No abstract

Nonviral systemic delivery is one of the most attractive approaches for cancer gene therapy. To achieve this goal, various laboratories have developed cationic liposomes. However, when injected intravenously, cationic lipid-DNA complexes accumulate mostly into and transfect lung tissue. Here, we describe a method by which these complexes can be targeted to tumors using folic acid. Adding polyethylene glycol (PEG)-lipids to the complexes dramatically reduced both lung accumulation and gene transfer to lungs and tumors after intravenous administration. The presence of folic acid at the distal end of the PEG-lipid did not modify tumor accumulation of the complexes. However, with folate-targeted complexes, gene transfer activity was restored in tumors while the activity in lungs was reduced by 50- to 100-fold compared with nontargeted lipid-DNA complexes. This approach provides a first in vivo proof of concept to achieve targeted tumor gene delivery.

Our results represent an important step towards the design of multimodular BGTC-based systems for improved in vivo gene transfection.

Polyvalent carbohydrate-protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands to inhibit polyvalent processes; however, both reproducible synthesis and appropriate characterization of such complex entities is demanding. Herein, we present an alternative concept avoiding conventional macromolecules. Small glycodendrimers which fulfill single molecule entity criteria self-assemble to form non-covalent nanoparticles. These particles-not the individual molecules-function as polyvalent ligands, efficiently inhibiting polyvalent processes both in vitro and in vivo. The synthesis and characterization of these glycodendrimers is described in detail. Furthermore, we report on the characterization of the non-covalent nanoparticles formed and on their biological evaluation.

Nonviral gene vectors remain inefficient in vivo largely because of their rapid clearance from the circulation and also their nonspecific association with the extracellular matrix. To overcome such drawbacks, cationic lipoplexes are now frequently coated with hydrophilic polymers such as PEGs to reduce nonspecific interactions, and ligands are also linked to their surface to obtain cell-specific gene transfer. In view of the development of vectors for systemic gene delivery, we have designed and studied lipoplexes that carry a triantennary galactosyl ligand attached to the distal end of a (PEG)45-conjugated lipid. We incorporated this targeted PEGylated lipid into lipoplexes using two strategies of formulation, i.e., using either preformed micelles or liposomes. We demonstrated that the incorporation of PEG chains stabilized lipoplexes and masked, but only partially, the positive charges exposed on the surface of the particles. We have also shown that incorporation into lipoplexes of a lipidated PEG chain, bearing a ligand at its distal end, yielded particles that exhibited an accessible ligand throughout the whole range of cationic lipid to DNA ratios. We obtained a targeted transfection in HepG2 cells with one of the formulations. Our results strengthen the validity of using a ligand carried by a long PEG spacer arm for targeted gene transfer.

A new and very convenient route to oxidized poly(ethylene glycol), with a catalytic nitroxyl radical oxidant (2,2,6,6-tetramethyl-1-piperidinyl-oxyl) regenerated in situ by stoichiometric amounts of [bis(acetoxy)-iodo]benzene, is described. Under these conditions, the reaction is quantitative and leads to the pure product by a simple process such as precipitation and washing with diethyl ether.

No abstract

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