Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy Rachael Mooney a, ⁎, Yiming Weng b , Elizabeth Garcia a , Sukhada Bhojane b , Leslie Smith-Powell d , Seung U. Kim e , Alexander J. Annala a , Karen S. Aboody a,c,1 , Jacob M. Berlin b,1, ⁎⁎ a Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA b Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA c Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA d Department of Analytical Pharmacology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA e Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada abstract article info Article history: Received 17 January 2014 Accepted 11 June 2014 Available online xxxx Keywords: Neural stem cells Nanoparticle distribution Nanoparticle retention Tumor tropism Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previous- ly shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor cov- erage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid deliv- ery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releas- ing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to im- prove the efficacy of many chemotherapy drugs after intratumoral administration. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Direct injection of chemotherapeutics into tumors is an obvious ap- proach to reduce systemic toxicities while increasing the active drug concentration at the tumor site. Historically, clinical administration of intratumoral (IT) chemotherapy has been retarded by concerns that it would have minimal impact on distant metastases and that the primary tumor would be more easily removed using surgical resection. Howev- er, recent studies have shown that IT therapy can be used to generate an immune response against distant metastases, and that IT therapy prior to surgery can greatly reduce surgical morbidity by shrinking, or in many cases, completely killing the primary tumor [1]. This research has sharply increased interest in IT therapy such that it is now used in a number of clinical scenarios: (1) neoadjuvant treatments that reduce tumor burden prior to radiation and/or surgery; (2) adjuvant treat- ments that treat positive margin following radiation and/or surgery; and (3) standalone therapies when radiation and surgery are not possi- ble [2]. Ideally, IT administration would result in even drug distribution throughout the tumor and the drug would be retained long enough to act primarily at the tumor site. Unfortunately, drug distribution in the tumor is often non-uniform and quickly cleared [3,4]. This is primarily due to poor drug penetration through the stiff tumor extracellular ma- trix, and poor drug retention in the presence of outward fluid- pressure gradients [5,6]. Drug retention within the tumor can be im- proved by encapsulating drugs in particles or hydrogels [7–10]. Unfor- tunately, loading drugs into macromolecules only exacerbates their poor distribution as these larger constructs have very limited tumor penetration capabilities even when enhanced with pressure-driven flow [11]. Thus, a delivery system is needed that can enhance both re- tention and distribution of drugs following IT administration. We have previously shown that HB1.F3 neural stem cells (NSCs) are tumor tropic and selectively migrate to a number of tumor types, Journal of Controlled Release xxx (2014) xxx–xxx ⁎ Correspondence to: R. Mooney, Department of Neurosciences and Neurosurgery, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel.: +1 626 256 4673. ⁎⁎ Correspondence to: J. M. Berlin, Division of Molecular Medicine, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel.: +1 626 256 4673. E-mail addresses: rmooney@coh.org (R. Mooney), jberlin@coh.org (J.M. Berlin). 1 Principal investigators K.S. Aboody and J.M. Berlin contributed equally to this manuscript. COREL-07249; No of Pages 8 http://dx.doi.org/10.1016/j.jconrel.2014.06.015 0168-3659/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel Please cite this article as: R. Mooney, et al., Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy, J. Con- trol. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.06.015