Delivery of Plasmid DNA into Tumors by Intravenous Injection of PEGylated Cationic Lipoplexes into Tumor-Bearing Mice

Abstract

For systemic injection of cationic liposome/plasmid DNA (pDNA) complexes (cationic lipoplexes), polyethylene glycol (PEG)-modification (PEGylation) of lipoplexes can enhance their systemic stability. In this study, we examined whether intravenous injection of PEGylated cationic lipoplexes into tumor-bearing mice could deliver pDNA into tumor tissues and induce transgene expression. PEGylation of cationic liposomes could prevent their agglutination with erythrocytes. However, when PEGylated cationic lipoplexes were injected intravenously into tumor-bearing mice, they accumulated in tumor vascular vessels and did not exhibit transgene expression in tumors with both poor and well-developed vascularization. Furthermore, PEGylated cationic lipoplexes of CpGfree pDNA could not increase transgene expression in tumors after intravenous injection. These results suggested that PEGylation could not extravasate cationic lipoplexes from vascular vessels in tumors and abolished transgene expression although it enhanced the systemic stability of cationic lipoplexes by avoiding interactions with blood components such as erythrocytes. Successful delivery of pDNA to tumors by PEGylated cationic liposomes will require a rational strategy and the design of liposomal delivery systems to overcome the issue associated with the use of PEG.

Desialylation of Sonic-Hedgehog by Neu2 Inhibits Its Association with Patched1 Reducing Stemness-Like Properties in Pancreatic Cancer Sphere-forming Cells

“…One group was injected with vehicle control whereas the other group was injected intratumorally with 1.5 mg/kg body wt. PcDNA3.1-Neu2 plasmid in admixture with Lipofectamine 2000 (1:2) twice a week for 3 weeks [25][26][27]. Tumor size was monitored periodically.…”

Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

“… ▪ PEG density; ▪ The adverse effect related to PEG, such as hand-foot syndrome (HFS); ▪ Additional surface modification with non-specificand/or specific targeting strategy is needed to cross the BBB. ( 33 , 39 – 43 ) Specific targeted liposome ▪ Can be achieved by conjugating liposome (or PEGylated liposome) to single functional ligand ( F and G ) or multiple ligands ( H ) to facilitate a specific binding to the BBB surface receptors or carrier proteins; ▪ Targeted delivery leverages the delivery efficiency of liposomes to the brain; ▪ Targeted delivery improves the therapeutic index by increasing target site drug accumulation whereas decreasing peripheral toxicity. Hence, it opens a possibility for reducing dose or dosing frequency; ▪ Targeted ligands can be antibodies ( G ), cell-penetrating peptides ( F ), or endogenous molecules ( F ) (e.g., transferrin, GSH, ApoE, lactoferrin).…”

“…There have been numerous cationic liposome-related studies improving brain tumor treatment based on this mechanism ( 13 ). Moreover, a positively charged lipid surface can facilitate adsorption of polyanions, such as DNA and RNA, and is now widely recognized for cancer treatment ( 32 , 33 ).…”

“…A PEGylation of cationic liposome-plasmid DNA (pDNA) complexes (lipoplexes) successfully increased the systemic stability by preventing agglutination with erythrocytes or other proteins present in the blood. An in vivo model study showed that PEGylation of lipoplexes increases the drug delivery to brain tumor ( 33 ). There are more applications of PEGylated nanocarriers for brain targeting of bioactive compounds under development.…”

“…As indicated, the use of surface-charged PEGylated liposomes aids drug delivery to the brain. However, surface-charged liposomes, such as cationic liposomes, have non-specific binding mechanisms to the targeted tissue and may undergo rapid clearance ( 13 ), whereas only PEGylated liposomes prolong only the liposome half-life without improving tissue penetration ( 33 ). Conjugation of liposomes with other functional ligands, such as targeting peptide vectors, endogenous molecules, and antibodies, can increase brain delivery efficiency.…”