International Journal of Pharmaceutics 267 (2003) 1–12
Review
Improving anti-angiogenic therapy via selective delivery of
cationic liposomes to tumour vasculature
Crispin R. Dass
∗
Johnson & Johnson Research, Box 4555, Strawberry Hills 2012, Australia
Received 29 May 2003; received in revised form 15 August 2003; accepted 15 August 2003
Abstract
In the past three decades, two very important findings regarding tumour vasculature have been made. Firstly, it has been
known a solid tumour has to establish an adequate blood supply to grow beyond a critical mass. Secondly, it has been proven that
the tumour vasculature is relatively more aberrant, dynamic and permeable than healthy host tissue. This review discusses the
potential of delivering therapeutic nucleic acids to tumour vasculature using cationic liposomes, vehicles recently demonstrated
to be selectively delivered to tumour vasculature.
© 2003 Elsevier B.V. All rights reserved.
Keywords: Cancer; Tumour; Vasculature; Liposome; Lipoplex
1. General characteristics of solid tumours
hindering effective therapy
When initially diagnosed, most tumours are well
advanced. Fidler (1991) stated that a 1 g, 1 cm
3
neo-
plasia (the smallest size clinically detectable) contains
approximately a billion cells. An eradication of even
99.9% of these cells would still leave a million vi-
able cells for expansion. For complete cure, all cells
need to be destroyed. Additionally, in nearly 50% of
the patients, surgical excision of the primary tumour
is not curative due to metastasis, the process whereby
mutated cells spread from the primary site via the
bloodstream to establish neoplasms in secondary sites
such as the liver or lung (Fidler and Ellis, 1994). Of-
ten, metastases are undetectable due to their small size
∗
Present address. GeneType Research Laboratories, 60-70
Hanover Street, Fitzroy 3065, Australia. Tel.: +61-3-94164076;
fax: +61-3-84127032.
E-mail address: crispin.dass@genetype.com.au (C.R. Dass).
(<5 mm in diameter) and may persist in a dormant
state for years following removal of the primary tu-
mour (Meltzer, 1990). The greatest obstacle to success
of therapy is the heterogeneous composition of tu-
mours. Individual cells within a tumour vary in terms
of genetic, biochemical, immunological and biological
characteristics (Dass et al., 1998). These differences
may involve cell-surface receptors, enzymes, kary-
otypes, cell morphologies, cell cycling times, sensitiv-
ities to various therapeutic agents, tissue architecture
and metastatic potential. Such heterogeneity reduces
the ability of both surgery and therapeutic agents to
kill all neoplastic cells.
Additionally, in certain solid tumours, such as
those of the colon, kidney and adrenal glands, over-
expression of the p-glycoprotein gene causes tu-
mour cells to acquire drug-resistance to therapeu-
tic agents such as cisplatin (Tsuruo and Tomida,
1995). Drug-resistance is due to the p-glycoprotein
excreting cytotoxic drugs from the cell via its ATPase
action (Hamada and Tsuruo, 1988). Dense packing of
0378-5173/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2003.08.010