Targeted Drug Delivery and Penetration Into Solid Tumors

Abstract

Delivery and penetration of chemotherapeutic drugs into tumors are limited by a number of factors related to abnormal vasculature and altered stroma composition in neoplastic tissues. Coupling of chemotherapeutic drugs with tumor vasculature-homing peptides or administration of drugs in combination with biological agents that affect the integrity of the endothelial lining of tumor vasculature is an appealing strategy to improve drug delivery to tumor cells. Promising approaches to achieve this goal are based on the use of Asn-Gly-Arg (NGR)-containing peptides as ligands for drug delivery and of NGR-TNF, a peptide-tumor necrosis factor-α fusion protein that selectively alters drug penetration barriers and that is currently tested in a randomized Phase III trial in patients with malignant pleural mesothelioma.

Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors

“…Efficacy of our system, however, could be improved by combination therapy. For example, a significant increase of the response to targeted TNF was found with either chemotherapy or immunotherapy, both active and adoptive (20)(21)(22). Remarkably, strong synergistic effects were achieved (including tumor eradication), compared with the modest reduction induced by targeted TNF alone (23).…”

Interleukin-27 Gene Delivery for Modifying Malignant Interactions Between Prostate Tumor and Bone

“…S1), suggesting that the dose delivered can be increased further, and future experiments in vivo will assess the exposure limit of persistent IL-27 after sonodelivery to help characterize any potential toxicity. Other strategies by which the therapy efficacy can be augmented are by utilizing cytokine combinations proven successful for other preclinical studies, such as IL-27 + IL-12 (Zhu et al, 2010) or IL-27 + IL-2 (Salcedo et al, 2009), and ligand-mediated targeting strategies in order to enhance cytokine efficacy via increased retention within tumors [reviewed by Corti et al (2011)]. …”

Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy

“…For example, although serum CgA in the blood of normal subjects is about 1 nmol/L (21), increased levels of CgA, up to 4 to 8 nmol/L have been detected in the sera of a subgroup of patients with NSCLC, despite the lack of neuroendocrine differentiation, with important prognostic implication (37). Considering that the combination of NGR-TNF and chemotherapy is currently under investigation in patients with NSCLC, hepatocellular carcinoma, or other nonneuroendocrine tumors (9)(10)(11)(12)(13)(14), the results showing inhibitory activity of CgA in animal models of nonneuroendocrine tumors might be clinically relevant. A growing body of evidence suggest that administration of proton pump inhibitors, which are drugs commonly used in the treatment of acid peptic disorders, can enhance 2 to 3 times, and in certain patients even up to 10 times, the circulating levels of CgA, depending on the time of administration (32,33).…”

“…NGR-TNF can also induce, at later time points, vascular damage and inflammatory/immune responses (4,8). Phase I and II clinical studies with low-dose NGR-TNF, alone and in combination with chemotherapy, showed manageable toxicity profile and evidence of disease control, particularly in subpopulations of patients with hepatocellular carcinoma and pleural mesothelioma (9)(10)(11)(12)(13)(14). A randomized double-blind phase III study of NGR-TNF (in combination with chemotherapy or supportive care) started in 2010 in patients with malignant pleural mesothelioma (http://www.…”