title: Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy.
abstract: 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 previously 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 coverage 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 delivery 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 releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration.
authors: Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. Electronic address: rmooney@coh.org.
authors: Rachael
authors: R
authors: Mooney
authors: Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Yiming
authors: Y
authors: Weng
authors: Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Elizabeth
authors: E
authors: Garcia
authors: Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Sukhada
authors: S
authors: Bhojane
authors: Department of Analytical Pharmacology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Leslie
authors: L
authors: Smith-Powell
authors: Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada.
authors: Seung U
authors: SU
authors: Kim
authors: Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Alexander J
authors: AJ
authors: Annala
authors: Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA; Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Karen S
authors: KS
authors: Aboody
authors: Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. Electronic address: jberlin@coh.org.
authors: Jacob M
authors: JM
authors: Berlin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015552:Injections, Intralesional; D007700:Kinetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050997:Nanomedicine; D053758:Nanoparticles; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry; D012995:Solubility; D013499:Surface Properties; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D011108:Polymers; D011109:Polymethacrylic Acids; D043823:Taxoids; C511861:poly(2-(diisopropylamino)ethyl methacrylate); D000077143:Docetaxel; D011092:Polyethylene Glycols
keywords: Nanoparticle distribution; Nanoparticle retention; Neural stem cells; Tumor tropism