Neoadjuvant Nanomedicines for vascular Normalizati.. (NeoNaNo)
Neoadjuvant Nanomedicines for vascular Normalization
Start date: Jan 1, 2013,
End date: Dec 31, 2017
The aim of my proposal is to establish ‘Neoadjuvant Nanomedicines for vascular Normalization’ (NeoNaNo) as a novel concept for improving the efficacy of combined modality anticancer therapy. This concept is radically different from all other drug targeting approaches evaluated to date, since nanomedicines are not used to directly improve drug delivery to tumors, but to normalize the tumor vasculature, and to thereby indirectly improve drug (and oxygen) delivery. The need for such an alternative concept can be exemplified by taking the (pre-) clinical performance of nanomedicines into account: whereas in animal models, they generally improve both the efficacy and the tolerability of chemotherapeutic drugs, in patients, they often only attenuate the toxicity of the intervention, and they fail to improve the efficacy of the drug. To overcome this shortcoming, I here propose to use corticosteroid-containing nanomedicines, targeted to tumor-associated macrophages (TAM), to inhibit pro-inflammatory and pro-angiogenic signaling by TAM, and to thereby homogenize the tumor vasculature, increase tumor perfusion and reduce the interstitial fluid pressure. As a result of this, the tumor accumulation, intratumoral distribution and antitumor efficacy of subsequently administered chemotherapeutics, as well as of radiotherapy (because of enhanced oxygen delivery) can be substantially improved. To achieve these goals, liposomal, polymeric and micellar corticosteroids, several different animal models, and several different imaging agents and techniques will be used to (I) visualize and optimize nanomedicine-mediated vascular normalization; to (II) potentiate chemotherapy; and to (III) potentiate radiotherapy. These efforts will not only provide a solid basis for a completely new paradigm in nanomedicine research, but they will also result in novel, broadly applicable and clinically highly relevant combination regimens for improving the treatment of advanced solid malignancies.
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