Available online at www.jbr-pub.org Open Access at PubMed Central The Journal of Biomedical Research, 2017 31(3): 177–188 Review Article Recent advances in arsenic trioxide encapsulated nanoparticles as drug delivery agents to solid cancers Anam Akhtar, Scarlet Xiaoyan Wang, Lucy Ghali, Celia Bell, Xuesong Wen✉ Department of Natural Sciences, School of Science and Technology, Middlesex University, London NW4 4BT, UK. Abstract Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago, its anti-cancer properties for various malignancies have been under intense investigation. However, the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers. This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site. Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success. This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells. Different approaches that have been employed to increase arsenic's efficacy, specificity and bioavailability to solid cancer cells were evaluated and compared. The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed. Keywords: arsenic trioxide, solid cancer, nanotechnology, drug delivery, liposome Introduction Despite being the mainstay of materia medica since the past 2,400 years, ATO faced an escalating decline in Arsenic is a naturally occurring metalloid found as a its use as a therapeutic agent in the twentieth century [1] trace element in the earth's crust . Instead of being due to an increasing awareness of its toxicity[4]. Its present in its elemental forms; it exists as highly toxic resurgence transpired in the late twentieth century when arsenates of metals like calcium, sodium and potassium a group of Chinese physicians recognized it as the main or as oxides and sulphides. Among its three inorganic anti-leukemic ingredient in traditional Chinese medi- forms, arsenic trioxide (ATO) manifests as white arsenic cine and decided to evaluate its therapeutic potency in and is industrially produced as a by-product while treating patients with acute promyelocytic leukemia roasting arsenic containing ores and purifying the (APL), a subtype of acute myeloid leukemia[5]. Clinical [2] smoke . The transformation of ATO from being the trials using ATO to treat APL patients as a single agent "king of poisons" to a "broad spectrum anti-cancer or in combination with conventional chemotherapy drug" is one of the most exciting stories in clinical yielded highly encouraging results[5]. ATO was conse- [3] oncology . quently approved by the Food and Drug Administration ✉ Corresponding author: Dr. Xuesong Wen, Department of Natural The authors reported no conflict of interests. Sciences, School of Science and Technology, Middlesex University, This is an open access article under the Creative Commons The Burroughs, London NW4 4BT, UK. Email: [email protected]. Attribution (CC BY 4.0) license, which permits others to distribute, Received 03 May 2016, Revised 29 July 2016, Accepted 22 August remix, adapt and build upon this work, for commercial use, provided 2016, Epub 20 September 2016 the original work is properly cited. CLC number: R730.51, Document code: A © 2017 by the Journal of Biomedical Research. All rights reserved doi:10.7555/JBR.31.20160059 178 Akhtar A et al. J Biomed Res, 2017, 31(3) (FDA) as frontline therapy for APL in 2000[6]. Similar remarkable results were observed from the clinical trial clinical successes were subsequently translated for other with patients of relapsed and refractory APL after very hematological malignancies, for instance, acute myeloid low doses of intravenous ATO were administered[15].It leukemia, chronic myelogenous leukemia, Hodgkins was a major breakthrough in treating APL relapsed disease and multiple myeloma although not signifi- patients as the mortality rate with routine treatment i.e. cantly for solid tumors[7]. Rapid clearance of ATO and all-trans retinoic acid (ATRA) and anthracycline based its products from the blood by the reticuloendothelial chemotherapy was 20-30% and bone marrow trans- system (RES) limits the therapeutic dose reaching the plantation was the only option[14]. The findings, which tumor site. Increasing ATO dosage could not be a were later successfully replicated in United States, led to solution as it leads to systemic toxicities such as long- the approval of ATO (TrisenoxTM) by FDA as a frontline term memory damage, liver failure, cardiac failure and drug for relapsed and refractory APL in 2000[6]. peripheral neuropathy[8]. Although some successes of ATO therapy have also Since then, several attempts have henceforth been been observed in other hematological cancers, the carried out to utilize arsenic's significant anti-cancer therapeutic dosage administered is relatively low, and properties for treating solid tumors by increasing its hence the commonly reported side effects are low grade bioavailability and specificity for carcinoma cells while and reversible after ceasing ATO therapy. However, the reducing its administered dosage[9]. These include same kind of clinical success has not been translated for sensitizing the cells prior to ATO treatment, employing solid cancers in humans despite ongoing clinical trials to it in combination therapy with other conventional investigate arsenic's efficacy on a variety of solid chemotherapeutic agents to explore their synergistic cancers[15] (http://www.clinicaltrials.gov). This is pri- actions or employing nanotechnology to increase marily due to the rapid clearance of ATO and its bioavailability of ATO while reducing its systemic metabolites from the blood by RES. Compromised toxicity[10–13]. therapeutic dose of ATO reaches the tumor site, and, This review aims to summarize the advances that therefore, an increased dosage is required which might, have been made till date regarding therapeutic applica- in turn, lead to systemic toxicities and long-term tions of ATO drug with an emphasis on the ongoing memory damage and hormonal imbalance[8,16]. There- involvement of nanotechnology in the current ATO fore, there is a crucial need for analyzing various therapy in treating various malignancies. possible approaches of increasing the bioavailability of ATO without raising its dosage. Arsenic trioxide (ATO) history: rise, decline and resurgence Therapeutic strategies in using ATO alone or in combination ATO presents a rich history in medicinal applications dating back to more than 2400 years[14]. It was used in Anti-cancer activity of free ATO has been tested on a traditional Chinese medicine to treat syphilis, psoriasis variety of solid tumor cell lines with positive experi- and rheumatism[2]. Other applications were also mental results but limited clinical success. Zhao and reported with ATO being effective as an anti-spasmodic, coworkers[17] administered direct intra-tumoral injec- anti-pyretic, anti-periodic, caustic and sedative[14]. tions of ATO to human esophageal carcinoma xeno- However, the awareness of its toxicity began to rise grafts in mice and investigated ATO distribution and its when people realized that long-term chronic exposure to efficacy within the tumor. Tumour growth inhibition of ATO could cause hyperpigmentation of the skin, 13.56%, 62.37% and 76.92% was observed with cancers of the lung, kidney, bladder and prostate along administration of 1, 5 and 10 mg of ATO respectively with rare cases of neuropathy, encephalopathy, leuco- without appreciable systemic side effects. These results penia and diabetes[6]. Consequently, by the turn of the provided encouraging evidence for potential clinical twentieth century, its medicinal use started to decline utility of direct intra-tumoral injections of ATO as one due to its acquired reputation of being a toxic substance form of treatment for solid cancers. However, there is an and a carcinogen. escalating need to investigate other approaches where ATO resurged as a therapeutic compound in 1990s ATO can be delivered selectively to its site of action and following an initial study at Harbin Medical University to penetrate inside the tumor without being toxic to where its anti-leukemic properties were identified in surrounding healthy tissue. Some of the approaches treating APL[14]. A group of physicians at Shanghai that have been tested or proposed are outlined below Second Medical University continued the study and (Fig. 1). Encapsulated arsenic trioxide for solid cancers 179 Fig. 1 Key therapeutic strategies employed in the attempt to increase the efficacy of ATO as a drug in treating solid tumors without escalating its dosage[9,11–12,18–39]. ATO: arsenic trioxide; ROS: reactive oxygen species. Glutathione depleting agents levels. Ascorbic acid further auto-oxidises to release H O which might enhance pro-apoptotic effects of One of the key targets of ATO is glutathione (GSH), a 2 2 arsenic. L-Buthioninesulphoximine (BSO) is another tripeptide molecule which protects the cells from drug which inhibits a critical step in glutathione oxidative stress. It is involved in a number of bio- synthesis by inhibiting the rate limiting