Particle-Mediated Intravascular Delivery of Oligonucleotides to Tumors: Associated Biology and Lessons from Genotherapy

Abstract

For a solid tumor to become life-threatening, an adequate blood supply has to be established. Although neovascularization has dire consequences for the host, it furnishes a common route through which tumors may be accessed and eradicated by drugs. The fact that a tumor's vasculature is relatively more permeable than that of healthy host tissue means selective delivery of drugs may be achieved. The role played by the cells making up the tumor vascular bed, vascular endothelial cells (VECs), has to be evaluated closely in attempts to design ways for enhancing drug delivery to solid tumors via the vasculature. The two major roles of VECs in the body, as barrier and as transport, are both highly pertinent to drug delivery. Our review examines how VECs may be manipulated in vivo to improve the selective delivery of carriers for oligonucleotide constructs to solid tumors. It also discusses how oligonucleotide drugs may be targeted against tumor VECs on the premise that by killing these cells, the tumor itself will perish. Cationic liposomes and microspheres are the major delivery vehicles discussed, with added analyses of such other nucleic acid carriers as nanospheres, dendrimers, and polyethyleneimine.

Review: doxorubicin delivery systems based on chitosan for cancer therapy

“…Sub-micron-sized vesicles made up of lipid layers Classified as unilamellar or multilamellar depending on number of lipid bilayers [58] Synthetic Doxorubicin [10] Oligodeoxynucleotides [59] Plasmid DNA [60][61][62][63][64][65][66][67] Camptothecin [68,69] Unilamellar systems entrap water-soluble drugs due to aqueous core Multilamellar systems encapsulate lipid-soluble drugs Able to extravasate into defective, leaky vasculated tumours and be retained [11] Maximises amount of drugs reaching tumour sites while minimising systemic toxicity [70,71] pH-sensitive formulations provide sensitivity to lowered pH; allows for degradation in areas of tumour hypoxia [72] Requires stearic stabilisation, through the coating of inert polymers, due to electrostatic, hydrophobic and van der Waals forces affecting and disintegrating liposomes [14,73] authors also speculated that the initial phase of doxorubicin release could be attributed to doxorubicin located at the surface of the particles, while the remainder of the unreleased doxorubicin was assumed to be entrapped within the chitosan nanoparticles. The degradation of chitosan would therefore be essential for accomplishing doxorubicin release.…”

Reduction of tamoxifen resistance in human breast carcinomas by tamoxifen-containing liposomes in vivo

“…Liposomes are able to reduce toxic side-effects of anti-cancer agents while maintaining or enhancing their therapeutic effects [7,9,18,22,23], e.g. by improvement of traffic through inter-and intracellular barriers [24][25][26].…”

Nanostructure-mediated drug delivery

“…Nanostructuremediated drug delivery, a key technology for the realization of nanomedicine, has the potential to enhance drug bioavailability, improve the timed release of drug molecules, and enable precision drug targeting [8,9]. Nanoscale drug delivery systems can be implemented within pulmonary therapies [10], as gene delivery vectors [11], and in stabilization of drug molecules that would otherwise degrade too rapidly [12,13].…”