Nanoparticle-based polychemotherapy: optimizing drug synergy for efficacious cancer treatment.

Abstract

Specificity as the major limitation of combination chemotherapy Efficacious patient outcomes in cancer increasingly rely on chemotherapeutic regimens comprising multiple drugs. The criteria for polychemotherapy, as outlined by Seidman and coworkers, simply state that component drugs should possess single-agent activity, work synergistically with one another, and have non-overlapping safety profiles [1]. Unfortunately, these criteria are rarely met. While survival benefits have been observed, clinically approved combination regimens fail to bring about significant improvements in patient outcomes, and more importantly, result in substantial morbidity. As an example, anthracyclines and taxanes are administered concomitantly to metastatic breast cancer patients. However, no clear mechanism of synergy warrants their combination, and both elicit significant deleterious effects, hindering their use at appropriate doses required to bring about efficacy. Combination chemotherapy has indeed evolved substantially in recent years, driven in large part by an enhanced understanding of the molecular machinery responsible for tumor growth and spread. Consequently, several aberrant pathways and overexpressed moieties have become attractive targets for therapy. As an example, the discovery that the human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–30% of breast cancers resulted in the development of the antibody trastuzumab. Since its approval, trastuzumab has been used in combination with taxanes and platinum-based drugs, and is currently being explored in more than 70 different combination clinical trials. Recent efforts are also aimed at targeting dysregulated signaling cascades, such as the PI3K/Akt/mTOR pathway. Several rapamycin analogues exist that inhibit mTOR and are currently being explored clinically in combination with taxanes. Likewise, similar approaches are underway for agents that potentially target IGF, FGF, MAPK and MET pathways [2]. Combination chemotherapy regimens are thus becoming more personalized and rationally designed, pairing novel or repositioned agents that act specifically on molecular targets with traditional chemotherapeutics, all with the hope of maximizing antitumor efficacy while minimizing patient side effects. The incorporation of agents that are capable of discriminating between healthy and malignant cells indeed represents a giant leap forward in improving patient responses. However, this only partially addresses the major problem facing combination chemotherapy, which is the same age-old limitation facing single-agent therapy – delivery. The series of biological barriers that impede adequate delivery of drugs to tumor sites, including enzymatic degradation and nonspecific uptake in healthy organs, are now well known, and unfortunately remain a formidable challenge for present-day drug formulations. Importantly, this non-specificity severely limits the bioavailability of drugs at Nanoparticle-based polychemotherapy: optimizing drug synergy for efficacious cancer treatment