Weiwen Zheng

Stabilization of cationic liposome-plasmid DNA complexes by polyamines and poly(ethylene glycol)-phospholipid conjugates for efficient in vivo gene delivery

Stable complexes of cationic liposomes with plasmid DNA were prepared by (1) including a small amount of poly(ethylene glycol)‐phospholipid conjugate or (2) condensing the DNA with polyamines prior to the formation of liposome‐plasmid complexes. These preparations were stable for months at 4°C and gave reproducible high transfection activity for in vivo gene delivery after intravenous injection in mice. Under these conditions, the expression of marker gene (luciferase) was primarily in the lungs (reaching values up to 3 ng expression per mg tissue protein), but also in other tissues to a lesser extent. Non‐stabilized formulations lost all their transfection activity in 4 days. In these formulations cholesterol, not dioleoylphosphatidylethanolamine, was the helper lipid effective for sustaining high transfection activity in vivo. These new developments in formulation technology should enhance the potential for liposome‐mediated gene therapy.

CHAPTER 4.7 – Targeting of sterically stabilized liposomes to cancers overexpressing HER2/neu proto-oncogene

This chapter describes HER2 (c-erbB-2, neu) oncoprotein as a target recognition molecule in cancer. In contrast to a number of previous liposomal targeting systems for anticancer agents, sterically stabilized anti-HER2 immunoliposomes were not only capable of target-specific binding and internalization by cancer cells in culture but were also able to cross the vascular barrier. Malignant phenotype is often associated with the expression of proto-oncogene. The HER2 proto-oncogene encodes a 185 kDa receptor tyrosine kinase, which belongs to the family of receptor tyrosine kinases, including also the products of epidermal growth factor HER3 and HER4 genes. Overexpression of HER2 was first observed in 20–30% of breast carcinomas and was associated with aggressive tumor growth, high recurrence rate, and poor prognosis for the patients. Further studies showed ubiquitous overexpression of HER2 in a variety of malignancies, including cancers of the ovary, endometrium, lung, stomach, pancreas, bladder, and prostate. Over the past decade, the introduction and refinement of “long-circulating” liposomes preparation techniques, and “remote loading” methods for drug loading into liposomes greatly advanced liposomal pharmacology. The “rational design” of cancer cell-targeted sterically stabilized liposomes leads to a re-evaluation of tumor targeting paradigms and opens new avenues for better a treatment of cancer.

Sterically Stabilized Immunoliposomes: Formulations for Delivery of Drugs and Genes to Tumor Cells in Vivo

Immunoliposomes represent a promising strategy to achieve targeted drug delivery for the treatment of cancers overexpressing specific surface receptors. Advances in immunoliposome design have been facilitated by independent progress in the areas of antibody-based therapeutics and liposomes, which can now be utilized for tumor-targeted drug delivery Park et al., 1997a).