Seite - 35 - in Cancer Nanotheranostics - What Have We Learnd So Far?

REVIEWARTICLE published:25August2014 doi: 10.3389/fchem.2014.00069 Nanomedicines forcancer therapy: state-of-the-artand limitations topre-clinical studies thathinder future developments CharleneM.Dawidczyk1,2,3†, LuisaM.Russell1,2,3† andPeterC.Searson1,2,3* 1 Institute forNanobiotechnology, JohnsHopkinsUniversity,Baltimore,MD,USA 2 JohnsHopkinsCenterofCancerNanotechnologyExcellence, JohnsHopkinsUniversity,Baltimore,MD,USA 3DepartmentofMaterialsScienceandEngineering, JohnsHopkinsUniversity,Baltimore,MD,USA Editedby: JoãoConde,Massachusetts InstituteofTechnology,USA Reviewedby: Yanli Zhao,NanyangTechnological University,Singapore FernandoNovio, InstitutCataláde Nanociència iNanotecnologia,Spain *Correspondence: PeterC.Searson, JohnsHopkins University, 100CroftHall, 3400 NorthCharlesStreet,Baltimore,MD 21218,USA e-mail: searson@jhu.edu †Theseauthorshavecontributed equally to thiswork. The ability to efficiently deliver a drug or gene to a tumor site is dependent on awide range of factors including circulation time, interactionswith themononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics, tumor accumulation, and biodistribution. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokineticsofFDA-approvednanomedicines.Nextwereviewnanomedicinesunder development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics.We showhow the lack of uniformity in preclinical trials prevents systematic comparisonandhence limitsadvances in thefield. Keywords:drugdeliverysystems,nanoparticles, targetedtherapy,pharmacokinetics, tumoraccumulation INTRODUCTION Drug therapy often involves the use of small molecules such as alkylating agents (e.g., busulfan), anti-metabolites (e.g., gemcitabine), anti-microtubule agents (e.g., paclitaxel, vin- cristine), topoisomerase inhibitors (e.g., topotecan), and cyto- toxic inhibitors(e.g.,doxorubicin).Thesecytotoxicmoleculeskill highly proliferative cancer cells, but also other proliferative cells inbonemarrow, thegastrointestinal (GI) tract, andhair follicles, leading to common side effects such as compromised immune system, inflammation and ulceration of the GI tract, and hair loss. Nanotechnology provides the possibility of creating deliv- ery systemswhere thedesignconstraints aredecoupled, allowing newapproachesforreducingtheunwantedsideeffectsofsystemic delivery, increasing tumoraccumulation,and improvingefficacy. Thedevelopment of safe and efficient delivery systems is also important foradvances inhumangenetherapy(Packetal., 2005; Jones et al., 2013).Adelivery systemmust transport a genewith highefficiency to target cells,withminimal toxicity and immune response.Themainchallengesforgenedeliveryareprotectingthe geneticmaterial fromdegradation incirculation,avoidingdegra- dationby enzymes in endosomes in the target cell, and escaping from endosomes to reach the nucleus or target compartment (MintzerandSimanek,2009;Zhangetal., 2012). Keyproperties fordrugandgenedeliverysystemsarebiocom- patibility, stability in circulation, and increasing the fraction of thedoseaccumulatinginthetumor.Drugtoxicitycanbereduced by encapsulating the free drug (e.g., liposomes) or by locally activating a pro-drug. Stability in circulation can be improved by developing strategies tominimize protein binding and evade the immune system. The efficiency of accumulation at a tumor site can be improved by active targeting of the delivery system or by increasing extravasation by the enhanced permeation and retention(EPR)effect. The FDA-approved nanomedicines in clinical use have demonstratedthepotential for increasingbioavailability,enhanc- ing drug solubility, active targeting, and high drug loading (Dawidczyk et al., 2014). However, there remain many chal- lenges in exploiting advances in nanotechnology and bioengi- neering to develop systems that will have significant impact on patient survival rates. The development of delivery systems remains largely empirical and the lack of standardization of pre-clinical studies is a barrier to establishing design rules for nanomedicines.Whilestudiesofcomplexsystemswithcombined reporting/sensing functions along with drug or gene delivery mayultimately improvediagnosis and treatment, therearemany fundamental issuesthatneedtobeaddressedtoestablishtherela- tionshipbetweenphysico-chemicalproperties,pharmacokinetics, biodistribution,andsurvival rates. Tumor uptake is modulated by the EPR effect (Jain and Stylianopoulos,2010;Fangetal.,2011;Torchilin,2011)andhence increasing the circulation time generally increases tumor accu- mulation. A common approach for increasing circulation time www.frontiersin.org August2014 |Volume2 |Article69 | 35