Active-Targeted Nanotherapy Strategies for Prostate Cancer

954

Current Cancer Drug Targets, 2011, 11, 954-965

Active-Targeted Nanotherapy Strategies for Prostate Cancer M. Katsogiannou*,1,2, L. Peng3, C.V. Catapano4 and P. Rocchi1,2 1

INSERM, U624 «Stress Cellulaire», Marseille, F-13288, France; 2Aix-Marseille Université, Campus de Luminy, Marseille, F-13000, France; 3Centre Interdisciplinaire de Nanoscience de Marseille, CNRS UPR 3118, Département de Chimie, 163 avenue de Luminy, 13288 Marseille cedex 09, France; 4Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland Abstract: Castration-resistant prostate cancer remains incurable and a major cause of mortality worldwide. The absence of effective therapeutic approaches for advanced prostate cancer has led to an intensive search for novel treatments. Emerging nanomedical approaches have shown promising results, in vitro and in vivo, in improving drug distribution and bioavailability, tumor penetration and in limiting toxicity. Nanoscaled carriers bearing finely controlled size and surface properties such as liposomes, dendrimers and nanoparticles have been developed for successful passive and active tumortargeting. Enhanced pharmacokinetics of nanotherapeutics, through improved target delivery and prolonged tissue halflife provides optimal drug delivery that is tumor-specific. Tumor-targeting may be improved through ligand directed delivery systems binding to tumor-specific surface receptors improving cellular uptake through receptor-mediated endocytosis. Recently published data have provided pre-clinical evidence showing the potential of active-targeted nanotherapeutics in prostate cancer therapy; unfortunately, only a few of these therapies have translated into early phase clinical trials development. Hence, progress of active-targeted nanotherapy improving efficiency of site-specific drug delivery is a critical challenge in future clinical treatment of prostate cancer. Exploring specific prostate cell-surface antigens or receptor overexpression may elaborate promising strategies for future therapeutic design. This review presents an overview of some new strategies for prostate cancer active-targeting nanotherapeutics.

Keywords: Active targeting, castration-resistant prostate cancer, nanotherapeutics, prostate cancer, receptor overexpression, targeted therapy. INTRODUCTION Despite the recent advances in cancer treatments, prostate cancer (PC) continues to be a major health issue; PC remains the second most frequently diagnosed cancer in men worldwide (903 000 new cases, 13.6% of the total) and the fifth most common cancer overall [1, 2]. With an estimated 258 000 deaths worldwide in 2008, PC is the sixth leading cause of cancer-related death in the male population [3]. Early diagnosed localized disease can be successfully cured by radical surgery or radiation; however, the majority of locally advanced and all metastatic diseases are treated with androgen deprivation (AD). AD induces tumor regression and a biochemical response for a period of 14-20 months, without actually prolonging survival [4-7]. Unfortunately, PC gradually progresses to a castration-resistant (CR) state, which currently remains incurable. Until recently, chemotherapy has provided only a slight benefit in CR disease and no therapeutic regimen has emerged so far as standard second-line therapy for this advanced state PC [8]. The paucity of efficacious treatments for PC has led to an urgent need for the development of novel targeted therapies. Much effort has been generated in this direction on the basis of the increased understanding of the molecular mechanisms driving PC development, progression and therapeutic resistance [8-15]. Moreover, given the intrinsic molecular and clinical heterogeneity displayed by CRPC among

*Address correspondence to this author at the INSERM U624 “Stress Cellulaire”, Parc Scientifique et Technologique de Luminy, 163 Rte de Luminy, 13289 Marseille, France; Tel (+33) 491 828 808; Fax: (+33) 491 826 083; E-mail: [email protected] 1568-0096/11 $58.00+.00

patients, optimal novel therapeutic strategies will likely require personalized therapy with a wide range of targeted agents and combination treatments [16-18]. Further, it has been shown that molecular therapeutics developed during the last few years (e.g., proteasome inhibitors, antiangiogenic agents, growth factor receptor inhibitors) may interfere selectively with certain pathways specifically activated in cancer cells as compared to conventional chemotherapeutic agents. Nevertheless, administration of novel therapeutics may be hindered by pharmacokinetic issues, such as unfavorable distribution upon intravenous administration, rapid clearance, limited accessibility to the tumor site and intolerable toxicity. Recently emerging nanomedicine approaches, based on the use of tumor-targeted nanotherapeutics, may represent promising treatment modalities to overcome such limitations [19]. The primary asset of tumor-specific nanotherapeutics is to deliver the active drug molecules selectively to the tumor site and not to the normal tissues, thus assuring enhanced antitumor activity and reduced damage of normal tissues [20]. The specific delivery of a drug to the tumor site can be achieved through either active or passive targeting (Table 1) [19]. Passive targeting is based on the principle of enhanced permeation and retention (EPR) effect and exploits both the locally increased vascular permeability at the tumor site and the reduced lymphatic drainage at the tumor tissue in order to accumulate the nanotherapeutics in the tumor. For active targeting, ligands attached to delivery systems act as homing devices and bind specific surface receptors expressed on the target cells (e.g., cancer cells, cancer associated stromal or endothelial cells) within the tumor ensuring nanotherapeutics uptake through receptor-mediated endocytosis to achieve the targeting purpose [21]. In this review, we briefly present the © 2011 Bentham Science Publishers

Prostate Cancer Active-Targeting

Current Cancer Drug Targets, 2011, Vol. 11, No. 8

current status of targeted nanotherapeutics in cancer and then focus on active-targeting for PC therapy. Table 1.

Different nanotherapeutics targeting modes for drug delivery to the tumor tissue.

Targeting Nanotherapeutics Modes

Strategies adopted by nanotherapeutics

Passive

EPR effect

Active

Ligand/Receptor Binding Antigen/Antibody Binding Aptamers Lectins

APPLIED NANOTECHNOLOGY THERAPY

FOR

CANCER

Nanotechnology is a multidisciplinary area of science and technology involved in the design, synthesis, characterization and application of materials systems whose functional organization is in the nanometer scale [22]. The importance of nanotechnology in drug delivery and targeting lies in the flexibility to modify or adapt the nanomaterials to meet the needs of specific conditions and therapeutic applications [23-25]. Various types of nanoscale delivery systems or nanocarriers (NC) (10~400 nm) such as liposomes, micelles, polymers, dendrimers, nano-tubes, or nanoparticles (Fig. 1), have been developed for passive and active tumor-targeting [26].

Liposome

Dendrimer

Polymeric micelle

Nano‐tube

Polymer

Nanoparticle

955

capable of carrying high payload of drugs, having prolonged circulation time and facilitating selective tumor accumulation via enhanced EPR effect [30]. For example, it has been demonstrated that a 70 nm nanoparticle can carry approximately 2 000 siRNA molecules, more than antibody conjugates [31, 32]. The ideal NC size should be between 10 and 200 nm [33, 34]. The lower size limit is based on measurements of the sieving coefficients for the glomerular capillary wall as the threshold for kidney elimination is 10 nm [35]. The upper size limit is based on the capacity of tumor vasculature to be leaky to macromolecules which can accumulate within tumors (EPR effect). Another important parameter is the NC surface charge. Both highly positive and highly negative charged NC are susceptible to rapid clearance by the reticuloendothelial system (RES) [36]. A frequently used method for reducing NC recognition by the RES is by coating NC surfaces with polyethylene glycol (PEG) thus prolonging NC half-life circulation [30]. PEG is also frequently used as a linker increasing distance between NC and targeting ligands, thereby reducing the steric interference of NC to receptorbinding. Fine control of the size and surface properties of nanotherapeutics can therefore provide prolonged circulation time in the body and increased accumulation in tumor sites, properties which render nanotherapeutics well suited for application in cancer [37, 38]. NC are under investigation as ideal vectors for delivery of a variety of low-molecular weight compounds, both cytotoxic and molecular targeted drugs [39]. A field where the use of NC is particularly relevant is the delivery of new classes of RNA based therapeutics such as small interfering RNA (siRNA), microRNA mimics and antagonists [40, 41]. These RNA based molecules have high therapeutic potential but limitations such as rapid degradation, poor tissue penetration and cell uptake hinder their clinical use. Even though basic and preclinical research in this field has made remarkable advances in tumor-targeting nanotherapeutics [42-46], to date only a limited number of nanoscale delivery systems have been approved for clinical use [19, 47-51]. A major focus in nanomedicine is targeted delivery by exploiting surface expressed receptors of cancer cells. In order to get the recent insights of this domain, we will briefly present below the strategies for active-targeting nanotherapeutics in cancer treatment. Active-Targeted Nanotherapeutics

Fig. (1). Nanoscale delivery carriers for drug targeting.

Nanotherapeutics aim at improving the stability, solubility, absorption and therapeutic efficacy of a drug within the target tissue and allow its controlled and longterm release thanks to their unique properties [20, 22, 27-29]. In fact, conventional anticancer drugs alone have relatively low molecular mass and a hydrophilic-lyphophilic balance allowing uptake across the lipid membranes. Once within the systemic circulation, they are distributed throughout the body attaining all tissues and are rapidly metabolized by the liver and excreted by the kidney. Nanotherapeutics are

Ultimate delivery of nanotherapeutics specifically to cancer cells can be achieved by specific interactions with cell surface through nanocarriers bearing ligands such as small molecules, peptides, proteins or antibodies. The basic principle underlying this approach is that ligands would bind antigens or receptors overexpressed on the target cells relative to normal tissues. Nanotherapeutics can then enter the cell by receptor-mediated internalization [52] which has been shown to be crucial for optimal targeting therapy [53]. There is growing evidence that the uptake and sorting pathways of conjugated and unconjugated nanotherapeutics determine their intracellular retention as well as the therapeutic efficacy of the delivered agent [54, 55]. For example, anti-HER2 immunoliposomes are capable of

956 Current Cancer Drug Targets, 2011, Vol. 11, No. 8

penetrating tumor tissue and are specifically internalized by HER2 overexpressing cancer cells, increasing drug delivery and efficiency [55]. Likewise, transferrin-conjugated nanoparticles have shown enhanced anti-cancer drug effects [54]. It is suggested that receptor-mediated endocytosis could follow an intracellular sorting pathway different from that of unconjugated nanoparticle. In fact, it has been observed that uptake of unconjugated nanoparticles leads to inefficient escape from the endosomal vesicles. An important fraction of nanoparticles undergoes exocytosis whereas the remaining seems to release the encapsulated drug slowly. Moreover, active targeting has shown the potential to suppress multidrug resistance (MDR) via deviation of Pglycoprotein-mediated drug efflux [24, 56]. Among the targeting moieties that can be used for ligandbased cancer therapy, antibodies, antibody fragments [57], aptamers [58, 59], lectins [60], peptides [61], transferrin and vitamins like folic acid have been described [52, 62]. The choice of the appropriate ligand to be used to target cancer cells should be made according to the following important considerations, described below. Receptor Expression, Binding Affinity and Ligand Density For optimum drug delivery, the targeted antigen or receptor should have a high density on the target cells’ surface [21, 52, 63, 64]. For example, it has been demonstrated that 105 ErbB2 receptors per cell were required for an improved therapeutic effect of anti-ErbB2-targeted liposomal doxorubicin in metastatic breast cancer [65]. There is evidence that ligand density of nanotherapeutics should be low but with high avidity and binding specificity to cell surface antigens or receptors [66, 67]. Nonetheless, there is ongoing debate on this issue as ligand binding and uptake efficacy seems to be dependent on the type of NC and the type of tumor targeted. Studies have shown that when binding affinity is high, ligand-based nanotherapeutics have a decreased penetration in solid tumors because of the “binding-site barrier”, resulting from the strong binding of the first targets encountered and failure to diffuse deeper in the tumor [68, 69]. Conversely, high binding affinity is desirable in targets in which most of the cells are readily accessible to the ligand-based nanotherapeutics, such as certain hematological malignancies. Further, it has been shown that in some cases where the ligand is an intact antibody on liposomes and polymers, high densities have been associated with increased clearance of the nanotherapeutics from the circulation, resulting in decreased localization to the target tissue [70]. Non-Antibody versus Antibody Targeting Ligands The choice of the targeting ligand is critical to the success of targeting therapy. Non-antibody moieties including growth factors, cytokines and ligands are often readily available, of low-cost production and easy to handle. Among these ligands, folate has been widely used to target folate receptor often overexpressed in a wide range of tumors [46, 71, 72]. Moreover, transferrin receptors (TfR) are overexpressed by 2 to 10-fold in most of the tumor cells (especially in lung, lymphoma and breast cancer) as compared to normal cells and have also been extensively used for transferrin-mediated targeting [73].

Katsogiannou et al.

Alternatively, antibody-coupled nanotherapeutics are considered as an attractive targeting system due to their specificity and stability towards biological systems [74]. Further, despite drawbacks like immunogenicity, high cost and large ligand size, latest advances in antibody engineering have allowed specific targeting of tumors both in vitro and in vivo [75, 76]. In addition, protein biomarkers overexpressed on the surface of cancer cells, known as tumor-associated antigens, provide valuable insights for antibody-mediated targeting. Recently, the use of antibody fragments as a targeting moiety has been shown to reduce immunogenicity and improve the pharmacokinetic profiles of nanotherapeutics namely the decreased clearance rates and increased circulation half-lives [37, 77, 78]. Internalization of antibody-coupled nanotherapeutics, as previously described, has shown more efficacious delivery than nanotherapeutics conjugated with non-internalizing antibody [21]. Nevertheless, in some cases, non-internalizing antibody may have a benefit in enhancing immunological responses, such as antibody-dependent cellular toxicity [79]. Peptides have also gained growing attention as targeting ligands because of their small size, lower immunogenicity and higher stability as well as ease of manufacture [80]. Moreover, improvement of technologies such as phage display has led to the development of peptides with high affinity and specificity for various cells, tissues and organs [81]. Once the nanotherapeutics are internalized, efficient cytoplasmic drug delivery in specific intracellular organelles can be accomplished by various strategies including: 1) increase of endosome/lysosomes escape triggered by acidic pH, reducing environment or by incorporation of fusogenic peptide [82], 2) nanotherapeutics designed to bypass the endosomal pathway by conjugation of cell-penetrating peptides which bind to scavenger receptors [83], and 3) attachment of a specific trafficking signal on nanotherapeutics for direct drug delivery to a particular organelle, like the nucleus (Fig. 2) [84]. Numerous studies indicate that both non-antibody and antibody targeting ligands do not influence nanotherapeutics localization to the tumor but instead influence nanotherapeutics uptake in cancer cells versus non cancer cells [55, 65, 85, 86]. Nevertheless, for successfully targeted therapy some obstacles remain to be overcome, such as the heterogeneity of antigens on malignant cells, high interstitial pressure within the tumor preventing target binding and penetration especially in solid tumors [75, 87]. STRATEGIES FOR PROSTATE TUMOR ACTIVE TARGETING During the last decades, several factors have interfered with new therapeutic strategies development in CRPC. As this disease often affects elder men, the risk/benefit ratio has often discouraged extreme experimental therapeutic approaches. Further, the intrinsic molecular interpatient heterogeneity of CRPC accounts, in part, for the multiple negative phase III studies. Up to date, the only nanotherapeutics approved for CRPC clinical trials concern SGN-15 (doxorubicin-cBR96) [19] and ASG-5ME (antimicrotubulin conjugate) [88], which are both monoclonal antibody-drug conjugates. SGN-15 delivers doxorubicin to



957

Peptide‐phospholipid‐ based biomimetic nanocarrier

Drug‐loaded ligand‐conjugated nanocarriers

(1)

(2)

Receptor‐mediated internalization

SR‐BI

(3)

Membrane invagination

Drug‐loaded NLS‐conjugated Nanocarriers for nucleus targeting

Early endosome

Acidified endosome

Endosome escape

Endosome escape Drug release

cytoplasm

nucleus DNA

Fig. (2). Schematic representation of strategies for efficient intracellular drug delivery. (1) receptor-mediated uptake with endosome/lysosomes escape triggered by acidic pH, (2) bypass of the endosomal pathway by conjugation of cell-penetrating peptides and drug uptake mediated by scavenger receptor class B type I (SR-BI), and (3) attachment of a specific trafficking signal on nanotherapeutics for direct delivery to a particular organelle (here the nucleus, NLS for nuclear localization signal).

tumor tissues expressing the Lewis-y (Ley) antigen (or CD174) and ASG-5ME targets SLC44A4 (AGS-5), a transmembrane antigen which is highly and specifically overexpressed in different epithelia tumors, delivering antimicrotubulin drug monomethyl auristatin E (MMAE), which is otherwise very toxic for normal cells. The clinical benefit of SGN-15 combined with Docetaxel as compared to Docetaxel alone is evaluated in patients with CRPC in a phase II study, initiated in 2002. A phase I trial of the safety and pharmacokinetics of ASG-5ME monotherapy in patients with advance PC is ongoing since October 2010 [88]. The scarcity of clinical trials for CRPC highlights the evident need for development of active targeting systems specific to prostate tumors which is paramount for improving CRPC targeted therapy [89]. We present below a brief survey on antigens, receptors and proteins that are frequently overexpressed on the surface of PC cells and that could be explored to elaborate promising active-targeting strategies to treat CRPC (Table 2).

internalization rate and undergoes recycling in similar compartments as cell-surface receptors, such as TfR and epidermal growth factor receptor (EGFR). Indeed, it has been demonstrated that PSMA-antibody complex is internalized through clathrin-coated pits and finally ends up in lysosomes [99]. Recently, several studies have demonstrated the anticancer efficacy of PSMA-targeting in vitro and in vivo [100-107] leading to the admission of firstgeneration products in clinical testing. Current phase I-III clinical trials use gene-modified autologous T cells to target PSMA on PC cells and kill these cells; autologous dendritic cells are also used as vaccines to generate T cells that recognize PSMA as an antigen, leading to activated T cellmediated killing of PC cells anywhere in the body [88]. These novel strategies in immunotherapy underline the promise of PSMA targeting as a safe therapy for CRPC treatment.

Prostate Specific Membrane Antigen

The Transferrin receptor (TfR) is a highly conserved cell membrane-associated glycoprotein involved in the iron uptake and cell growth regulation of rapidly dividing cells [108, 109]. TfR is overexpressed 2 to 10-fold in PC cells compared to normal prostate cells [110]. In addition, it is also highly expressed in breast and pancreatic cancer cells [111]. Internalization of transferrin (Tf)-conjugated systems occurs through clathrin-mediated endocytosis and has shown successful delivery in targeted tumors [73, 112-114]. The high levels of expression of TfR in different types of cancer cells (up to 100-fold higher in average than expression in normal cells) [115, 116], its extracellular accessibility and ability to internalize make TfR an attractive target and a promising strategy which is currently being actively explored. The successful TfR-based tumor targeting and

Prostate Specific Membrane Antigen (PSMA) is a type II integral membrane glycoprotein [90] widely used as a marker for PC cells and a well-known imaging biomarker for monitoring therapy. Its elevated expression is associated with the majority of prostate tumors, particularly undifferentiated, metastatic and castration resistant PC [91, 92]. Due to its highly restricted expression in the prostate and overexpression in all prostate tumor stages, PMSA is an extremely attractive target for antibody-based diagnostic and therapeutic interventions in PC [93, 94]. However, it is to note that PSMA is also present in the brain, liver, kidney, salivary glands, biliary tree and the neovasculature in renal cell carcinoma [95-98]. In addition, PSMA has a high

Transferrin Receptor


Table 2.

Katsogiannou et al.

Summary of proposed targets for prostate cancer active-targeting. 1

Target

Role

Tumor Target

Preclinical/Clinical Trials; strategy used

Refs

PSMA

metallopeptidase

prostate

Phase I-III; gene-modified autologous T cells

[a]

TfR

iron uptake, cell growth

prostate, breast, pancreas

Glioblastoma; Tf-CRM107

[b,c]

Melanoma; siRNA RRM2 STEAP

iron homeostasis

prostate, bladder, lung, colon, ovary, Ewing’s sarcoma

none

none

PSGR

negative regulation of cell proliferation

prostate

none

none

GRPR

cell growth

prostate, breast, lung

Preclinical pancreas; bombesinconjugated nanoparticles

[d]

HER-2

cell growth, survival, adhesion, migration, cell differentiation

prostate, breast, pancreas, gastric

Phase II in breast cancer; trastuzumab. Phase I; Her-2 vaccine

[a, e,f]

HSP

cell cytoprotection, survival

prostate, breast, colon, lung, ovary, pancreas

none

none

1

Letters are footnotes referring to the numbered reference in the text and are provided at the bottom of this page. [a] 88; [b] 119; [c] 120; [d] 142; [e] 151; [f] 155.

drug delivery have been widely demonstrated by various approaches such as monoclonal antibodies, Tf-conjugated and TfR antibody-conjugated polymers, liposomes and nanoparticles [109, 117]. Efficacious delivery of aromatase inhibitor 7alpha-APTADD in breast cancer cells has been demonstrated in vitro [118]. In addition, a more effective aromatase inhibition in these cells was shown by the 7alphaAPTADD loaded Tf-conjugated lipid-coated nanoparticles than the unconjugated nanoparticles [118]. Moreover, preclinical and clinical studies have used Tf-conjugated diphtheria toxin (Tf-CRM107) for localized therapy of malignant glioma, taking advantage of the scarcity of TfR in normal brain versus overexpression in glioblastoma cells [119]. Notably, in these trials, no symptomatic systemic toxicity was observed. Recently, the use of Tf-conjugates has also been explored with success for efficient siRNA delivery and subsequent specific gene silencing [M2 subunit of ribonucleotide reductase (RRM2)] by decreasing mRNA and protein levels, in biopsies from melanoma patients [120]. Given the fact that no TfR-based approaches have been reported, to date, for PC future studies in this direction would be extremely interesting. Six-Transmembrane Epithelial Antigen of the Prostate Six-transmembrane epithelial antigen of the prostate (STEAP) is a transmembrane protein expressed predominantly in human prostate tissue. STEAP is highly overexpressed in various cancer types including advanced PC, bladder, lung, colon and ovarian carcinomas, as well as in Ewing's sarcoma [121, 122]. Its elevated levels of expression at the surface of tumor cells along with its restricted expression in normal prostate tissue could make STEAP a promising target for PC treatment. Interestingly, STEAP overexpression has been observed in prostate metastases to lymph node and bone. Moreover, in vitro data have suggested a potential role of STEAP in tumor cell intercellular communication [123]. Recently, STEAPtargeting has gained increasing attention and efficient tumor growth inhibition has been demonstrated in vivo using

monoclonal antibodies binding cell surface STEAP [123]. Further, engineered T-cell targeting STEAP on renal and bladder cancer cells has shown effective antitumor responses in vitro [124]. Finally, STEAP-based vaccination has shown efficient antitumor response in vivo, by inducing a specific CD8 T-cell response [125]. Until now, no STEAP-based targeting strategies have been explored for PC but given the promising data previously reported, STEAP could represent a valuable option to prostate tumor targeting. Prostate Specific G-Protein Coupled Receptor Prostate specific G-protein coupled receptor (PSGR) is a prostate-specific member of the G-protein coupled odorant receptor family which is overexpressed in prostate intraepithelial neoplasia (PIN) and PC [126] suggesting that PSGR may play an important role in PC development and progression [127-129]. Recent published data demonstrated the efficiency of antibody-mediated antitumor treatment, in vivo, by immunization of mice with dendritic cells transduced with genes encoding the human PSGR [130]. Immunized mice produce considerable amounts of antibodies against PSGR expressed on the cancer cells surface [130]. To date, this is the only report on PSGR targeting and results of this study may be useful for further development of PSGR antibody-mediated active targeting against PC. Moreover, a recent study has shown that PSGR is activated by steroid hormones and trigger intracellular signaling cascades involved in cell survival, making PSGR a potentially worthwhile therapeutic target for PC [131]. Gastrin-Releasing Peptide Receptor Gastrin-releasing peptide receptor (GRPR) is a glycosylated, 7-transmembrane G-protein coupled receptor associated with the phospholipase C signaling pathway and whose endogenous ligand is the gastrin-releasing peptide or bombesin. PC and high-grade PIN have aberrantly elevated GRPR expression while normal prostate tissue and benign prostate hyperplasia (BPH) are predominantly GRPR-


negative [132, 133]. GRPR is also overexpressed in breast cancer and small-cell lung carcinoma [134, 135]. Labeled bombesin analogues have been developed and widely applied in clinical and preclinical imaging. Interestingly, growing experimental evidence over the last two decades, have suggested that gastrin-releasing peptide and other bombesin-like peptides that have high affinity for GRPR may act as growth factors in many types of cancer [136]. GRPR antagonists have therefore been developed as anticancer compounds revealing remarkable antitumor activity both in vitro and in vivo [137-139]. Moreover, the recent development and use of bombesin-conjugated nanoparticles has shown efficient targeting to GRPR-positive tumors [140-142]. GRPR elevated expression in various types of human cancer, as well as the demonstration of its role as a tumor growth factor in various tumor models gives support to the use of GRPR targeting in PC therapy. Human Epidermal Growth Factor Receptor 2 Human epidermal growth factor receptor 2 (Her-2) or Her-2/neu is a transmembrane tyrosine kinase receptor and a member of the ErbB (EGFR) family, which forms heterodimers with other ErbB receptors to induce signaling pathways favoring cell growth, survival, adhesion, migration and cell differentiation. Her-2 overexpression induces spontaneous homodimerization and activation of the receptor’s tyrosine kinase moiety even in the absence of ligand [143], promoting tumorigenesis and has an oncogenic role that has been well described in breast, pancreatic and gastric carcinomas [144-147]. Interestingly, the Her-2 pathway is closely linked to the activation of the androgen receptor (AR) pathway and the clinical progression of CRPC [148-150]. Precisely, Her-2 overexpression induces AR transactivation and AR protein stabilization while promoting AR binding to androgen regulated genes [149]. In clinical practice, Her-2 targeting has been widely applied for breast antitumor therapy using the Her-2 monoclonal antibody trastuzumab alone or in combination with conventional chemotherapy in women with Her-2 positive tumors [88, 151]. Recent advances in anticancer immunotherapy have also focused on Her-2 and have shown promising results [152-154]. However, evaluation of Her-2-based therapy for CRPC is still at the clinical trial level [155] and has not yet provided conclusive results [156]. Nevertheless, active targeted gene therapy using adenovirus conjugated with trastuzumab has shown encouraging results in vitro and in vivo in Her-2-overexpressing cancer cells [157]. These data should guide future development of Her-2 active targeting strategies for CRPC. Heat Shock Proteins Heat shock proteins (HSPs) constitute a superfamily of highly conserved proteins whose expression is induced in response to a wide range of physiological and environmental insults. Mammalian HSPs are classified in four major families according to their molecular weight: HSP90, HSP70, HSP60 and small HSPs (15-30 kDa) that include HSP27. Stress-inducible HSPs have elevated levels of expression in tumor cells and are primarily involved in cell cytoprotection and survival by various mechanisms such as


959

proper folding of misfolded proteins to ensure protein stability, preventing protein aggregation and proteasomal degradation as well as enhancement of the anti-apoptotic machinery [158]. Alterations of metabolic and signaling pathways during tumorigenesis require proteins such as stress-inducible HSPs for maintenance of cancer cell survival. Indeed, growing evidence has shown abnormally elevated expression of HSP90, HSP70 (also known as Hsp72), GRP78 (or BiP) and HSP27 correlates with cells chemoresistance in various types of cancer cells including PC cells [159-164]. The inhibition of HSPs is progressively emerging as a novel anticancer strategy. Interestingly, it has been reported that HSP70, HSP90, HSP27 as well as GRP78 are expressed on the cell surface of tumor cells where they have been found to play key roles in the activation of the immune system [165-170]. This membrane-bound expression specific to tumor cells (in contrast to intracellular localization in normal cells) suggests a role of HSP70 and HSP90 as surface markers of tumor cells [171-173] making these stress proteins very promising targets for future PC nanotherapeutics [174]. Currently, few reports describe the use of surface-associated HSP targeting, thus representing a very challenging and original field of research [175-178]. CHALLENGES AND FUTURE DIRECTIONS The complexity of treatment of CRPC originates in the intrinsic clinical heterogeneity among patients demands for multiple therapeutic approaches. Efficacious treatment of CRPC may be achieved only by relying on “personalized medicine”-combining the identification of specific targets within individual tumors followed by the use of combination treatments that may hit multiple targets and pathways. Massive work has been invested in the development of novel targeted therapeutics, aiming at increasing the efficacy of treatment, improving clinical outcomes and reducing sideeffects. Notably, several studies have shown improved efficacy of drug delivery to tumors via targeted nanotherapeutics. However, it is evident that due to the molecular heterogeneity characterizing CRPC, it would be difficult to find a common receptor expressed in all prostate tumors and not at all in normal cells. Therefore, development of PC-targeting strategies may have to rely on the use of personalized diagnostics in combination with nanomedicine. Personalized diagnostics could allow assessing the level of a cell-surface antigen or receptor overexpression in a specific tumor or tumor type as compared to normal cells. This information would be fundamental for constructing customtailored nanotherapeutics for tumor-specific targeting. For example, TfR and GRPR targeting remain very attractive strategies for enhanced drug delivery in solid tumors as a result of their significant overexpression in cancer cells compared to normal cells. Moreover, in vivo and clinical studies have proven the efficient site-specific TfR- and GRPR-oriented drug delivery and deserve further exploration. Further, the crosstalk between the Her-2 and AR signaling pathways indicates that Her-2 is a promising target for prostate cancer therapy especially since the clinical use of Her-2 targeting in other types of solid tumors has shown encouraging results. Likewise, HSP are a new exciting protein target area that has gained growing interest and merits to be further explored in PC active-targeting. What


makes this family of proteins really unique for anticancer drug targeting is their specific membrane expression in cancer cells and the absence of the membrane-bound form in normal cells. Finally, it should be considered, according to recent advances, that multifunctional targeted NC further increase the potential of nanotherapeutics. Indeed, simultaneous targeting of two receptors on the cell surface leads to greater affinity and specificity of NC [179]. Moreover, the use of new experimental approaches and technologies such as proteomics, genomics, deep sequencing, antibody engineering and phage display, will likely expand the repertoire of potential targets and tools to build effective nanotherapeutics to PC targeting. Indeed, a multitude of proteins are constitutively expressed on the membrane of PC cells as well as “normal” cells infiltrating the tumor tissue, which could be exploited as targets for building ligand-targeted NC. Molecular computational studies coupled with molecular and structural biology and synthetic chemistry could greatly accelerate the process from target to ligand identification and targeted NC design and transfer of the findings to preclinical and clinical cancer research. In conclusion, a large amount of published work has demonstrated the remarkable therapeutic potential of targeted nanotherapeutics in PC therapy. However, only very few nanotherapeutics have reached the stage of clinical trials and none of them has been approved by the Food and Drug Administration (FDA) at the moment. Therefore, there is still a long way to go to achieve the final goal of selective and effective PC targeting with nanotherapeutics. ACKNOWLEDGEMENTS This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC), the international ERA-Net EURONANOMED European Research project DENANORNA, the CNRS and INSERM. We are particularly grateful to Alan So for his English proof of the manuscript.

Katsogiannou et al.

PSMA

= prostate specific membrane antigen

RES

= reticuloendothelial system

STEAP = Six-transmembrane epithelial antigen of the prostate Tf

= transferrin

TfR

= transferrin receptor

REFERENCES [1] [2] [3]

[4] [5]

[6]

[7] [8]

[9]

[10]

[11]

The authors declare no conflict of interest. [12]

ABBREVIATIONS [13]

AD

= androgen deprivation

AR

= androgen receptor

CRPC

= castration-resistant prostate cancer

EGFR

= epidermal growth factor receptor

EPR

= enhanced permeability and retention

GRPR

= gastrin-releasing peptide receptor

Her-2

= Human epidermal growth factor receptor 2

HSPs

= heat shock proteins

NC

= nanocarriers

PC

= prostate cancer

PEG

= polyethylene glycol

PIN

= prostate intraepithelial neoplasia

PSGR

= prostate specific G-protein coupled receptor

[14]

[15]

[16]

[17]

[18]

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Accepted: August 01, 2011