving total cure (100% tumor-free) in an animal model of human breast tumor [ 20 , 21 ]. Therefore, this study attempts to address the unmet needs described above by utilizing autologous dendritic cell membrane proteins (DC MP), which highly expressing MHC and pulsing protein antigens [ 3 ] (Additional file 1 , upper).…”

Targeting strategies with lipid vectors for nucleic acid supplementation therapy in Fabry disease: a systematic review

“…Active targeting can be achieved by incorporating or attaching ligands on the surface of the carrier that specifically bind to receptors present exclusively in the target tissue or cell [14][15][16]. Different types of molecules have been employed as active targeting moieties of non-viral nucleic acid delivery systems, such as antibodies [17] or antibody fragments [18], peptides [19] and carbohydrates [20]. However, it remains a challenge to design targeted carriers with high quality and good clinical translation and large-scale manufacturing capacity [21].…”

Transdermal nanolipoplex simultaneously inhibits subcutaneous melanoma growth and suppresses systemically metastatic melanoma by activating host immunity

“…Our previous study proved that the LPPC delivery system enhanced the skin penetrability, drug accumulation ability, and e cacy of breast cancer therapies [21]. In addition, LPPC could enhance the cytotoxicity of the drug against different cancer cells [22], and LPPC provided their activities by adsorbing proteins and nucleotides without chemical modi cation [23,24]. Moreover, when combined with different adjuvants, the LPPC increased and switched immune responses [25].…”