Responsive nanomedicines enhanced by or enhancing physical modalities to treat solid cancer tumors: Preclinical and clinical evidence of safety and efficacy

Abstract

Nanomedicine has improved cancer treatment but not to the extent anticipated. Responsive nanomedicines enhanced by physical modalities (radiation, ultrasounds, alternating magnetic fields) or enhancing the activity of physical modalities such as radiotherapy to kill cancer represents an important approach in improving the safety and anticancer effectiveness. Importantly, the combined treatments have shown promise for the treatment of difficult to treat tumors, such as tumors that are resistant to chemotherapy (multi drug resistant, MDR) or radiotherapy and hypoxic tumors, and for the prevention of tumor metastasis. In this review, the mechanisms of responsive nanomedicines activity enhancement by physical means and vice versa are presented and preclinical and, most importantly, clinical evidence of the safety and efficacy of nanomedicines enhanced by or enhancing by physical modalities in treating solid tumors are critically discussed.

Introduction

Despite recent advances, cancer remains a leading cause of death worldwide [1]. Conventional cancer therapies, such as chemotherapy, radiotherapy and surgery, although effective in treating certain types of cancer at the early stages, they are ineffective in advanced metastasized cancer. In addition, conventional chemotherapy and radiotherapy are associated with significant toxicity and adverse effects [2], [3]. The loading of chemotherapy drugs to especially designed nanocarriers to form nanomedicines provided a chance to overcome the problems associated with conventional chemotherapy, mainly toxicity, and improve cancer treatment [4]. Either through passive or through active targeting, the nanomedicines could accumulate in the tumors, increasing the dose of the drug that reaches the site of its action and reducing the dose of drug that distributes to healthy tissues. Thus, nanomedicines have been designed to increase anticancer efficacy while at the same time decreasing systemic toxicity, a major problem in cancer chemotherapy. However, despite of the intense research efforts of last three decades, resulting to thousands of publications, and the large number of preclinical and clinical studies, few anticancer nanomedicines have made it to the clinic [5], [6]. Poorly designed nanocarriers, difficulties in large scale production and batch-to-batch reproducibility as well as the underestimation of the complexity of the in vivo situation in human cancers are reasons for this low rate of nanomedicines translation from the laboratory to the clinic [5], [6], [7], [8].

In order to increase anticancer efficacy, responsive nanomedicines have been designed which when combined with physical modalities (e.g. radiation, focused ultrasounds, alternating magnetic fields) exhibit themselves a more potent anticancer activity or augment the efficacy of physical modalities to kill cancer cells [9]. The mechanisms of enhancement and the preclinical and clinical evidence for the enhanced anticancer efficacy of the combination of especially designed nanomedicines with physical modalities will be discussed in the present review. The use of inorganic nanoparticles (such as gold Auroshell nanocages [10]) and radiation to kill cancer tumor cells through photothermal ablation (PTA) is not considered as an enhancing interaction between the nanomedicine and the physical modality and is beyond the scope of this review.