Seite - 68 - in Cancer Nanotheranostics - What Have We Learnd So Far?

REVIEWARTICLE published:26November2014 doi: 10.3389/fchem.2014.00105 Cancer immunotherapy:nanodeliveryapproaches for immunecell targetingandtracking JoãoConniot1, JoanaM.Silva1, JoanaG.Fernandes1, LianaC.Silva1,RogérioGaspar1, SteveBrocchini2,HelenaF.Florindo1*andTeresaS.Barata2* 1 Faculdade deFarmácia, Institutode Investigação do Medicamento (iMed.ULisboa), Universidade deLisboa, Lisboa, Portugal 2 EPSRC Centre for Innovative Manufacturing inEmergent Macromolecular Therapies, UCLSchool ofPharmacy, London, UK Editedby: João Conde, Massachusetts Institute of Technology, USA Reviewedby: Min-HoKim, Kent StateUniversity, USA JinjunShi, HavardMedicalSchool, USA *Correspondence: Helena F. Florindo, Faculdade de Farmácia, Institutode Investigação do Medicamento (iMed.ULisboa), Universidade de Lisboa, Avenida Professor GamaPinto, Edificio E, 1649-003 Lisboa, Portugal e-mail: hflorindo@ff.ul.pt; Teresa S.Barata,EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies, UCLSchool of Pharmacy, 29-39 BrunswickSquare, London WC1N1AX, UK e-mail: t.barata@ucl.ac.uk Cancer is one of themost common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and havemodest efficacy at best. Increased understanding of tumorbiologyand immunologyhasallowedthedevelopmentofspecific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. Thedevelopment of targetednanodelivery systems inwhich therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodeliverystrategiespresently investigatedforcancer immunotherapy,cancertargeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniquesandascancer treatmentoptions. Keywords:nanosystems,cancer, targeteddelivery, cell tracking, immunotherapy INTRODUCTION Cancer is a heterogeneous disease that results fromamulti-step process, characterized by uncontrolled tumor cell proliferation, invasionandmetastasis.Tumorcellshavealsotheability toevade cell death (Fernald andKurokawa, 2013) and to escape immune systemsurveillance(Zitvogel etal., 2006). Despite improvements in diagnosis and therapies, cancer is still the most fatal disease worldwide with 11.5 million deaths being predicted in 2030. Strategies for cancer treatment include chemotherapy, radiotherapy, immunotherapy and surgery (Wu et al., 2014). Many of these approaches are unspecific with severe side effects (Peer et al., 2007). More effective and spe- cific alternative treatments continue to beneeded. In fact, it has been described that those single treatment regimens have lim- ited chances to eliminate cancer cells in a permanent manner due to its heterogeneous nature (Hanahan andWeinberg, 2000; Helmy et al., 2013).The success of cancer therapy is dependent on the development of additional strategies to overcome severe sideeffects,drugresistanceandcircumvent tumorevasionmech- anisms(Girardietal.,2001;Dunnetal.,2002;Koebeletal.,2007; Chenetal., 2014b;Xuetal., 2014). Although the general body immune response is often not robust enough to escape to cancer cell tactics (Palucka and Banchereau,2012),ourunderstandingoftumorimmunologyhas been evolving. It is accepted that tumor cells, parts of tumor cells or even specific substances isolated from tumor cells can be recognized by the immune system, which can then respond to these malignant cells. The possibility for immune system- based responses has brought new insights into the development ofnovel cancer immunotherapytreatments. Immunotherapyhas beguntomeet itspromiseforcancertreatment.Monoclonalanti- bodies (mAbs) to specific targets that are engaged with tumor mechanismsareusedclinically, includingalemtuzumab(lympho- cytic leukemia)andtrastuzumab(breastcancer)(Kirkwoodetal., 2012). Additionally, cancer vaccination has shown encouraging preclinical results and has also been extensively explored, being www.frontiersin.org November2014 |Volume2 |Article105 | 68