Abstract
While nanoparticles have shown great promise as drug carriers in cancer therapy, their effectiveness is critically dependent on the structural characteristics of the tumor vasculature. Here we demonstrate that several agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the accumulation of nanoparticles in tumors. The vascular-active agents tested in this study included a bacterium, a pro-inflammatory cytokine, and microtubule-destabilizing drugs. Using radiolabeled nanoparticles, we show that such agents can increase the tumor to blood ratio of radioactivity by more than 20-fold compared to nanoparticles alone. Moreover, vascular-active agents dramatically improved the therapeutic effect of nanoparticles containing radioactive isotopes or chemotherapeutic agents. This resulted in cures of animals with subcutaneous tumors and significantly prolonged the survival of animals with orthotopic brain tumors. In principle, a variety of vascular-active agents and macromolecular anticancer formulations can be combined, which makes this approach broadly applicable and particularly suited for the treatment of patients who have failed standard therapies.
Highlights
Wounding results in increased vascular permeability, a process that is markedly enhanced if a wound becomes infected
We hypothesized that a radiolabeled anti-liposomase antibody would synergize with C. novyi-NT by binding to liposomase secreted by the bacteria, thereby eradicating the oxygenated tumor rim through β-particle irradiation
The major limitation for most chemotherapeutic agents is their toxicity toward normal tissues, which prohibits the use of doses high enough to eradicate all cancer cells
Summary
Wounding results in increased vascular permeability, a process that is markedly enhanced if a wound becomes infected. The mammalian host mobilizes an army of immunoglobulins, complement, white blood cells and cytokines. To allow this army to engage the enemy, the vascular system at the site of infection must open its gates. This process has been studied in detail and many of the biochemical mechanisms have been identified[1]. It is known that the vasculature of tumors is different from that of normal cells, and much effort has gone into exploiting this difference through therapeutic agents like Avastin[3,4,5]. One notable example is Doxil, a liposomal formulation of doxorubicin, which has been approved for the treatment of human cancers
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