Nanosized Drug Delivery Vectors and the Reticuloendothelial System - Intracellular Delivery: Fundamentals and Applications - page 156

NPC Non-parenchymal cell

HPI Hydrogenated phosphatidylinositol

DPPG 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol)

DAB Diaminobutane

Gd-DAB Gadolinium conjugated diaminobutane dendrimer

HLA-DR Human leukocyte antigen DR

BAI Brain specific angiogenesis inhibitor

GM1 Monosialoganglioside GM1

DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphocholine

DSPC L-alpha-phosphatidylcholine distearoyl

DSPG L-alpha-phosphatidyl-DL-glycerol-distearoyl

1 Introduction

A number of attributes of nanosized drug delivery particles are driving their
application in a wide range of uses in medicine and as drug delivery vectors. Their
circulation behaviour in plasma can be extended by controlling size to be on the
one hand sufficiently small to permit intravenous administration, while on the
other hand being sufficiently large to hinder passage through endothelial gap junc-
tions, leading to extended circulation time. Drugs can be incorporated into their
structures either via entrapment or surface conjugation. Particles can be engi-
neered to permit entrapped drugs to gradually leak out of the structures down a
concentration gradient, to enable an extended release-type delivery of drug to
systemic circulation, or to liberate drug specifically under physiological condi-
tions encountered at the desired site of drug action. They can be engineered for
tissue-specific drug delivery either passively (for instance via the enhanced perme-
ation and retention effect in solid tumours) or actively via the surface presentation
of ligands to cell surface receptors. In addition, association of drugs with nano-
sized delivery vectors allows delivery into the cells in the form of a nano-drug
formulation bypassing the efflux mechanism giving rise to resistance. This is par-
ticularly relevant in the treatment of cancer, where cytotoxic drugs often develop
multidrug resistance phenotypes.
A wide range of potential structures based on lipids, polymers, dendrimers, solid
drug particles, surfactants and other matrix materials have been described for use
as particulate or macromolecular drug delivery systems for intravenous application.
A range of these structures are illustrated below in Fig. 1 . The two classes of par-
ticulate nanomaterials, i.e. the macromolecules and matrix-based particles associ-
ated with drug molecules, are collectively called 'nanomedicines' for the purpose
of this contribution.
Although nanomedicines have shown a number of beneficial attributes for their
application in drug delivery, they are also prone to recognition and removal via the
reticuloendothelial system (RES), which can severely limit their application.
Specifically, recognition of nanomedicines by the RES can result in very rapid