Editorial Novel Oncology Therapeutics: Targeted Drug...

Hindawi Publishing CorporationJournal of Drug DeliveryVolume 2013, Article ID 918304, 5 pageshttp://dx.doi.org/10.1155/2013/918304

EditorialNovel Oncology Therapeutics: Targeted DrugDelivery for Cancer

Andreas G. Tzakos,1,2 Evangelos Briasoulis,2 Theresia Thalhammer,3

Walter Jäger,4 and Vasso Apostolopoulos5,6

1 Department of Chemistry, University of Ioannina, GR45110 Ioannina, Greece2 Cancer Biobank Center, University of Ioannina, GR45110 Ioannina, Greece3 Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Immunology and Infectiology,Medical University of Vienna, Vienna, Austria

4Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria5 VA Consulting Services, Melbourne, VIC 3030, Australia6Victoria University, College of Health and Biomedicine, Melbourne, VIC 3021, Australia

Correspondence should be addressed to Andreas G. Tzakos; [email protected]

Received 5 September 2013; Accepted 5 September 2013

Copyright © 2013 Andreas G. Tzakos et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Despite the progress in techniques for cancer prevention,detection, and treatment, as well as for increasing the publicawareness in recent years, this disease is projected to becomethe leading cause of death worldwide. Advancements inomics, analytical procedures, and high throughput screeningin the last five years have led to the realization that humandiseases and especially cancer are more complex than wereoriginally conceived. Cancer is not a static entity that canbe easily monitored and manipulated. It is characterizedby a dynamic and time-dependent network of constantlyaltered molecular and cellular interactions between playersin different pathways. This network is not invariable andrigid but is constantly reshaped and altered conformingto the pliable signaling processes/responses implicated. Itscomplexity is apparent by the fact that the disease state is nota disruption of a single node or specific nodes in the networkorganism but is organism-patient dependent, thus requiringpersonalized perspective approaches.

Numerous challenges hamper effective cancer treatmentand development of effective drugs such as ineffective ther-apeutic drug concentration reaching the tumor site, life-threatening side-effects caused by nonspecific tissue distri-bution of anticancer agents, and acquired resistance of the

cancer cell upon chemotherapy that triggers cross-resistanceto a wide range of different drugs.

Such multifactorial states require the development ofvery delicate approaches in the course of the drug discoverypipeline. The scientific roots of the drug development phi-losophy should be shifted from the traditional concept of the“magic bullet” drug (i.e., scalped for a single drug target) tothe formulation of a navigated vehicle which could spatio-temporally deliver the drug in the correct location and theappropriate time.Thus, the term targeted drug delivery shouldgive its place to navigated drug delivery since it is not onlythe cytotoxic drug that targets a specific cellular location butrather a vehicle that navigates the course of the loaded drug tothe appropriate site of action. Such drug loaded and navigatedvehicles in order to enhance the selective uptake of thecytotoxic agent by the tumor cells and spare the normal cells,should consist of a multidimensional architecture (Figures1 and 2). The major components of these vehicles are thetransporting vehicle (i.e., lipid), the cytotoxic agent thatis loaded, the “programmable” navigating/targeting agent(i.e., receptor specific ligand) that enables the appropriatedelivery routes to avoid toxicity on healthy proliferatingcells as also ineffective concentration of the cytotoxic agent

2 Journal of Drug Delivery

Cytotoxic agent

Transportingvehicle (i.e., lipid)

Stealth/biocompatibility polymer(i.e., PEG)

Navigating/targeting moiety(i.e., receptor specific ligand)

Figure 1: Structural architecture and mechanical analogue of a navigated drug delivery nanoparticle.

?

?

?

Drug delivery vehicle equipped with

“GPS” navigator

“Blind” drugTransportation routes

GPSHealthy tissue

Tumour

Healthy tissue

Figure 2: Navigated drug delivery: the drug delivery vehicle is equipped with a “programmable navigation system” that allows thetransportation of the “blind” cytotoxic agent in the correct cellular location. In the absence of the drug delivery vehicle that is tagged withnavigating delivery routes, toxicity is triggered on healthy proliferating cells against the anticancer agent, and ineffective therapeutic drugconcentration reaches the tumor site.

to the tumor site (Figure 2), and the “stealth” nanocarriers(biocompatibility polymers, i.e., PEG) that enhance the shortplasma half-life of the drug-loaded transporting vehicle.

In line with the challenges raised by the complexity ofcancer, the aim of the present thematic issue is to providean accumulation of innovative molecularly targeted cancertherapies and entrepreneurial methods of drug deliveryin cancer (Table 1). It contains 12 papers embracing mostaspects of cancer related to the exploration of active targetednanoparticles for cancer treatment and diagnosis, includingthe exploitation of novel cancer drug targets, vaccine designagainst cancer, innovative methods for drug delivery-basedon focused ultrasound or convection enhanced delivery, and

mathematical modeling as an indispensable tool to analyzethe transport processes and predict the outcome of anticancertreatment.

A constant developmental effort is being conductedfor innovative nanoparticles to meet unmet needs in thetransportation of imaging and therapeutic agents for cancerdiagnosis and therapy. This happens since the nanoscale ofthese particles allows sculpting of diversity in their capa-bilities thus, enabling them to respond to a diverse arrayof functional requirements. Therefore, nanoparticles havebeen considered as appropriate vehicles to provide an idealplatform for personalized approaches to cancer diagnosis andtherapy in cancer disease management. A. D. Miller presents

Journal of Drug Delivery 3

Table 1: Some of the delivery systems appeared in this issue.

Vehicle Vehicle description Navigation device Target location Cancer type

Bionanocapsules

A bionanocapsule (BNC) is ahollow nanoparticle consisting of anapproximately 100 nm diameterliposome with about 110 moleculesof hepatitis B virus (HBV) surfaceantigen L protein embedded as atransmembrane protein.

Chlorotoxin MMP-2 protein Brain tumor

Enzyme-based cancerimaging agents

Dual aromatase-steroid sulfataseinhibitor (DASSI) radiotracers

11C-labelled inhibitorsof steroid sulfatase(sulfamate derivatives)

Enzymes of the“sulfatase pathway”,particularly steroidsulfatase

Breast, endometrial,ovarian, andcolorectal cancer

Cytotoxic drugscoupled toOATP-substrates orOATP-directedantibodies

Substrates of membrane-locatedOATP isoforms, selectivelyexpressed in cancer cells, forexample, microcystins as substratesfor OATP1B3

Selective ligands forOATP for example,microcystinsor OATP-directedantibodies in cancercells

Organic aniontransportingpolypeptides (OATPs)

Gastrointestinal tract,breast, prostate, lung,brain, bladder, kidney,liver, testis

Lipid-basednanoparticles

Genuine particles (approx 100 nmin dimension) assembled fromvarieties of lipid and other chemicalcomponents that act collectively toovercome biological barriers(biobarriers)

Bona fide biologicalreceptor specificligands

PEGylated Span 80vesicles PEGylatedSpan 80 vesicles withimmobilized ESA

Span 80 is a heterogeneous mixtureof sorbitan mono-, di-, tri-, andtetra-esters

Lectin-sugar bindingprotein (Eucheumaserra agglutinin)

Sugar chains on thetumor cell-surface Osteosarcoma

Doxorubicin(DOX)-loadedliposomes

Liposomes composed of DSPG,DSPC, cholesterol, andDSPE-PEG-2000

A triple-helicalsequence derived fromtype IVcollagen

CD44/chondroitinsulfate proteoglycan

CD44-overexpressingtumor cells

MannanOxidized or reduced mannan, apoly-mannose, conjugated to cancerantigen

Mannan Mannose receptor Adenocarcinoma

a rigorous and descriptive overview on the status of lipid-based nanoparticles (LNPs) in cancer diagnosis and therapy.Special focus is given on LNPs that conform to the ABCDnanoparticle structural paradigm (A: active pharmaceuticalingredient, B: lipids, C: a stealth/biocompatibility polymerlayer (like PEG), D: targeting layer-receptor specific ligand)and to triggered, multimodal imaging theranostic drug-nanoparticles for cancer therapy.

Clinical attrition rates are a critical issue in drug develop-ment. In oncology, fourfold higher rates of attrition have beendetermined in respect of other indications. This clearly pin-points the unmet necessity to steer for novel and traditionallyunexplored drug targets to be employed in the drug discoveryprocess towards the development of novel anticancer drugs.In this light, V. Buxhofer-Ausch et al. describe the capacityof members of the organic anion transporter family (OATP)to serve as tumor biomarkers and effective cancer drugtargets. The importance of these drug targets is due totheir implication on the uptake of clinically important drugsand hormones, thereby affecting drug disposition and cell

penetration. An OATP-targeted therapy holds promises tocombat cancer efficiently and with lesser side effects due tothe tissue specific expression of different OATPmembers andspecifically their differential expression in various cancer andnormal tissues.

Enzymes of the sulfatase pathway could offer anotherappealing cancer drug target. S. Lena et al. provide a compre-hensive review about the expression and function of enzymesof the sulfatase pathway, particularly of steroid sulfatase(STS), in breast, endometrial, ovarian, and colorectal cancer.Furthermore, it highlighted the applicability of STS inhibitorsto function as enzyme-based cancer imaging agents appliedin the biomedical imaging technique positron emissiontomography for the diagnosis and therapy of estrogen-sensitive cancers.

Since cancer is considered not only as a genetic but alsoas an epigenetic disease and tumorigenesis involves multiplegenetic and epigenetic alterations that contribute to the trans-formation of normal cells towards a malignant phenotype,epigenetics should also be the focus of discovering novel

4 Journal of Drug Delivery

cancer drug targets. E. Hatzimichael and T. Crook reviewedimportant advances in the field of cancer epigenetics andspecifically provide an overview of the clinical use of epi-genetics as cancer biomarkers and current progress in theutilization of epigenetic drugs in solid and blood cancers.

Navigated delivery of cytotoxic agents to special sites ororgans is a challenging issue that needs to be addressed inorder to surpass systematic toxicity.These challenges becomeeven more exigent for drug delivery in brain tumors whereintrinsic difficulties are met due to the hurdles faced tocross the brain-tumor and blood-brain barriers. To establisha targeting vehicle for glioblastoma cells, T. Kasai et al.exploited the capability of chlorotoxin to selectively bind tomatrix metalloproteinase-2 and other proteins on glioma cellsurfaces once it was fused to human IgG-Fcs and displayedon the surface of bionanocapsules. This chlorotoxin loadedbionanocapsule showed specific affinity to the surface ofglioma cells and internalized into the cytoplasmic spacesuggesting that is a promising drug delivery system fortargeting glioblastoma.

In order to establish a target-based agent to be specificallydelivered to osteosarcomas, K. Hayashi et al. focused on alectin (Eucheuma serra agglutinin) both as a tumor-targetingagent and as an antitumor agent. Lectins are carbohydratebinding proteins that are highly specific for sugar moietieson the surface of tumor cells. The authors formulated a drugdelivery system containing PEGylated Span 80 vesicles whichimmobilized the specific lectin. They noted that the specificsystem was not only selectively targeting osteosarcoma cellsbut was also cytotoxic to the targeted cells emphasizing thedual role adopted by lectins both as navigating and cytotoxicagents.

To achieve an effective approach for enhanced uptakeof anticancer drug-loaded vehicles by tumor cells, M. W.Ndinguri et al. explored cell surface proteoglycan CD44targeting as a way to selectively deliver therapeutic agentsencapsulated inside colloidal delivery systems. CD44 hasbeen recognized as a contributor to tumor chemoresistanceand as a cancer cell and cancer stem cell biomarker dueto its overexpression in cancer compared to normal cells(haematopoietic, epithelial, and neuronal cells). To targetCD44, the authors used a triple-helical peptide sequencederived from type IV collagen that was incorporated indoxorubicin-loaded liposomes (composed of DSPG, DSPC,cholesterol, and DSPE-PEG-2000). The CD44-targeted lipo-somes were found effective in reducing tumor size, highlight-ing their potential to be used for selective chemotherapeutictreatment of CD44 overexpressing tumor cells.

The immune system has evolved to protect the bodyagainst microorganism invasion and thereby prevent dis-eases. Thus, cancer vaccines could boost the immune systemto enable it to combat cancer more effectively. In vaccinedevelopment, a major aim is to induce strong, specific Tcell responses. This is achieved by targeting antigens to cellsurface molecules on dendritic cells (DCs) that efficientlystimulate T cell responses. The paper by V. Apostolopouloset al. focuses on the most attractive cell surface receptorsexpressed on DCs to be used as targets for antigen deliveryfor cancer immunotherapy. The DC cell surface receptors

(receptor kinases, Toll-like receptors, andC-type lectin recep-tors) which induce cellular responses and show promise astargets for vaccine design against cancer are highlighted.Along these lines, K.-C. Sheng et al. investigated the effect ofIFN-gamma onDC functionalmaturation andDCmeditatedhelper T cell activation, in the presence and absence of Toll-like receptor (TLR) ligation. The authors demonstrated anadjuvant effect of IFN-gamma on DC maturation and Tcell stimulation and proposed a novel use of IFN-gammatogether with Toll-like receptor agonists to enhance antigen-specific T cell responses, for applications in the developmentof enhanced vaccines and drug targets, against diseases,including cancer.

An alternative to the systemic drug delivery is theconvection-enhanced delivery (CED) on the basis of whichagents are delivered directly into the tumor and the surround-ing infiltrative edges with continuous, positive-pressure infu-sion, thus allowing direct access to the tumor bed, achievinghigh local concentrations of the drug with minimal systemicabsorption. The paper by J. Yun et al. focuses on the authorspreclinical and clinical experience with CED in glioblastomaand highlight the challenges and potency of this methodol-ogy. Special emphasis is given onto the translational goals ofthis work.

M. Thanou and W. Gedroyc provided a comprehensiveoverview on the utilization of MRI-guided focused ultra-sound (MRgFUS) as a new method of drug delivery. Thismethodology combines a high intensity focused ultrasoundbeam that can be used as an external stimulus to activatedrug delivery in tissues and Magnetic Resonance Imagingsystem (MRI) which visualizes patient anatomy and controlsthe treatment by continuously monitoring the tissue effect.The advantages of being noninvasive as well as controlledand focus could establish this methodology as valuable toolin clinic to increase drug targeting and tissue specific drugdelivery.

The transport of anticancer drugs and their consequenceon tumor cells implicates an array of physical and bio-chemical processes. Since multiple steps are involved inthe drug-transport, drug-release, and drug-uptake pipelines,mathematical models have become an indispensible tool toanalyze the transport processes and predict the outcomeof anticancer treatment. Mathematical modeling of cancerprovides a tool to assist our realization on the interaction anddrug-mediated perturbation of such complex processes, thus,fruitfully contributing to the optimization and refinement ofdrug delivery. W. Zhan and X. Y. Xu present the developmentof an improved mathematical model that was applied to anidealized geometry consisting of tumor and normal tissues.They predicted the efficacies of direct intravenous adminis-tration and thermosensitive liposome-mediated delivery andillustrated that thermo-sensitive liposome-mediated deliveryprovides a lower drug concentration in normal tissues thandirect infusion of non-encapsulated drug as also a signifi-cantly higher peak intracellular concentration. These com-putational results furnish a projection on the effectiveness oftwo different treatments, within a mathematical framework,and set the basis to develop and corroborate optimizedtreatments with reduced risk of associated side effects as also

Journal of Drug Delivery 5

effective tumor cell killing in a short time period of treat-ment.

Due to the complexity of the disease, efficient cancer ther-apy can emerge only upon interscience collaboration. Thisspecial issue aims to accumulate current knowledge onmolecularly targeted cancer therapies and innovative meth-ods of drug delivery in cancer. We believe that this accumu-lative knowledge will assist to accelerate progress developingmore precise navigated drug delivery in cancer based oninnovative tools.

Andreas G. TzakosEvangelos Briasoulis

Theresia ThalhammerWalter Jager

Vasso Apostolopoulos

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