Nanomedicines for Pediatric Cancers - ACS Publications

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Nanomedicines for Pediatric Cancers Carlos Rodríguez-Nogales, Yolanda González-Fernández, Azucena Aldaz, Patrick Couvreur, and Maria J Blanco-Prieto ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b03684 • Publication Date (Web): 02 Aug 2018 Downloaded from http://pubs.acs.org on August 2, 2018

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Nanomedicines for Pediatric Cancers Carlos Rodríguez-Nogalesa,b, Yolanda González-Fernándeza, Azucena Aldazc, Patrick Couvreurd*, María J. Blanco-Prietoa,b* a

Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona 31008, Spain b

Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona 31008, Spain

c

Department of Pharmacy, Clínica Universidad de Navarra, Pamplona 31008, Spain

d

Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Sud, Université ParisSaclay, Châtenay-Malabry Cedex 92296, France

*Correspondence to: M.J. Blanco-Prieto, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, 31080 Pamplona, Spain. Tel: +34 948425679, Fax: 34 948425740. E-mail: [email protected] – Prof. Patrick Couvreur, Université Paris-Sud, Institut Galien, UMR CNRS 8612 – France. Te: +33 1 46835396, Fax: 34 948425740. E-mail: [email protected]

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ABSTRACT Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents, and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs, makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.

KEYWORDS Pediatric cancer, nanoparticles, liposomes, drug delivery systems, chemotherapy, leukemia, glioma, neuroblastoma, osteosarcoma.


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Over the last twenty years, impressive progress has been made in the treatment of children with cancer due to advances in surgery, radiotherapy, chemotherapy and early diagnosis. Nevertheless, after domestic accidents, cancer still remains the second leading cause of death in children and adolescents1,2 and their perspectives are still poor when compared to adult cancer victims.3 The search for novel therapeutic strategies to treat cancer is, therefore, particularly important in the case of pediatric cancers. Independently of sex and age, the most representative cancer types in children and adolescents are mainly hematological cancers, while central nervous system (CNS) tumors are the second main priority for pediatric oncologists in terms of diagnosis and incidence. Following brain tumors, non-CNS embryonal tumors are the third most frequently diagnosed cancer, while bone tumors and soft tissue sarcomas conclude the list of the most prevalent tumors in children4–6 (Figure 1). As the field of nanotechnology research continues to progress towards ameliorating cancer therapeutics, this review summarizes our current understanding of its impact in the pediatric population and provides an outline of previous research in in vitro and in vivo pediatric models as well as taking account of the clinical perspectives. Chemotherapeutic toxicity in pediatric cancer Within the overall therapeutic options to manage pediatric cancer, chemotherapy emerges as the last opportunity for children with poor prognosis. Although the antitumor efficacy of common cytostatic drugs such as anthracyclines or alkylating agents is well-proven, their clinical use normally entails a risk of toxicity which is augmented in the pediatric population. Unfortunately, the intense doses of cytostatic drugs administered to these children to attain a long-term cure are still unbalanced and lead to poor tolerance as well as late toxicities. In this sense, the occurrence of side effects such as cardiotoxicity, cutaneous reactions, necrosis or lymphoid and myeloid suppression, sometimes leads to the abandonment of first-line treatments.7,8 In addition, chemotherapy exposure may cause subsequent related neoplasms, cardiovascular complications or future cognitive dysfunctions.9 On the other hand, despite considerable progress in our understanding of pharmacokinetics in pediatric patients, some erroneous methods for drug dose selection are still used in these patients. The main reason is the lack of studies about drug disposition in pediatric patients, due to ethical or economic causes or feasibility issues. On the few occasions when clinical pharmacokinetics is used in clinical practice, the limitations of dosing algorithms to predict drug exposition are self-evident. Extrapolation from adult dosing is a common method for dose selection in pediatric patients. This can be based on age, as in Fried’s method (valid up to 2 years of age) or Young’s method (for children from 2 to 12 years of age), on weight (as in Clark’s method), or on an allometric method (which uses the ratio children’s weight divided by adult’s weight, all raised to the power of ¾).10 However, all these algorithms only consider the children’s development and growth, without considering maturation in different children’s developmental stages. Their main drawback is the lack of proportionality between weight, age or body surface area and enzymatic development and maturation (ontogeny).11 In addition, around 70% of drugs used in children have not been appropriately studied in pediatric patients, which makes it necessary to use other methods that permit the extrapolation of pharmacokinetic and pharmacodynamic data obtained in adults to pediatric patients. 3 ACS Paragon Plus Environment

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All these facts support the need for physiology-based pharmacokinetic models (PBPK), as well as the design of nanoformulations for better control of drug delivery and biodistribution in children.

Physiology-based pharmacokinetic models (PBPK) PBPK integrate data from different sources, including ontogenesis of metabolizing and transporters routes, to predict the ADME process (absorption, distribution, metabolism, and elimination) in pediatric patients. PBPK give a mechanistic quantitative framework which, when relevant physiological properties of the target population are available, allows extrapolation of the information from another patient population to that population. Information incorporated in these models includes drug parameters and system parameters for a specific population.12 PBPK models have been developed for analgesic drugs, metilxantins, anesthetic drugs and anticancer drugs, such as docetaxel.13 They have demonstrated utility in finding solutions for pharmacotherapy optimization in pediatric patients. Precisely this should be crucial in the oncology field, given the chemosensitivity and curability of most prevalent tumors in the pediatric population, such as acute lymphoblastic leukemia (ALL), in which common errors in cytostatic drug dosage have fatal consequences. In this context, when comparing chemotherapy doses expressed as a body surface product between children and adults, the exposure to cytotoxic drugs tends to be higher in the pediatric population. Marsoni et al. observed that 16 out of 17 antineoplastic agents analyzed displayed a dose quotient between children and adults of 1.5 mg/m2.14 This behavior has been erroneously interpreted in routine clinical practice as showing better tolerance to chemotherapy side effects at younger ages, leading to negative consequences. Therefore, it is crucial to bear in mind the different pharmacokinetic profiles of distinct pediatric subgroups to avoid under or over-dosing.

Nanomedicine for pediatric cancers Drug delivery systems (DDS) have been widely studied with the aim of enhancing and preserving the clinical potential of drugs by improving their protection, absorption, penetration and distribution. This issue is crucial in the case of cytostatic drugs and has resulted in the development of several formulations based on polymer, metallic or lipid nanoparticles (NP), liposomes, micelles, nanofibers, and many other nanomaterials loaded with chemotherapeutics (Figure 1). These nanosized suspensions are able to increase the therapeutic index of loaded drugs and improve tumor targeting, thus modifying drug pharmacokinetics and tissue distribution.15–17 Drug targeting can be activated by surface ligand engineering18 or by the design of stimuli-responsive nanodevices.19,20 And even if limited to head and neck or Kaposi tumors, nanometric particles may also display some inherent passive accumulation in tumor tissue, which is known as the enhanced permeability and retention (EPR) effect, an effect that is not as well understood as was initially thought.21,22


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Figure 1. Nanomedicines as therapeutic strategies for the most relevant pediatric tumors. Nanoparticles (NPs), liposomes, dendrimers or micelles, among other drug delivery systems, may overcome common limitations derived from chemotherapy in central nervous system (CNS) cancers, blood cancers, non-CNS embryonal tumors and musculoskeletal tumors. The encapsulation of cytotoxic drugs in NPs confers sustained drug release, better tissue accumulation, bioavailability enhancement and improvement of the therapeutic index.

It is important to bear in mind that children are not just ‘small adults’ and that their unique physiology is an extra incentive for the design of nanomedicines to improve therapeutics in the pediatric population. Incorrect dosing regimens extrapolated from adults worsen the chemotherapeutic toxicity that is, in fact, reported to be more severe in children than in adults per se. And nanotechnology has demonstrated potential applicability in the field to ameliorate the therapeutic index of cytostatic agents by decreasing their toxicity. The use of anticancer nanomedicines in the pediatric population may therefore represent one step forward in avoiding problems associated with drug dose selection, as well as, the chemotherapeutic associated toxicity. However, the success of these nanotherapies resides in taking into consideration some key aspects such as the safety of the nanocarriers or the tumor microenvironment.23 Moreover, the arrival of novel therapies is hampered by common translational barriers in the pediatric research. These aspects are summarized in Figure 2.


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Figure 2. Schematic illustration of the proposed approaches to improve therapeutics in pediatric cancer management.

BLOOD CANCERS Hematologic malignancies account for about 40% of all pediatric cancers. ALL and acute myeloid leukemia (AML) occasion an abnormal blood cell increase that leads to an outcome that is fatal without treatment. On the other hand, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are a malignant proliferation of lymphocytes that generally arises from the lymph nodes of the immune system.

Leukemias The severe treatment-related toxicity of both chemotherapy and hematopoietic stem cell transplantation means that surveillance of cardiac toxicity, infectious diseases and other fatal outcomes is needed.24,25 Besides this, leukemia relapses are still incurable in most cases and pediatric oncologists have called for nanomedicines to be made available, in the hope that these will provide new opportunities. In this view, dexamethasone, a glucocorticoid frequently used in chemotherapy to induce apoptosis of B and T lymphocytes, was encapsulated in poly(ethylene glycol) (PEG) and poly(εcaprolactone) amphiphilic block copolymer nanoassemblies in order to improve the drug therapeutic index.26 The NPs developed were biocompatible, non-toxic, and increased the efficacy of dexamethasone in mice by increasing the drug’s half-life, allowing the authors to make arguments for the long-term use of encapsulated dexamethasone in ALL children. With respect to the therapeutic management of pediatric AML, methotrexate-gold NPs have been shown to improve the therapeutic index of this antimetabolite. NPs proved to be non-toxic in normal hematopoietic cells and displayed an augmented selective drug delivery of methotrexate against THP-1 AML cell line, achieving a pronounced 6 ACS Paragon Plus Environment

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anticancer potency. Their in vivo efficacy and safety was later evaluated in a murine xenotransplant model of primary human AML. Methotrexate-gold NPs ameliorated leukemic cell suppression without added toxicity in comparison to the control group and the free methotrexate.27 However, such nanoformulation would certainly deserve more detailed pre-clinical toxicological investigations to elucidate the elimination pathway after repeated administration, as well as, the absence of cell and tissue accumulation. Bearing in mind that the relevance of pharmacogenetics in methotrexate response in children is still controversial28 and that no full consensus in protocols about the management of methotrexate toxicities has been achieved,29 the encapsulation of methotrexate may represent a reliable advantage in the pediatric population. The use of targeted therapies against leukemic cells is still a major challenge for researchers, since cytotoxic agents must discern between malignant and normal circulating blood cells. In this sense, Basha et al. underlined the necessity of preserving the viability of healthy cells and postulated the design of reconstituted high-density lipoprotein (HDL) NPs to effectively target HDL/SR-B1 receptors, overexpressed in malignant lymphocytes.30 On the other hand, Matthay et al. investigated antibodyliposomes in pediatric leukemia cell lines 3 decades ago and reported the possible clinical benefits derived from their enhanced intracellular penetration.31 For instance, anti-CD33 antibodies targeting ligands against AML cells were coupled to lipid NPs,32 triggering a high NP uptake by CD33 positive cells. Moreover, the clinical potential of anti-CD33 for improving immune targeting of AML cells has been confirmed and finally, gemtuzumab ozogamicin (Mylotarg) has recently been approved by the FDA for children of 2 years of age and older, with relapsed or refractory CD33-positive AML.33 The above-mentioned approaches merely represent proof of the vast literature on NPs (e.g. refs. 34,35) but it is convenient to consider that in many cases, the distinction between adult and childhood leukemia research can be ambiguous. The majority of these publications have reported the nanomedicines’ potential to improve the therapeutic efficacy of antitumor drugs and to minimize toxicities in pediatric leukemia. However, it is difficult to elucidate if the proposed formulations are clinically relevant or provide a specific benefit for affected children as compared to common therapeutic extrapolation from adults. In the best-case scenario, the animal models used are based on rodents xenografted with pediatric leukemic cells that cannot be examined for late toxicities. In addition, physicians’ main concern is still the achievement of a global consensus in the chemotherapy dose adjustment in children. In fact, the progress made in the last decade has increased substantially the survival rates, so that the novel therapeutic strategies have to demonstrate strong evidence in order to attract pediatric oncologists’ attention and lead to modification of the established protocols. Importantly, some recent articles have reported the challenges faced when registering childhood cancers, both in terms of their incidence, and as regards our understanding of the reasons for survival.6,36 In any case, unlike adults, children are still at a disadvantage since more than the 50% of patients treated with an anthracycline will develop cardiac abnormalities during long-term follow-up, while 10% of children exposed to a cumulative anthracycline dose greater than 300 mg/m2 will develop congestive heart failure.37,38 In addition, a recent study reported the adult neurocognitive performance in childhood leukemia survivors in relation to intrathecal methotrexate.39 Although this kind of CNS-directed prophylactic chemotherapy prevents relapses and increases 7 ACS Paragon Plus Environment

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survival, the study revealed that childhood leukemia survivors displayed significant late neurocognitive sequelae. At the moment, the most realistic opportunities for these children reside specifically in the consolidation of best-in-class nanocarriers loaded with anthracyclines, methotrexate or taxanes among others. Indeed, when encapsulated into NPs or liposomes, those drugs have been shown to decrease both cardiac and neurological toxicity because they do not accumulate in those tissues.37

Hodgkin and non-Hodgkin lymphoma Nanotechnology has been also requested to challenge refractory and aggressive lymphomas, and the narrow relationship with ALL has supported still further the development of nanomedicines to combat overall lymphoid malignancies. The use of anthracyclines such as DOX in lymphomas is becoming compulsory given its high antitumor efficacy; however, its prolonged use entails several risks. In order to improve anthracycline safety, researchers have attempted to load this molecule into nanocarriers since the encapsulation of DOX was shown to dramatically decrease cardiac toxicity.40 Although survival rates have increased significantly following the implementation of the French protocol LMB 96, HL and NHL survivors after treatments are at risk of having secondary leukemias, breast cancer, myelosuppression, late cardiac complications and endocrine sequelae.41–43 The principal challenge for pediatric oncologists is nowadays to lower the aggressiveness of both radiotherapy and chemotherapy in order to avoid the above-mentioned late complications. Nanomedicines could help to maintain therapeutic concentrations of cytotoxic drugs below the toxic threshold for long periods, ameliorating the future outlook of survivors. Within this context, the encapsulation of anthracyclines could be an optimal therapeutic strategy for administering long-term therapies without compromising children´s health. The surface singularity of malignant lymphoid tissue has prompted researchers to design targeted nanomedicines for increasing drug selectivity. This could be optimal in diffuse tumors such as lymphomas, especially when common chemotherapy is unable to achieve a complete remission. Rituximab integrates the first generation of antibodies approved for B-cell antigen CD20, a well-known target moiety for NHL cells. Thus, Wu et al. conjugated the fab fragment of rituximab to DOX loaded liposomes.44 In vivo biodistribution assays demonstrated a high liposome accumulation in the tumor tissue, suggesting this formulation as a potential candidate for NHL children’s care. Similar results were obtained by conjugation of anti-CD20 antibodies to DOX-coated polymer active carbon NPs,45 DOX-mesoporous silica NPs46 and albumin bound-paclitaxel NPs.47 The application of targeted nanomedicines as non-viral nanovectors for small interfering RNA (siRNA) delivery was also explored for B cell malignancies. The poor stability in biological fluids and the low intracellular penetration of siRNAs hamper their therapeutic use, making the use of nanocarriers necessary.48 In this sense, Weinstein et al. prepared CD-38 targeted lipid NPs loaded with siRNAs against cyclin D1, a tumorigenic factor overexpressed in Mantle cell lymphoma cells. Coating NPs with anti-CD38 monoclonal antibodies permitted specific NP uptake by these cells, inducing efficacious gene silencing. Moreover, the administration of this nanoformulation demonstrated prolonged survival of tumor-bearing mice with no observed toxicity.49 8 ACS Paragon Plus Environment

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Unlike leukemia, lymphomas are solid tumors and there is a need to deliver drugs selectively toward malignant lymphoid tissues. Further preclinical studies are expected to enable these nanotechnology-based approaches to proceed to clinical trials.

Clinical nanomedicines in blood cancers Within the nanomedicines approved for clinical trials in cancer, mainly liposomes and polymeric micelles, only a few have been approved for clinical research in the pediatric population, and among these, the majority belongs to hematological malignancies rather than to other pediatric cancers.50 The reason probably arises from the high prevalence of these diseases in children. The different nanoformulations ongoing in clinical trials corresponding to pediatric leukemia and lymphoma are shown in Table 1. Liposomes were used as drug carriers in most of the studies because they are probably one of the safest nanoformulations reported to date and they can encapsulate distinct drugs in their phospholipid bilayers or aqueous cores. In brief, although data related to children are still limited concerning the clinical studies using vincristine sulfate liposomal formulation (Marqibo), the first reports are encouraging. The good tolerability makes Marqibo a solid candidate to replace the use of bulk vincristine in the future.51,52 Pediatric oncologists argue that the use of these liposomes will allow for dose intensification with the aim to ameliorate survival outcomes with reduced or comparable neurotoxicity in comparison to free vincristine. Liposomal daunorubicin is another nanomedicine being investigated. Phase I-II studies have generated satisfying results concerning the pharmacokinetic profile of encapsulated daunorubicin in comparison with its free counterpart.53–55 Although the comparison with investigations in adults showed no substantial differences in pharmacokinetics with respect to children, a longer follow up in children would be necessary to determine the ultimate role of these liposomes in avoiding cardiovascular complications in the future. In that sense, it has been reported that the myocardium is characterized by tight capillary junctions, which would prevent liposomal anthracyclines from crossing the capillaries into the myocardial tissue,37 thus suggesting that there may be lower cardiotoxicity in the future. Taking this setting into consideration, the International Berlin-FrankfurtMünster Study Group performed a randomized phase III study with liposomal daunorubicin added to FLAG (fludarabine + high-dose cytarabine + G-CSF). Although overall survival and toxicity were similar compared to FLAG alone, the combination with daunorubicin liposomes improved early treatment response in pediatric relapsed AML.56 Intrathecal liposomal cytarabine (ara-C) (DepoCyt) administration has been also approved in children with leukemia relapsing to CNS.57,58 The slow continuous release of ara-C results in a lower peak of ara-C levels and longer duration of exposure compared with standard ara-C.59 No permanent adverse neurological sequelae have been observed in combination with dexamethasone and intrathecal prednisolone succinate.60 However, larger prospective trials are still needed before liposomal ara-C can be used as first-line prevention of relapse. As seen in table 1, some clinical trials were terminated or the recruitment was suspended. The reasons for assays interruption are sometimes unavailable and may result from unexpected toxicological events, economic/logistic reasons or absence of treatment improvement.


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Table 1 Liposomal-based therapies undergoing clinical investigation for leukemia and lymphomas Formulation and NP size

Drug (trade name)

Age (years)

Type of cancer

1-21 Relapsed ALL All Non-PEGylated liposomes; 100 nm

Vincristine sulfate (Marqibo)

0-21 0-21

Relapsed leukemia and lymphoma

All

Non-PEGylated multivesicular liposomal matrix; 3-30 µm

Intrathecal ara-C (Depocyte)

Current status (update year) Phase I 2017 (recruiting) Phase I/II 2014 (completed) Phase II 2016 (recruiting) Phase I 2014 (terminated) Phase II 2012 (completed) Phase III 2016 (not recruiting)

Code

NCT02879643

NCT00144963 NCT02518750 NCT00933985 NCT00038207

0-21

High-risk HL

NCT01026220

3-31

Lymphomatous (NHL) meningitis

Phase II 2016 (recruiting)

NCT02393157

1-18

High-risk ALL (leukemic meningitis)

Phase III 2012 (recruitment suspended)

NCT00991744

1-21

Lymphomatous and leukemic meningitis

Phase I 2010 (unknown)

NCT00003073

Non-PEGylated ara-CRecurrent Phase I/II 2017 liposomes; Daunorubicin 1-21 NCT02642965 leukemia (not recruiting) 100 nm (CPX-351) Non-PEGylated Daunorubicin Phase III 2016 liposomes; 0- 17 AML NCT02724163 (Daunoxome) (recruiting) 45 nm PEGylated DOX Phase I/II liposomes; hydrochloride NCT00006029 All Relapsed HL 2016 90 nm (Doxil) (completed) Non-PEGylated DOX >18 Phase II 2011 liposomes; NCT01009970 NHL (Myocet) months (unknown) 100-200 nm Non-PEGylated Phase I 2011 liposomes; Annamycin 1-21 Leukemia NCT00430443 (terminated) 30 nm ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ara-C, cytarabine; DOX, doxorubicin; HL, Hogdkin lymphoma; NHL, non-Hodgkin lymphoma; NP, nanoparticle; PEG, poly(ethylene glycol).


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CANCERS OF THE CENTRAL NERVOUS SYSTEM After leukemias, brain tumors are the second most common type of childhood cancer. Brain tumor cells in children are mainly neurons and glial cells that give rise to astrocytomas/gliomas, medulloblastomas and ependymomas.

Nanotechnology and blood-brain-barrier The blood-brain barrier (BBB) is located in brain capillaries (Figure 3) and present fenestrated or continuous endothelial cells which are strongly linked by tight junctions and surrounded by astrocytes, pericytes and the continuous basement membrane.61,62 The BBB limits the transit of many molecules and protects the CNS from circulating agents such as xenobiotics or hydrophilic cytostatic drugs.63,64 Additionally, it results in a dramatic restriction of the antitumor drug arsenal which exacerbates the prognosis of affected children. Some pediatric CNS neoplasms have, however, been reported to exhibit BBB breakdown and therefore increased drugs permeability of the BBB.65 Nevertheless, standard cytostatic agents are unable to reach the tumor tissue and effect cures in these patients. This therapeutic failure could be due to the spread of malignant invasive tumor cells beyond the areas of BBB disruption.66,67 In that sense, chemotherapy could be delivered only in the necrotic tumor center with the disrupted BBB and not in the periphery of the growing tumor. Notably, data collected about the penetrability of drugs into the CNS have shown that the BBB permeability between adults and children is similar, at least after 4 months. Interestingly, there are strategies focused on temporarily disturbing the BBB to deliver more drug inside the brain.68,69 In view of the lack of awareness of chemotherapeutic failure in pediatric brain tumors, surface-functionalized nanomedicines with the possible ability to cross the BBB are becoming a valuable option. Over the past few years, nanotechnology has made significant progress in carrying chemotherapeutic drugs inside the CNS.70 The main materials investigated for nanomedicines in high-grade gliomas are gold, lipids and proteins conjugated with endothelial cell-penetrating molecules.71 Besides chemo-electric charge or particle size, another crucial aspect that determines the BBB passage is the particle surface.72 For instance, our group, among others, has reported that non-ionic surfactants such as Tween80 are decisive to achieve better brain uptake.73 Moreover, the existence of nutrient transporters in BBB cells such as insulin receptor, LAT-1, GLUT-1, transferrin receptor and lipoprotein receptors has prompted researchers to consider them as portals to carry drugs inside the brain stem (Figure 3). For targeting high-grade gliomas, transferrin, Angiopep-2, Apolipoprotein E-derived peptide and many other ligands have been conjugated to NPs, obtaining interesting outcomes.74–76 However, these experiments have been conducted with the aim of treating adult high-grade gliomas, and presumably pediatric brain tumors might not meet similar criteria77–79 so that these approaches should be further assessed in suitable pediatric brain tumor models.


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In general, the amount of NPs able to translocate intact BBB remains still limited to less than 1%/gr tissue of the injected dose,80 except when the tumor growth result in a sufficient breakdown of the BBB. In this case, anticancer compounds delivered to the brain may reach higher drug concentrations since nanoencapsulation can avoid drug degradation and favor the extravasation through EPR effect, which may constitute a significant improvement as compared to the drug free treatment.

Figure 3. Nanomedicines for crossing the blood-brain barrier (BBB) in pediatric brain tumors. The illustration shows transferrin (green) decorated nanoparticles (NP) (blue) loaded with cytotoxic drugs against a high-grade pediatric glioma. (1) NP ligands are recognized by nutrient receptors overexpressed in the endothelium of brain capillaries, triggering receptor mediated endocytosis of NPs. (2) NPs extravasate into central nervous system (CNS) by eluding endothelial cells, pericytes and astrocytes being further taken-up by malignant cells. (3) Internalized NPs release their cytotoxic drug content leading to tumor cell death.

Gliomas Compared to non-malignant astrocytomas, high-grade astrocytomas such as glioblastoma multiforme, diffuse intrinsic pontine glioma or anaplastic astrocytoma have a markedly poorer prognosis.79 Unfortunately, many anticancer drugs have shown only moderate success in clinical trials, including those which presented a suitable response in adult glioma, such as temozolomide.78 Indeed, Mueller and Chang remarked that pediatric high-grade gliomas are biologically different from their adult counterpart.81 The benefit of treating the pediatric population specifically with NPs results from the impossibility of accomplishing high-risk invasive procedures or giving high doses of cytostatic drugs and radiation. The infant population is, indeed, more vulnerable than adults to this kind of procedure, which may lead to premature deaths or late toxicities. Nanotechnology research for gliomas includes a wide range of studies regarding drug/gene delivery and brain-targeting, as well as, tumor imaging applications,82–85 but the literature lacks pre-clinical experiments concerning the use of nanomedicines 12 ACS Paragon Plus Environment

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specifically for pediatric glioma treatment. In such a paper by Li et al., carbon dots conjugated with transferrin were used for DOX delivery and pediatric glioma application.86 In vitro studies performed in SJGBM2 cells, a human-derived pediatric glioblastoma multiforme cell line, revealed marked cell uptake enhancement when DOX was encapsulated into the functionalized carbon dots. Blank transferrin carbon dots are supposed to be non-toxic in vitro, but the safety of this material for brain delivery in children is highly questionable since the fate of carbon dots in the brain parenchyma remains unanswered. Despite being higher in incidence, the available pediatric astrocytoma/glioma cell lines is very limited, probably because some of these tumors have been difficult to culture.87 This has probably hindered their investigation and may explain the absence of nanotechnology studies in comparison with standard pediatric brain cancers such as medulloblastoma.

Medulloblastoma After astrocytomas, this malignant embryonal tumor of the cerebellum is one of the most common brain tumors in children under 10 years.88 With the aim of improving therapeutics in this kind of tumor, some versatile nanomedicine platforms have been proposed. A recent proof is the design of glutathion tumor responsive albumin-NPs containing cisplatin.89 Cross-linked glutathion in NPs permitted, via redox, the cellspecific modulation of cisplatin delivery in DAOY cells, a standard pediatric medulloblastoma cell line,87 increasing the cytotoxic action of cisplatin in vitro. However, in vivo the question still remains if it is profitable to merely prolong the halflife of a cytostatic drug/gene if the drug is only distributed in the peripheral compartments and not in the CNS. At least, permeability studies on in vitro BBB models, which are of particular concern in pediatric CNS tumors, should be mandatory to further elucidate the potential of these approaches. The clinical investigation of liposomes has been extensively carried out in the last few decades, which has led regulatory agencies to approve DOX-liposomes (Doxil), the first nano-drug which has reached the market. Subsequently, liposomal DDS have also been proposed for multiple purposes, including brain drug delivery. In this regard, PEGylated liposomal DOX has been tested in combination with radiofrequency ablation therapy.90 Although tumor prognosis in old mice was found to be dissimilar to young mice, these studies demonstrated that radiofrequency ablation therapy combined with DOX loaded liposomes could overcome tumor progression regardless of tumor environment or age. Furthermore, due to encouraging results in clinical trials gathered mainly in hematologic tumors,57,58 ara-C-liposomes have also entered clinical trials in children with relapsed medulloblastoma.91 Clinicians have reported a prolonged progression-free survival after their intrathecal administration. Recently, albumin-bound-rapamycin NPs for use in combination with temozolomide and irinotecan in the pediatric and adolescent population have entered Phase I clinical trials (NCT02975882) for recurrent CNS neoplasms and other solid tumors. Bearing in mind that the main limitation that leads to therapeutic failure is the incapacity of cytostatic drugs to effectively reach the brain tumor tissue, we need to


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leverage the active targeting of NPs in order to carry antitumor drugs across the BBB and achieve a marked antitumor effect.

NON-CENTRAL NERVOUS SYSTEM EMBRYONAL TUMORS Although there are also embryonal tumors that arise from the brain or the musculoskeletal tissue, the following malignancies are grouped in this section because of their close similarity. These cancers are frequently diagnosed in children under 5 years and originate from the developing embryonal cells that constitute miscellaneous tissues and organs such as the peripheral nervous system (neuroblastoma), the eye (retinoblastoma) or the kidney (Wilms tumor).

Neuroblastoma Peripheral neuroblastic tumors are classified histologically as neuroblastoma, ganglioneuroblastoma and ganglioneuroma, neuroblastoma being the most clinically relevant variant due to its malignancy and heterogeneous behavior.92 Generalized cytotoxicity that leads to severe side effects is often derived from the use of potent alkylators such as cisplatin.93 In order to dispose of that issue, Zhen et al. prepared casein NPs to encapsulate cisplatin.94 The in vivo experiments determined a significant anticancer efficacy and toxicity improvement with encapsulated cisplatin. Nevertheless, Ghaghada et al. postulated that more data were required about NP interaction with tumor tissue in order to gain preclinical insights and better knowledge about their real advantages.95 The evaluation of a liposomal contrast agent in an orthotropic kidney capsule model of neuroblastoma made it possible to establish that the liposome cell uptake in pediatric solid tumors such as neuroblastoma was heterogeneous and not governed by tumor geometry. The aggressiveness of high-risk neuroblastoma calls into question the nanomedicines’ potential in eradicating tumor relapses. Nanoencapsulated alkylators have, indeed, proven drug prolongation in the organism, as well as drug safety and efficacy improvement. Notwithstanding, many of these nanoformulations have been tested only in vitro, and in vivo studies are mainly from xenograft tumor models that do not properly reproduce childhood neuroblastoma. Thus, the preclinical assessment of NPs for translation to clinical trials should certainly be improved. Standardization of animal models is mandatory96,97 in order to predict NPs response, and it should take into account the age differences, tumor environment, immune responses and late sequelae present in children. Children with high-risk neuroblastoma are at present given anti-disialoganglioside 2 mAb therapy due to the abundant levels of this cell surface antigen.98 This target has drawn attention not only as an immunotherapy approach99 but also for developing immune-targeting strategies, allowing tumor-specific delivery of cytostatic drugs for upgrading current therapies. For instance, porous silica NPs surface was coated with anti-disialoganglioside 2 antibodies to facilitate the targeted delivery of microRNA34a.100 The tumor-specific over-expression of microRNA-34a induced the activation of caspase-mediated apoptotic pathways, leading to a significant decrease of tumor growth 14 ACS Paragon Plus Environment

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in neuroblastoma bearing mice. Several other experiments have been further performed by using NPs to target disialoganglioside 2 in neuroblastoma cells. In these studies, antibodies against this receptor were conjugated to liposomes,101 iron102 and gold103 NPs before their administration. In vitro and in vivo assays confirmed the greater antiproliferative efficiency, the improved accumulation in tumor tissues and the specificity of these antibody-conjugated NPs, compared to their non-decorated NPs counterparts. Peripheral neuroblastic tumors are still challenging owing to their heterogeneity. Knowledge gained from genomic discoveries has shown that mutational burden increases on relapse.104,105 Thus, if personalized treatments represent opportunities for high-risk neuroblastoma children, the use of targeted nanomedicines like the ones described above might be required to improve therapeutics. Such approaches may be optimal in relapsed neuroblastoma even if, as with other embryonal tumors, extreme variability and poor understanding of the disease still restrain new therapeutic attempts.

Retinoblastoma Enucleation is the definitive treatment for intraocular retinoblastoma before the tumor spreads, while if there is a chance to save the patient’s sight, clinicians recur to cryotherapy, thermotherapy, laser photocoagulation, external beam radiation and chemotherapy, among other methodologies.106 The limitations of chemotherapy have attracted some attention in the pharmaceutical field, given that DDS might reduce the number of intravitreal or subconjunctival injections, thus improving local and systemic toxicity. On a preliminary note, it is worth stressing that safe biocompatible materials are mandatory in the design of nanocarriers for cytostatic ocular delivery in children. With the aim of overcoming the rapid clearance of free carboplatin from the eyes, Ahmed et al. leveraged the high biocompatibility of proteins and loaded carboplatin in apotransferrin and lactoferrin based nanocarriers.107 Carboplatin NPs exhibited a higher cell uptake, unlike soluble carboplatin, probably boosted by endocytosis mediate receptors. Notably, nanoformulations have been administered not only locally but also systemically,108 this bringing a certain degree of controversy about which is the best route of administration. Even though local therapies have demonstrated a substantial systemic toxicity reduction, intra-arterial chemotherapy is attracting interest nowadays. Thus, the current era of retinoblastoma management entails intra-arterial chemotherapy plus additional intravitreal chemotherapy.109,110 More studies are needed to elucidate the best route of administering nanomedicines, with a view to ameliorating globe salvage in eyes with advanced retinoblastoma in children. The aforementioned studies suggest an up-and-coming role of NPs for the local administration and non-invasive therapies of retinoblastoma. Interestingly, nanoencapsulated carboplatin for ocular administration is currently under clinical trials, but only in young adults with advanced retinoblastoma. Preliminary results show a sustained-release behavior of carboplatin in retina and vitreous without systemic side effects.111


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In light of the previous example, it is questionable if we should promote clinical research that can be translated into health opportunities not only in retinoblastoma but also in overall childhood cancers. Increasing the resources to achieve satisfactory submissions to ethics committees has to be encouraged mainly in the case of nanomedicines.

BONE TUMORS AND SOFT TISSUE SARCOMAS Musculoskeletal tumors are a heterogeneous group of diseases with a low global incidence. Among them, Osteosarcoma (OS) and Ewing sarcoma are the most common malignant bone tumors diagnosed.

Osteosarcoma Although OS accounts for only 5% of all childhood cancers,112 due to its aggressive progression together with the high tendency of primary OS to metastasize to the lungs, it is responsible for 9% of all cancer-related deaths in children.113 Methotrexate has been one of the key drugs in OS therapy since the early 1970s.114 However, despite its great efficacy, several drawbacks are associated with this antimetabolite, such as severe toxicity and rapid blood clearance. To avoid the need for rescue and to increase the drug half-life, methotrexate was encapsulated into poly(lactic-co-glycolic acid)-layered double hydroxide NPs and, in comparison with free methotrexate, this formulation showed higher efficacy for inhibiting OS tumor growth, and improved survival rates in vivo.115 The need for multi-agent therapy for the treatment of resistant tumors such as OS is widely known and accepted. The complementary cellular targets of DOX and edelfosine, an alkyl-lysophospholipid that had previously shown anti-OS activity led our group to evaluate whether their combination would be synergistic against OS cells. The combination of DOX-containing-lipid NPs and edelfosine-containing-lipid NPs showed a synergistic activity against cancer cells and, on the other hand, the encapsulated DOX could revert cellular drug resistance mechanisms and increase the effectiveness comparatively to the non-encapsulated drugs.116 The strong investment in clinical trials in Europe and in the USA to amend the standards of chemotherapy agents’ combinations and schedules has not improved the survival rates that were achieved in the last decades. Dose-response curve for some cytostatic drugs such as ifosfamide have reached the maximum;117 however, bearing in mind the pre-clinical results obtained with nanomedicines in OS, some of these nanoformulations could emerge in clinical practice as an implement to augment further the therapeutic index of the chemotherapeutic agents. Finally, the market authorization of liposomal mifamurtide (Mepact) in 2009 as a second line treatment for children with OS118 represented an encouraging advance, although this is an immunostimulant nanomedicine and not a cytotoxic per se. Bisphosphonates are commonly used drugs for the treatment of bone resorption disorders because they display a pyrophosphate-like structure able to coordinate to 16 ACS Paragon Plus Environment

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calcium ions present in the hydroxyapatite matrix of the bone.119 In this context, bisphosphonate-bound polymeric NPs have been developed to deliver chemotherapeutics to bone tumors.120–122 The higher efficacy of DOX when targeted by means of bisphosphonate-bound NPs was confirmed in vivo and very importantly, no sign of DOX-induced-cardiac toxicity was observed.120 The authors reported that, at short time after administration, the targeted and non-targeted carriers predominantly distributed close to the tumor areas in OS xenografts; however, only bisphosphonate-NP remained present in the tumor bulk after 7 days. The authors suggest that the initial uptake of non-targeted NP could be caused by a passive targeting owing to the EPR effect, but only the binding of bisphosphonate to hydroxyapatite could keep the NPs in the tumor area. Clearly, the knowledge of tumor cell epitopes has allowed the development of targeted nanovehicles able to selectively deliver antitumor compounds in the diseased area. The use of bisphosphonates,120–122 aptamers,123 folate124 or hydroxyapatite125 (Figure 4) has been shown to produce an increase in the effectiveness of the NPs treatments, while maintaining drug safety levels. Notably, the lung is the site where the majority of relapses occur and thereby, nanomedicines targeted to the lungs are called to overcome micro or gross metastases by enhancing the therapeutic levels of cytotoxic agents, without causing dose-limiting damage in children’s marrow. Thus, some oncologists suggest that the use of the inhalatory route could be optimal.126,127

Figure 4. Ligand targeted strategies for bone tumor selective drug delivery (green). (1A) NPs (nanoparticles) can be functionalized with folic acid to interact with folate receptors overexpressed in OS (osteosarcoma) cells. (1B) Bisphosphonate-decorated-NPs display high affinity to bone matrix by coordination with calcium ions of hydroxyapatite crystals. (1C) CD133 aptamers conjugated to NPs can bind the cluster of differentiation of the transmembrane glycoprotein CD133, present in OS cancer stem cells. (2) Hydroxyapatite based NPs have affinity to bone tissue since hydroxyapatite is a natural bone mineral composed of calcium phosphate crystals and several other trace elements.


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Ewing sarcoma The Ewing sarcoma is the second most malignant bone tumor in pediatric patients, appearing not only in bone but also in extra-skeletal soft tissue sites.128,129 Even though a systemic treatment is the most suitable approach for tackling tumor metastasis, local treatment of the tumor area is also necessary to avoid the metastatic spread. Thus, the irinotecan produg SN-38 has been loaded onto polymeric nanofibers to avoid a suboptimal tumor distribution of the free drug, which was responsible for failure in clinical trials.130 After subcutaneous implantation in the tumor-resection bulk, SN-38 was totally distributed in the tumor of nude mice, providing evidence of the suitability of polymeric nanofibers for the local control of potential metastatic tumors. Importantly, 95% of Ewing sarcoma tumors present a chromosomal translocation that leads to the formation of the oncogenic transcription factor EWS-FLI1, responsible for the oncogenic and metastatic processes.131 This drove several researchers to nanoencapsulate siRNA against the oncogene, and they reported effective oncogene expression knockdown in vitro and in vivo.132,133 For instance, poly (isobutyl cyanoacrylate) NPs with a chitosan corona were biotinylated, allowing the NPs to be functionalized with avidinylated anti-CD99 antibody. The authors observed that the chitosan-pluronic corona allowed the NPs to remain longer into the blood circulation, whereas, the inhibition of the EWS-FLI1 gene expression was higher when the siRNA was loaded onto immunoNPs, compared to the NPs without the ligand. Abraxane, paclitaxel-bound albumin NPs already approved for breast, metastatic pancreatic and non-small cell lung cancers, was tested by the Pediatric Preclinical Testing Program (PPTP) against Ewing sarcoma, OS and rhabdomyosarcoma xenograft models.134 The PPTP in vivo experiments gave evidence of the powerful activity of Abraxane against Ewing sarcoma and rhabdomyosarcoma models expressing secreted acidic cysteine rich glycoprotein SPARC. This nanomedicine is now in Phase I/II clinical trials, indicated for various pediatric solid tumors, incl. OS, Ewing sarcoma or neuroblastoma) (code NCT01962103). Faced with the impossibility of condensing all the studies reviewed for this article, the following chart (Figure 5) gives a global perspective of the current state of the art of nanotechnology approaches for pediatric cancers.


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Figure 5. Nanomedicines for pediatric cancers: an estimation of the state of the art. Prevalence and 5-years survival rate percentages include also low-grade tumors but survival rates decrease dramatically in the case of aggressive tumors, which are of particular concern in this review. Research reviewed on nanotechnology approaches for childhood cancers in the last 5 years (%) is matched with their global burden of prevalence and 5-year survival rate (gross data estimations refer to children and adolescents between 0-19 years in the last decade) 1,2,4–6. Global overview of current state of the art shows a deficit of research on CNS tumors in spite of their high prevalence and mortality, whereas blood cancers and non-CNS embryonal tumors feature a balanced quotient. Finally, although bone tumors are the least prevalent, the literature contains a wide range of studies.

KEY MILESTONES IN PEDIATRIC CANCER NANOMEDICINE The urgent need for pediatric investigation plans when companies request approval for medicines drove the FDA to grant a law about pediatric exclusivity research in the Modernization Act enactment of 1997 (Figure 6). Even if those incentives have been updated and reauthorized subsequently, since the market approval of Doxil in 1995, several anticancer nanomedicines have been authorized for their use in adults but not in the pediatric population. Although a specific protocol for pediatric clinical research already exists, which was standardized and regulated in Europe and updated in the USA (FDA Amendments Act) in 2007, there is still a lack of compliance and collaboration between different institutions that hampers the inclusion of children in clinical trials.135– 139 Notwithstanding, some nanoformulations have recently reached phases III in pediatric clinical trials (see Table 1) and in 2009, liposomal mifamurtide was approved for pediatric osteosarcoma.118 Regarding the use of off-label nanomedicines, ferumoxytol, a superparamagnetic iron oxide NP approved in 2009 by the FDA for the treatment of iron deficiency anemia in adults was used as a contrast agent for clinical pediatric imaging.140 More recently, it has been clinically reported to be effective as a magnetic resonance contrast agent in cancer staging of children with solid tumors.141


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Figure 6. Historical timeline in the field of cancer nanomedicine and clinical research incentives in children.

CONCLUDING REMARKS Pediatric cancer management remains elusive and the survival rates are still low. Despite recent progress in nanotechnology applications for treating adult cancers, such approaches are not well developed for use in pediatric oncology. Childhood cancers are commonly treated by applying combinations of highly toxic chemotherapeutic agents. These agents were originally designed to treat adult cancers, and adult treatment regimens were modified for use in pediatrics. Since combination chemotherapy has proven to be effective in controlling cancer progression, its use in pediatric cancer therapy has changed little over the last twenty years. Nevertheless, since children are growing and developing, they may well respond differently to chemotherapy drugs. Moreover, if a child becomes resistant to a drug and he or she is on the maximum tolerable dose, there is no scope to still increase the dose further without toxic side effects. Sadly, long-term survivors can experience lifelong health impacts from their treatment: about 70% of childhood cancer survivors suffer side effects, especially cardiovascular, which may even also include secondary cancers. Bearing in mind our current knowledge about late toxicities and the standstill in improvement of the survival rate, the severe imbalance between adults and children, as far as the use of nanomedicines is concerned, should draw our attention. The main obstacle is progression to clinical trials. The inclusion of children in the therapeutic programs is, indeed, hampered by current pediatric clinical trial protocols, especially in relation to ethical issues. Moreover, the clinical bottleneck in children is exacerbated given that in vivo pre-clinical proofs are sometimes insufficient to reproduce correctly the disease or the age differences in children while late toxicities are not evaluated, which is of particular concern in pediatric cancer. More active collaboration between technologists, pediatric oncologists and clinicians is mandatory to design appropriate strategies. One reason to be optimistic is that at present, more than twenty years of 20 ACS Paragon Plus Environment

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experience with nanomedicines in the clinic endorses their potential for improving therapeutics in childhood cancers, which means that considerable progress is likely in the near future.


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VOCABULARY Physiology-based pharmacokinetic models, a mathematical framework similar to traditional pharmacokinetic models but including physiological knowledge; targeted nanomedicines, surface-modified nanocarriers with antibodies, aptamers or peptides among others that display active targeting towards specific tissues; nanoparticle pegylation; a strategy that endows stealth properties to nanoparticles for improving the efficiency of drug delivery; blood-brain barrier, a biological barrier at brain capillaries with highly selective permeability that protects the central nervous system; xenograft tumor model, a cancer disease animal model based on the transplantation of cancer cells from one species to another.


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Acknowledgements Asociación Española Contra el Cáncer (AECC) (CI14142069BLAN) and Fundación Caja Navarra/Obra Social La Caixa are gratefully acknowledged.

Competing interests statement The authors declare no competing interests.


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