Metronomic chemotherapy and nanocarrier platforms

Cancer Letters xxx (2016) 1e11

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Mini-review

Metronomic chemotherapy and nanocarrier platforms Amr S. Abu Lila a, b, c, Tatsuhiro Ishida a, * a Department of Pharmacokinetics and Biopharmaceutics, Institute of Medical Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan b Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt c Department of Pharmaceutics, Faculty of Pharmacy, Hail University, Hail 2440, Saudi Arabia

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 September 2016 Received in revised form 30 October 2016 Accepted 2 November 2016

The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods eknown as “metronomic chemotherapy”e is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic “metronomic” therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed. © 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Dosing schedule Liposomes Maximum tolerated dose Metronomic chemotherapy Nanoparticles Tumor priming

Introduction Angiogenesis, or the formation of new blood vessels, is known to be vital for cancer growth and dissemination, which makes it an attractive therapeutic target for cancer therapy [1e3]. The targeting of genetically stable and easily accessible tumor vascular endothelial cells (ECs), rather than the tumor cells themselves, by chemotherapeutic agents is assumed to reduce the likelihood of developing drug resistance and overcomes the physiological barriers that might hinder the effective delivery of drugs to tumors [4,5]. Metronomic chemotherapy, which was originally designed to inhibit tumor angiogenesis when using conventional chemotherapeutic agents, is currently regarded as a promising strategy for anti-angiogenic cancer therapy in both preclinical studies and clinical trials [6,7]. Metronomic chemotherapy is characterized by the frequent administration of comparatively lower doses of cytotoxic agents at close regular intervals without prolonged drug-free breaks compared with conventional maximum tolerated dose (MTD) chemotherapy. The major pharmacological basis of metronomic chemotherapy is that, by comparison with normal or other types of tumor cells, tumor vascular endothelial cells (ECs) are highly sensitive to low * Corresponding author. Fax: þ81 88 633 7259. E-mail address: [email protected] (T. Ishida).

doses of chemotherapeutic agents when exposed in a frequent or continuous manner. In addition, metronomic chemotherapy can suppress systemic angiogenesis that is mediated by circulating bone marrow-derived pro-angiogenic cells, such as circulating endothelial progenitors (CEPs), and it induces the secretion of endogenous angiogenesis inhibitors such as thrombospondin 1 (TSP-1) that suppresses tumor neovascularization [6,7]. Furthermore, the administration regimen of metronomic chemotherapy efficiently shortens the time between dosing cycles, and, thus, it prevents the recovery of the damaged tumor vasculature [6]. Nevertheless, contrary to common opinion, a growing body of evidence has shown that the anti-angiogenic potential of metronomic chemotherapy could enhance the intratumor distribution and delivery of drugs and/or macromolecules, which includes drugdelivery carriers. This notion is associated with a reduction in the tumor micro-vessel density that is accompanied by morphological and functional maturity, resulting in what is known as “intratumor vascular normalization.” Such “vascular normalization” is thought to trigger better perfusion and improved drug delivery and efficacy [8e10]. Accordingly, in addition to direct anti-angiogenic activity, metronomic chemotherapy might also augment the therapeutic efficacy of co-administered drugs and/or macromolecules including drug-delivery carriers.

http://dx.doi.org/10.1016/j.canlet.2016.11.007 0304-3835/© 2016 Elsevier Ireland Ltd. All rights reserved.

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Mechanism(s) of action for metronomic chemotherapy

Modulation of antitumor immunity

Tumor progression is a complex process that involves the interaction of cancer cells with non-malignant surrounding microenvironments [11,12]. Accordingly, efficient cancer treatment might require a fight against multiple possible targets such as cancer cells, cancer stem cells, tumor vasculature, extracellular matrix, and/or immune cells infiltrating the tumor. In fact, metronomic scheduling of chemotherapeutic agents, namely “metronomic chemotherapy,” is currently considered a multi-targeted treatment. In this section, we focus briefly on the possible anticancer mechanisms that could be attributed to metronomic scheduling (Fig. 1).

Despite the fact that high doses of chemotherapeutic agents sometimes trigger host inflammatory immune responses that can ablate immune surveillance [18], such detrimental effects on a host's immune system can be reversed by changing the dosing and timing of the chemotherapy. Several pre-clinical and clinical studies have emphasized that lower doses and more frequent administration of chemotherapeutic agents, consistent with the metronomic basis of therapy, can restore antitumor immunity and suppress pro-tumor immune responses. This happens predominantly via the selective depletion of immunosuppressive regulatory T cells (Tregs), which is a Foxp3þCD25þCD4þ subpopulation of T cells that inhibits antigen-specific immune responses via both cytokinedependent and cell contact-dependent processes [18e22]. In addition, metronomic chemotherapy could induce apoptotic tumor cells to release tumor-specific antigens that could be taken up by antigen-presenting cells, where they would then be processed and presented to antigen-specific CD8þ T cells [23e25]. Furthermore, the signals released by killed tumor cells could induce the maturation of dendritic cells (DCs) and enhance their phagocytic ability [26e30]. An extensive review of the immunoregulatory effects of metronomic chemotherapy has recently been published [31].

Anti-angiogenic activity A mounting body of evidence has declared that the anticancer activity of metronomic chemotherapy is mediated predominantly by inhibiting tumor angiogenesis. Browder et al. [13] have emphasized that chemotherapeutic agents can cause apoptosis of tumor-associated vessels in ectopically growing mouse tumors. Such anti-angiogenic potential is more prominent with protracted exposure to low doses of chemotherapeutic agents from frequent administrations during “metronomic administration” compared with conventional administration at MTD. In addition, recent studies have revealed that the anti-angiogenic potential of metronomic chemotherapy can also be mediated via a suppression of the mobilization of CEPs [14,15] and the inductive production of an anti-angiogenic glycoprotein referred to as TSP-1, which is an endogenous inhibitor of angiogenesis, in order to reduce tumor neo-vascularization [6,16,17]. Nonetheless, it is worth noting that other mechanisms might contribute to the antitumor response of several cytotoxic drugs when administered on a metronomic schedule.

Induction of tumor dormancy Experimental and clinical evidence supports the existence and the crucial role of tumor dormancy both in repression of cancer progression and in cancer relapse [32,33]. Tumor dormancy occurs as a result of cell-cycle arrest or a dynamic equilibrium between cell proliferation and apoptosis [32e34]. Three different mechanisms are reported to participate in the induction of tumor dormancy: suppression of angiogenesis, induction of apoptosis in cancer cells, and tumor immune surveillance [20,35]. Thus, it is easy to postulate

Fig. 1. Illustrating diagram for the possible mechanism(s) of action of metronomic chemotherapy.

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that the metronomic chemotherapy-mediated inhibition of tumor angiogenesis and/or reinforced anticancer immunity (mentioned above) could trigger tumor dormancy. However, thus far, no clear evidence has shown that metronomic chemotherapy directly induces cellular dormancy in cancer cells. Four-dimensional “4-D” effect Andre and Pasquier [36] have hypothesized a “Drug-Driven Dependency/Deprivation (4-D) effect” to clarify the anticancer efficiency of different therapeutic regimens using intermittent drug interruptions. According to this hypothesis, long exposures of cancer cells to chemotherapeutic agents followed by sudden withdrawal or replacement therapy might trigger cell death. This hypothesis is supported by several clinical and preclinical studies demonstrating the positive effect of a sudden break/cessation in long-term anticancer therapies [37e39]. Cytotoxic effect against cancer stem-like cells Despite numerous published studies emphasizing the antiangiogenic efficacy of metronomic chemotherapy, those concerning the efficacy of metronomic chemotherapy against cancer stemlike cells (CSCs) are scarce. CSCs, also known as tumor-initiating cells, are a subpopulation of self-renewing cells that are more resistant to chemotherapy and radiation therapy than the other surrounding cancer cells [40]. CSCs are characterized by a selfrenewal capacity, and by the ability to differentiate into progenitor cells that can reconstitute and sustain tumor growth, as well as by a higher level of invasiveness and resistance to many anticancer agents [41,42]. Folkins et al. [43] have demonstrated that treatment with low dose metronomic cyclophosphamide (CTX) along with a

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direct anti-angiogenic drug significantly reduced the number of CSCs in a subcutaneous rat C6 glioma model. In a similar manner, Vives et al. [44] challenged the effectiveness of a multi-targeted chemo-switch (CeS) schedule that combines metronomic gemcitabine chemotherapy after treatment with the maximum tolerated dose (MTD) in a human pancreatic adenocarcinoma orthotopic model. They demonstrated that CeS treatment induced a substantial increase in thrombospondin-1 expression and a significant reduction in the number of CD133þ cancer cells and triple-positive CD133þ/CD44þ/CD24þ CSCs, which indicates that a CeS schedule has the potential for eradicating chemo-resistant CSCs. Drugs used in metronomic chemotherapy Metronomic chemotherapy regimen usually comprises the use of either a single agent or a combination of various agents of different classes having anti-angiogenic, apoptotic and/or immuneestimulatory properties. Although almost all chemotherapeutic agents could exert some anti-angiogenic potential, not every chemotherapeutic agent is a suitable metronomic agent. Only drugs that could exert a remarkable anti-angiogenic activity at relatively lower doses, rather than conventional MTD, are considered ideal candidates for the metronomic paradigm. Cytotoxic drugs, such as cyclophosphamide, methotrexate, vinblastine, paclitaxel or etoposide, have been reported to exert a potent anti-tumor efficacy against both circulating endothelial cells and CEPs, when being administered continuously at lower doses rather than at MTD [45e48]. Metronomic dosing with such drugs has proven efficacy in many clinical studies against different types of tumors including myeloma [49], ovarian cancer [50,51], prostate cancer [52], colorectal cancer [53e55] and breast cancer [45,56e58] (Table 1). Nonetheless, metronomic chemotherapy showed disappointing clinical results against glioblastoma

Table 1 Selected list of some metronomic chemotherapy regimens used in clinical settings. Patient profile

The drug(s) used

Metronomic dosing schedule

TTP (months)

Reference

Metastatic breast cancer

Methotrexate (MTX) Cyclophosphamide (CTX) Vinorelbine (VNB) Cyclophosphamide (CTX) Capecitabine (CAP)

MTX (oral, 5 mg/twice weekly) CTX (oral, 50 mg/day) VNB (oral, 70 mg/m2/trice weekly) CTX (oral, 65 mg/m2/day for 2 weeks) CAP (oral, 2  1000 mg/m2/day for 2 weeks)

2.8

[45]

7.7 5.2

[56] [58]

Methotrexate (MTX) Cyclophosphamide (CTX) Trastuzumab Vinorelbine (VNB) Capecitabine (CAP) Trastuzumab Cyclophosphamide (CTX) Bevacizumab Irinotecan (CPT-11) uracil/tegafur (UFT) Capecitabine (CAP) Celecoxib (CXB) Irinotecan (CPT-11) Doxifluridine (50 -DFUR) Cyclophosphamide (CTX) Celecoxib (CXB) Cyclophosphamide (CTX) Cyclophosphamide (CTX) prednisone Cisplatinum (CDDP) Etoposide (ETO) Bevacizumab Cyclophosphamide (CTX) Dexamesathone

MTX (oral, 5 mg/twice weekly) CTX (oral, 50 mg/day) Trastuzumab (i.v., 6 mg/kg every 3 weeks) VNB (oral, 80 mg/m2/week) CAP (oral, 2  1000 mg/m2/day for 2 weeks) Trastuzumab (i.v., 2 mg/kg/week) CTX (oral, 50 mg/day) Bevacizumab (i.v., 10 mg/kg/every 2 weeks) CPT-11 (oral, 40 mg/m2/week) UFT (oral, 335 mg/m2/day) CAP (oral, 2  500 mg/day) CXB (oral, 2  400 mg celecoxib/day) CPT-11 (oral, 40 mg/m2/week) 50 -DFUR (oral, 800 mg/day) CTX (oral, 50 mg/day) CXB (oral, 2  400 mg/day) CTX (oral, 50 mg/day) CTX (oral, 100 mg/day) prednisone (oral, 10e20 mg/day) CDDP (oral, 30 mg/m2/trice weekly) ETO (oral, 50 mg/day for two weeks) Bevacizumab (i.v., 10 mg/kg/week) CTX (oral, 50 mg/day) Dexamesathone (oral, 1 mg/day)

6

[48]

12.8

[57]

7.2

[50,51]

NR

[53]

4

[54]

6

[55]

4.7

[60]

2 15

[61] [49]

7.6

[46]

3

[52]

Cyclophosphamide (CTX) Methotrexate (MTX) Vinblastine (VLB) Celecoxib (CXB)

CTX (oral, 2.5 mg/m2/day) MTX (oral, 15 mg/m2 twice weekly) VLB (i.v., 3 mg/m2/week) CXB (oral, 2  100e400 mg/day)

18

[47]

Metastatic breast cancer Heavily pretreated patients with metastatic breast cancer. HER2þ metastatic breast cancer

HER2þ metastatic breast cancer

Recurrent Ovarian cancer Colorectal cancer Metastatic Colorectal cancer Metastatic Colorectal cancer Refractory aggressive nonHodgkin's lymphoma Metastatic melanoma Advanced multiple myeloma Advanced non-small cell lung cancer Hormon-refractory prostate cancer previously treated by androgen deprivation Refractory or relapsed Pediatric solid tumors

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and renal cell carcinoma [59]. For detailed Phase II clinical studies and/or retrospective reports regarding metronomic chemotherapy, the readers are directed to an extensive review by Romiti et al. [20]. In fact, optimizing a metronomic anticancer therapy is still a challenging task even after a decade of clinical investigation. Furthermore, future cancer research should be directed towards the identification of the best agents to use according to tumor type, to calculate the doses of each agent to be used alone or in combination and to define the timing of drug administration. Tumor priming using metronomic chemotherapy The tumor microenvironment is a complex assembly of cells (cancer-associated fibroblastic cells, infiltrating immune cells, and angiogenic vascular cells), signaling molecules and an extracellular matrix, all of which constitutes a key influence on tumor progression [62e64]. Several pioneering reports have revealed that targeting the tumor microenvironment as a whole, rather than simply a specific component, could represent a standard solution for the complete eradication of tumors [65e68]. Recently, metronomic chemotherapy has been acknowledged not only for its antiangiogenic potential but also for its ability to prime the tumor microenvironment via inducing vascular normalization and/or alleviating mechanical stress. As a consequence, this process enhances the intratumor delivery and distribution of drugs and/or macromolecules including drug delivery carriers. Recently, Chen and co-workers [10] have investigated the effect of metronomic paclitaxel (PTX) dosing on the pathophysiology of tumor vasculature and the microenvironment. They reported that tumor priming with metronomic paclitaxel could induce tumor vasculature normalization, as evidenced by the increased coverage of the pericytes and basement membranes of endothelial cells, by the enhancement of pO2 and vascular perfusion, and by decreases in the interstitial fluid pressure. Such tumor vasculature normalization efficiently enhanced systemic delivery and the resultant anticancer efficacy of a conventional chemotherapeutic agent, doxorubicin (DXR), administered during the induced normalization window. In the same context, we previously reported that, compared with a monotherapy of either metronomic CTX dosing or DXR-SL, the combination of metronomic CTX dosing with sequential injections of doxorubicin-containing PEGylated liposome (DXRSL) exerted synergistic antitumor activity in a murine solid-tumor model [69]. Such a potent antitumor effect was partially attributed to the enhanced vascular permeability and/or transient tumor vascular normalization induced by metronomic CTX dosing, and

resulted in enhanced accumulation and a subsequent deep diffusion of DXR-SL in solid tumors. Later, we reported that metronomic synergistic dosing with S-1, an oral formulation of the 5-FU prodrug Tegafur (TF), augmented the therapeutic efficacy of oxaliplatin (lOHP)-containing PEGylated liposome without increased toxicity in an animal model [70]. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via the transient normalization of tumor vasculature, along with an alleviation of intratumor pressure. Such changes in the tumor microenvironment imparted by S-1 treatment contributed collectively to the efficient delivery of PEGylated liposomes to tumor tissue and permitted their deep penetration/distribution into the tumor mass. Consequently, metronomic chemotherapy-mediated alteration of the tumor microenvironment might be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer chemotherapeutics that otherwise suffer from inadequate/ heterogeneous delivery to tumor tissues (Fig. 2). In addition, metronomic chemotherapy-mediated tumor priming has been reported to improve the in vivo systemic delivery and transfection efficiency of siRNA molecules. We have investigated the effect of metronomic S-1 dosing on intratumor accumulation and the resultant therapeutic efficacy of PEGylated liposomes complexed with the anti-apoptotic protein Bcl-2 [PEG-coated siBcl2 lipoplex (siBcl-2 lipoplex)] in a DLD-1 xenograft mouse model [9]. Results have shown that daily S-1 dosing significantly enhances the intratumoral accumulation of siBcl-2 lipoplex (Fig. 3). In addition, the combined treatment of metronomic S-1 dosing and siBcl-2 lipoplex exerted potent antitumor activity via a doublemodulation machinery; S-1 treatment significantly enhanced the intratumor accumulation and permitted the efficient delivery of siBcl-2 lipoplexes into tumor tissue, while the tumor-accumulated siBcl-2 lipoplexes simultaneously activated the cellular apoptotic pathway, thus enhancing the cytotoxic activity of 5-FU. In order to prove this concept, we explored the influence of metronomic S-1 dosing on intratumor accumulation and the resultant therapeutic efficacy of PEG-coated siAgo2-lipoplex in Lewis lung carcinoma cells (LLCC) in a mouse solid-tumor model [8]. Results emphasized that metronomic S-1 dosing improved the systemic delivery of intravenously injected PEG-coated siAgo2-lipoplex (siAgo2 lipoplex) into a LLCC solid tumor, which maximized the antitumor efficacy of a combined therapy of S-1 and siAgo2 lipoplex against LLCC tumors. Based on the aforementioned findings, metronomic chemotherapy might represent a promising therapeutic strategy to

Fig. 2. Cartoon depicting the effect of metronomic chemotherapy-mediated tumor priming on the intratumor accumulation of nanocarriers.

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Fig. 3. Effect of S-1 treatment on in vivo tumor accumulation of PEG-coated siRNAlipoplexes [modified from Ref. [9]].

conquer cancer progression via improving the systemic delivery of co-administered drug/biomolecules. The use of nanocarrier platforms in metronomic chemotherapy Metronomic chemotherapy with conventional chemotherapeutic agents represents a promising strategy for anti-angiogenic

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cancer therapy, as described above. Nonetheless, since most metronomic chemotherapies are based mainly on free smallmolecule drugs, which lack tumor-targeting specificity, the development of long-term toxicities might be of clinical concern. Nanoscale drug delivery platforms that target specific elements in the tumor microenvironment are currently of considerable interest. Consequently, metronomic chemotherapy-adopting nanoscale drug-delivery platforms could offer significant benefits to reduce off-target side effects, decrease administered doses, improve the efficacy of tumor-vasculature targeting, and/or sustain drug release to maintain continuous tissue exposure to the cytotoxic effects of the encapsulated drug. Recently, many preclinical studies have exploited the concept of metronomic chemotherapy using targeted nanocarrier platforms (Table 2) [10,71e74]. Amoozgar et al. [75] postulated that metronomic dosing could be attained by using a suitable drug delivery system that sustains drug release and penetrates deeply into the tumor tissue. Accordingly, they engineered polymeric poly(lacticco-glycolic acid) nanoparticles (PLGA NPs) that could encapsulate the cytotoxic drug PTX. The surface of such NPs was modified by a dual-layer coating of both polydopamine, to retard the release rate of encapsulated drugs and thus mimics the metronomic dosing, and polyethylene glycol (PEG), to prevent NP recognition by the cells of a mononuclear phagocyte system (MPS). Such surface modifications are reported to not only reduce the cumulative release of PTX from nanoparticles but also to sustain drug release for about 3 days. In vivo therapeutic experiments showed that, by comparison with free PTX, a low intraperitoneal dose of PTX-loaded surface-coated NPs (5 mg/kg), administered twice weekly to drugresistant murine ovarian tumor-bearing mice efficiently induced a substantial therapeutic effect that was manifested by superior survival benefits. In the same context, Upreti and co-workers [71] also investigated the efficacy of an extended-release liposomal formulation of the cytotoxic drug topotecan (TPT) to simulate metronomic chemotherapy while evading the systemic hematological toxicities encountered upon the sequential administration of the free drug. Liposomal encapsulation of TPT is reported to protect it from rapid systemic clearance, which allows preferential uptake and extended tissue exposure in solid tumors [76,77]. This pharmacokinetic alteration supports the rationale of liposomal TPT to simulate metronomic chemotherapy. In vitro experimental results have revealed that the sustained release of TPT from the liposomal formulation enhanced TPT toxicity against a 3-D tumor-endothelial spheroid model and showed a potential to mimic metronomic therapies while alleviating the inconvenience encountered with continuous intravenous administration and/or frequent administration of free TPT. Sood and colleagues [72] developed a novel delivery vehicle, poly(lactic acid-co-glycolic acid)-particle replication in nonwetting template (PLGA-PRINT®) nanoparticles for the efficient metronomic dosing of the anticancer drug, docetaxel (DTX). DTX entrapment within such PLGA-PRINT® nanoparticles conferred higher plasma exposure and preferential accumulation within tumor tissues, compared with free DTX. Importantly, these nanoparticles showed a “bursterelease profile,” in which 100% of the entrapped drug was released within 24 h d considered to be an ideal property for metronomic drug delivery. Therapeutic experiments have used subcutaneous ovarian cancer mouse models to reveal how the metronomic dosing of DTX entrapped within PLGAPRINT® nanoparticles triggers potent anti-proliferative, antiangiogenic and anti-apoptotic effects, and that a combination therapy with siRNA against a potent anti-angiogenic factor, CHmEZH2, incorporated into chitosan nanoparticles substantially suppressed tumor growth.

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Table 2 Selected list of nanocarrier-based metronomic chemotherapy. Drug

Nanocarrier

Experimental tumor model

Metronomic dosing schedule

Ref.

Paclitaxel

Ovarian cancer cell line (BR5FVB1-Akt)

5 mg/kg twice weekly for a total of 5 doses. (i.p.) 2.5 mg/kg every other 2 days, i.v.

[75]

Paclitaxel

PEGylated polydopamine-coated PLGAnanoparticles (PDP-NP) F56 peptide-conjugated nanoparticles (F56-NP) Sterically stabilized liposomes (SSL)

[84]

Paclitaxel

Cationic liposome (EndoTAG™-1)

Lewis lung carcinoma cell line (LLCC) Pancreatic tumor cell line (L3.6 pl)

Paclitaxel

Cyclic NGR-modified sterically stabilized liposomes (NGR-SSL) Particle replication in non-wetting templates poly (lactic-co-glycolic acid) nanoparticles (PLGA-PRINT® NP) Sp5.2 peptide-conjugated nanoparticles (Sp5.2-NP) NGR-modified stealth liposomes (NGRSSL) Ruthenium-thiol protected nanoparticles (RU-MUA@Se) Liposomes

Human fibrosarcoma cell line (HT1080)

6 mg/kg, for five consecutive days and repeated second time with 6-day interval. (i.v.) 5 mg/kg three times weekly for 2 weeks. (s.c.) 5 mg/kg three times weekly for 2 weeks. (i.v.) 5 mg/kg every day for 12 consecutive days. (i.v.) 0.5 mg/kg three times weekly. (i.p.)

Human breast cancer cell line (MDAMB-231 cells) Human neuroblastoma cell line (SHSY5Y) A human liver cancer cell line (HepG2)

3.2 mg/kg every other day for a total of 10 doses. (i.v.) 1 mg/kg/every other 2 days for a total of 9 doses. (i.v.) 3 mg/kg every day for two weeks. (s.c.)

[74]

Tumor-endothelial spheroids (TES) (in vitro model)

e

[71]

Paclitaxel

Docetaxel

Docetaxel Doxorubicin Selenium Topotecan

Human breast cancer cell line (MDAMB-231 cells) Human breast cancer cell line (MDAMB-231)

Epithelial ovarian cancer cell lines (HeyA8 and SKOV3 ip1)

Chen and colleagues have explored the potential use of a nanoparticulate delivery system that can actively target tumor vasculature in metronomic chemotherapy. For achieving active tumor vasculature targeting, the surface of poly(lactic-co-glycolic acid)-based nanoparticles was decorated with a specific ligand moiety, SP5.2 peptide, a ligand for VEGFR-1 highly expressed on tumor vascular ECs [78,79]. The anti-angiogenic/antitumor efficacy of the prepared SP5.2 peptide-conjugated nanoparticles encapsulating the cytotoxic drug DTX (SP5.2 DTX-NP) was challenged against a breast cancer xenograft tumor model using either MTD or metronomic dosing. Results revealed that metronomic SP5.2-DTXNP exhibited potent antitumor activity, mainly via the antiangiogenic potential of DTX, which was selectively delivered into tumor vascular endothelial cells via the interaction of SP5.2 peptide with the over-expression of VEGFR-1 on tumor vessels. In addition, targeted metronomic chemotherapy induced superior antitumor activity with minimal drug-associated toxicity, compared with treatment given in a maximum tolerated dose (MTD) regimen [74]. Later, the same research group [10] investigated the efficacy of a metronomic PTX using a tumor-vasculature targeted nanocarrier, which consisted of F56-conjugated PTX-loaded nanoparticles (F56PTX-NP) in a breast cancer xenograft tumor model. F56 is a peptide ligand with high binding avidity to the VEGFR-1 highly expressed on tumor vascular ECs [78,79]. Results have shown that F56-PTXNP selectively targets tumor vascular ECs. In addition, multiple dosing of F56-PTX-NP with a two-day break significantly alters the tumor microenvironment, which is manifested by enhanced pO2, lower interstitial pressure, enhanced vascular perfusion, and, more importantly, the induction of a tumor vascular normalization window of at least 9 days. Furthermore, therapeutic experiments using a tumor xenograft mice model revealed that a combined treatment of metronomic F56-PTX-NP plus DXR, administered within the vascular normalization window, significantly suppresses tumor growth, compared with a monotherapy of either metronomic F56-PTX-NP or DXR. Selenium nanoparticles have received much attention as nanocarriers due to their biocompatibility, straightforward synthesis, degradability in vivo and their excellent anticancer activities and low toxicity [80e82]. Sun et al. [83] have recently challenged

[10]

[73]

[89] [72]

[90] [83]

thiol-modified selenium nanoparticles with attached photosensitizers Ru(II)-polypyridyl complexes (RU-MUA@Se) for their anticancer/fluorescence imaging potential in a hepatic cancer xenograft model when administered in a metronomic-based fashion. They reported that the subcutaneous administration of 3 mg/kg/day RuMUA@Se to SCID mice bearing HepG2 tumor xenografts for 15 consecutive days effectively inhibited tumor angiogenesis and suppressed tumor growth with low side effects. In addition, such nanoparticles possessed high tumor-targeted fluorescence imaging potential. Accordingly, they suggested the applicability of such functionalized nanoparticles for theranostic purposes. Liposomal drug delivery systems also address anti-angiogenic potential when administered metronomically. In general, the ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, makes them attractive vehicles for drug delivery. In addition, great technical advances such as remote drug loading, triggered drug release liposomes, and ligand-targeted liposomes have led to the widespread utilization of liposomes in the field of cancer therapy. Zhang and co-workers [84] scrutinized the anti-angiogenic potential of metronomic chemotherapy with PTX-containing sterically stabilized liposomes (SSL-PTX) in a breast cancer xenograft tumor model. PTX was verified for its anti-angiogenic potential at ultralow concentrations [85]. However, clinically relevant concentrations of the formulation vehicle Cremophor EL (CrEL) in Taxol (a commercial product of PTX) have been reported to nullify the antiangiogenic activity of PTX [17]. Results have shown that, unlike Taxol, metronomic SSL-PTX significantly induced a potent tumor growth suppressive effect in a MDA-MB-231 xenograft model via an anti-angiogenic mechanism. These results emphasized that liposomal encapsulation and a metronomic dosing schedule can restore the anti-angiogenic potential of PTX and thus maximize its antitumor efficacy while minimizing its dose-limiting side effects. Tumor ECs are known to over-express negatively charged cell surface molecules such as glycoproteins, proteoglycans and anionic phospholipids [86,87]. The notion of exploiting accessible anionic sites along with tumor vessels is promising for achieving selective delivery of anticancer agents by means of cationic liposomes. Eichhorn et al. [73] utilized a cationic lipid-complexed paclitaxel

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(Endo-TAG™-1) for the selective delivery of PTX to the tumor vasculature. They evaluated the therapeutic efficacy of such a cationic liposomal formulation against both orthotopic L3.6 pl pancreatic cancer and a subcutaneous LLCC model. Results demonstrated that the therapeutic efficacy of Endo-TAG™-1 is critically dependent on the application schedule, and the best therapeutic results are achieved using a metronomic dose rather than the maximum tolerated one. In addition, a significant decrease in tumor microvessel density with a resultant reduction in the tumor burden was observed only if the total weekly dose of EndoTAG™-1 therapy was administered in a metronomic pattern rather than in one shot with MTD. Such findings were intimately correlated to the EC turnover time in solid tumors. The potential minimal doubling time of the tumor endothelium is approximately 2.5 days in mouse solid tumors [88]. Therefore, the high EC turnover can compensate for the anti-vascular effects of EndoTAG™-1 therapy given only once weekly. Taking advantage of the unique epitopes expression on tumor ECs has also been extensively exploited in targeted anti-angiogenic therapy of cancer via the use of a liposomal delivery system. Pastorino et al. [90] exploited the over-expression of aminopeptidase N, a marker of angiogenic ECs [91], for the active targeting of tumor vasculature. For such a purpose, DXR-containing PEGylated liposome was modified with NGR peptides that target the angiogenic EC marker aminopeptidase N. In an orthotopic neuroblastoma xenograft model, metronomic administration of NGR-SL[DXR] (1 mg/kg/every other 2 days x 9) induced complete tumor eradication in all animals. Furthermore, the observed tumor growth inhibition was maintained for more than 4 months in 50% of the treated animals, resulting in long-term survival by comparison with control animals or mice treated with free DXR. Interestingly, the anti-tumor activity in an NGR-SL[DXR] MTD treatment group was superior to that induced by a metronomic dosing of free DXR. These results, which apparently contradict metronomic chemotherapy, might be explained by the fact that liposomes behave as a “metronomic dosing system” because they are long-circulating and have sustained-release properties (the half-life for the release of DXR from liposomes was 315 h). Luo et al. [89] also exploited the over-expression of aminopeptidase N receptors for the selective targeting of NGR-modified sterically stabilized liposomes containing PTX (NGR-SSL-PTX) to tumor ECs. The antitumor efficacy of the metronomic dosing of NGR-SSL-PTX was evaluated in HT1080 tumor-bearing mice. Results revealed that the prolonged circulation characteristics of NGR-SSL-PTX, along with selective tumor vasculature targeting, improved its treatment efficacy. In addition, frequent administration of NGR-SSL-PTX, at doses lower than MTD, trigger a superior tumor growth inhibitory effect and a potent antiangiogenic response, compared with non-targeted SSL-PTX administered either at MTD or in a metronomic fashion. Clinically, the efficiency of PEGylated liposomes as a nanocarrier system for the metronomic application of the cytotoxic drug DXR was challenged in extensively pre-treated metastatic breast cancer patients. Munzone et al. [92] postulated that the pharmacokinetic characteristics of PEGylated liposomes containing DXR (PLD) were superior to free DXR, as manifested by a longer intravascular circulating half-life, a slower plasma clearance, and/or a reduced volume of distribution. This supported the rationale for using PLD in a metronomic fashion, which potentially enabled the exploitation of the efficacy of anthracyclines together with minimizing their toxicity profile. In this study, patients received PLD at a dose of 20 mg/m2 every 14 days via a 60 min intravenous infusion, and each treatment cycle was repeated every 2 weeks until either disease progression and/or any toxicity warranted the cessation of treatment. Results indicated that the metronomic administration of PLD represents an efficient alternative to classic anthracyclines

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administered at MTD, which balances clinical efficiency with an enhanced quality of life in terms of reduced side effects and low personal costs for patients. Nevertheless, despite all the aforementioned data emphasizing the benefits associated with the utilization of nanocarrier delivery systems in metronomic chemotherapy, recent reports have verified that the clinical applicability of “PEGylated” nanocarriers might restrain the therapeutic outcomes of metronomic chemotherapy [93,94]. A well-known immunogenic phenomenon referred to as the “accelerated blood clearance (ABC) phenomenon” has been extensively reported upon the sequential administration of PEGylated nanocarriers [95e98]. In this phenomenon, a preceding dose of PEGylated nanocarrier primes the host immune system, mainly splenic B cells, to create an antibody response (anti-PEG IgM production), which triggers the rapid systemic clearance of a subsequently administered dose of PEGylated nanocarrier [99]. More seriously, such a phenomenon is highly manifested at lower doses, even though they contain cytotoxic drugs such as DXR, rather than at higher doses of PEGylated nanocarriers [100,101]. Accordingly, it is easy to assume that PEGylated nanocarriers will be more vulnerable to rapid systemic clearance, particularly at the low dose range applied with a metronomic dosing regimen. Yang et al. [93] investigated the anti-tumor efficacy of epirubicin-containing PEGylated liposomes in S180 tumor-bearing mice following sequential low-dose injections. They demonstrated how the treatment efficacy disappeared after the sixth day of repeated injections, accompanied by an increased level of anti-PEG IgM and decreased residual complement activity in mouse serum. They speculated that the anti-PEG IgM-mediated accelerated clearance of subsequently injected doses of PEGylated epirubicin liposomes was strong evidence for an impairment of the therapeutic efficacy of PEGylated liposome-based metronomic chemotherapy. Similarly, we have recently reported the elicitation of the ABC phenomenon upon the repeated administration of Doxil® (a marketed liposomal formulation of DXR) in Beagle dogs. We demonstrated how the sequential administration of Doxil® at a therapeutic dose (MTD; 20 mg DXR/m2) did not cause the ABC phenomenon [102]. On the other hand, Doxil® administered sequentially at lower doses (<2 mg DXR/m2) that mimic metronomic administration significantly induced a robust production of anti-PEG IgM antibodies, thereby triggering a rapid clearance of the second and/or a third dose of Doxil® in Beagle dogs. In addition, we noticed that, compared with rodents, the beagle dogs were more sensitive to PEGylated liposomes containing DXR (Doxil®) in terms of the antiPEG IgM response and the induction of the ABC phenomenon. Accordingly, in a later study we investigated the issue of whether Doxil® could elicit the ABC phenomenon in several species (mice, rats, monkeys and minipigs) [103]. Results have shown that despite the fact that the ABC phenomenon was not elicited at the clinically recommended MTD of Doxil® in all animal species, the ABC phenomenon could be induced in a wide range of animal species at much lower doses upon repeated administration. Consequently, we emphasized the possible detrimental impact of the ABC phenomenon on the therapeutic efficacy of many PEGylated nanocarrierbased metronomic chemotherapies. Effect of dosing schedule and rationale design on the antitumor efficacy of a metronomic-based combination therapy Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. Currently, the paradigm of metronomic chemotherapy, which aims to use conventional chemotherapeutics to inhibit tumor angiogenesis, is emerging as a promising strategy for anti-angiogenic cancer therapy in both preclinical studies and

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clinical trials [6,7]. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Instead, remarkable antitumor effects can be realized in the clinical setting only by combining anti-angiogenic “metronomic therapy” with either conventional chemotherapy or radiotherapy. Nonetheless, to glorify the potential benefits of combination therapy, issues of dosing scheduling and treatment sequencing are critical. As demonstrated earlier, metronomic chemotherapy with CTX augments the accumulation of DXR-SL in solid tumors and thereby improves its therapeutic efficacy [104]. Such synergistic antitumor effects of metronomic CTX in combination with DXR-SL were dosing-schedule dependent. Sequential administration of DXR-SL (every 6 days) either 3 days before or on the same day of the first CTX metronomic dosing was found to significantly increase median survival time (MST) in a B16BL6 melanoma-bearing mice model. On the other hand, sequential administration of DXR-SL (every 6 days) 3 days after the first CTX metronomic dosing shortened the MST of tumor-bearing mice. We revealed that metronomic CTX temporarily normalized the tumor vasculature, with a normalization window of 1e2 days, resulting in better perfusion and improved drug delivery/efficiency. Given that DXR-SL exhibited longcirculating characteristics and accumulated in solid tumors via the EPR effect [105e108], we assumed that a prior, or concomitant, administration of DXR-SL could result in a synchronized delivery of SL to tumor tissue within the vascular normalization window induced by metronomic CTX. As a consequence, a synergistic antitumor effect was observed. On the other hand, late administration of DXR-SL could trigger an inadequate presentation of SL to tumor tissue outside the normalization window leading to a potentially compromised intratumor accumulation and/or antitumor efficacy of the combined treatment. In a similar manner, Luan et al. [10] recently reported that metronomic dosing of PTX, delivered by surface-functionalized nanoparticles (F56-PTX-NP), induced tumor vascular normalization within a window of at least 9 days in a subcutaneous breast cancer xenograft mouse model. In addition, combined treatment of metronomic F56-PTX-NP and DXR, concomitantly injected during the normalization window, substantially delayed tumor growth, compared with a combination of therapies in which DXR was injected outside the normalization window. Collectively, to maximize the antitumor response of metronomic-based combination therapies, the administration schedule should be well optimized. It is noteworthy that, besides the administration schedule of metronomic-based combination therapies, the rational design of a combination therapy represents a potential prerequisite for effectiveness. In a series of studies [70,109], we found that oral metronomic S-1 dosing combined with oxaliplatin (l-OHP)-containing PEG-coated “neutral” liposomes significantly altered the tumor microenvironment, which was exemplified by enhanced tumor blood flow and/or alleviation of intratumor pressure. These results permitted the deep penetration/distribution of l-OHP-containing PEG-coated “neutral” liposomes within tumor tissue, which resulted in augmented antitumor activity. By contrast, we recently emphasized that a combination treatment of oral metronomic S-1 dosing plus l-OHP-containing PEG-coated “cationic” liposomes showed an antitumor efficacy that was lower than that of l-OHPcontaining PEG-coated “cationic” liposomes alone, and that a combined treatment of S-1 and l-OHP-containing PEG-coated “cationic” liposomes seemed to be antagonistic rather than synergistic [110]. Such disappointing results were attributed mainly to the competition for the same target by each component of combined therapy. The antitumor efficacy of l-OHP-containing PEGcoated “cationic” liposomes was confirmed to be mediated mainly through their electrostatic binding to the negatively

charged plasma membrane of tumor-derived angiogenic vascular ECs [111], rather than by extravasation into tumor tissue via the EPR effect, as with l-OHP-containing PEG-coated “neutral” liposomes [70,112]. Furthermore, metronomic dosing is known to exert its potential anti-angiogenic effect by targeting tumor vasculature ECs, rather than tumor cells [6,113]. Therefore, the decreased microvessel density induced by the anti-angiogenic potential of metronomic S-1 dosing was believed to have compromised/antagonized the antitumor efficacy of l-OHP-containing PEG-coated “cationic” liposomes via depriving them of available binding sites on the newly formed tumor angiogenic blood vessels. In the same context, Holtz et al. [114] have indicated that a combination of the antiangiogenic drug SU5416 (tyrosine kinase inhibitor) with a low dose of PTX did not provide a therapeutic advantage against VEGFmodified ovarian cancer (ID8) cells, and that the combination therapy was rather antagonistic. Accordingly, to rule out possible negative therapeutic outcomes from metronomic-based combination therapies, the chemotherapeutic agents should be critically selected with regard to the molecular target. Conclusions Metronomic chemotherapy holds much promise to circumvent several of the major pitfalls of MTD regimens. A lower incidence of drug resistance, restoration of anti-tumor immunity, reduced toxicity, better quality of life, and/or a lower financial burden for patients, collectively exalts the therapeutic potential of metronomic chemotherapy compared with MTD-administered conventional chemotherapies. It is unfortunate, however, that metronomic chemotherapy, as the sole therapeutic modality, has exhibited dismal therapeutic efficacy in many preclinical/clinical settings. The application of nanocarrier-based metronomic chemotherapy holds the potential to improve the therapeutic outcomes via achieving greater local drug concentrations at target sites while reducing the off-target side effects. Furthermore, optimizing metronomic chemotherapy represents a challenging task to be addressed even after the broad adoption of metronomic-based chemotherapy in many clinical settings. The best selection of chemotherapeutic agents to use according to tumor type along with issues of dosing, timing and sequencing are critical considerations. Acknowledgment We thank Dr. J.L. McDonald for his helpful advice in writing the manuscript. This study was supported, in part, by grants from Takahashi Industrial and Economic Research Foundation, Takeda Science Foundation, the Uehara Memorial Foundation and a Grantin-Aid for Scientific Research (B) (15H04639) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Abbreviations 50 -DFUR ABC CAP CDDP CEPs CPT-11 CrEL CeS CSCs CTX CXB DCs DXR

doxifluridine accelerated blood clearance capecitabine cisplatinum circulating endothelial progenitors irinotecan cremophor EL chemoeswitch cancer stem-like cells cyclophosphamide celecoxib dendritic cells doxorubicin

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DXR-SL doxorubicin-containing PEGylated liposomes ECs tumor vascular endothelial cells ETO etoposide F56-PTX-NP F56-conjugated paclitaxel-loaded nanoparticles LLCC Lewis lung carcinoma cells l-OHP oxaliplatin MPS mononuclear phagocyte system MTD maximum tolerated dose MTX methotrexate NGR-SSL-PTX NGR-modified sterically stabilized liposomes containing paclitaxel NPs nanoparticles PLD DXR-containing PEGylated liposomes PLGA NPs poly(lactic-co-glycolic acid) nanoparticles PLGA-PRINT® Poly(lactic acid-co-glycolic acid)-particle replication in non-wetting templates PTX paclitaxel SCID severe combined immunodeficiency SSL-PTX sterically stabilized paclitaxel liposomes TPT topotecan Tregs regulatory T cells TSP-1 thrombospondin 1 UFT uracil/tegafur VEGFR-1 vascular endothelial growth factor receptor-1 VLB vinblastine VNB vinorelbine Conflicts of interest The authors report no conflicts of interest in this work. References [1] P. Sreeramoju, S.K. Libutti, Strategies for targeting tumors and tumor vasculature for cancer therapy, Adv. Genet. 69 (2010) 135e152. [2] S. Ugel, J.G. Facciponte, F. De Sanctis, A. Facciabene, Targeting tumor vasculature: expanding the potential of DNA cancer vaccines, Cancer Immunol. Immunother. 64 (2015) 1339e1348. [3] A.S. Abu Lila, T. Ishida, H. Kiwada, Recent advances in tumor vasculature targeting using liposomal drug delivery systems, Expert Opin. Drug Deliv. 6 (2009) 1297e1309. [4] A. Pezzolo, F. Parodi, M.V. Corrias, R. Cinti, C. Gambini, V. Pistoia, Tumor origin of endothelial cells in human neuroblastoma, J. Clin. Oncol. 25 (2007) 376e383. [5] R.K. Jain, The next frontier of molecular medicine: delivery of therapeutics, Nat. Med. 4 (1998) 655e657. [6] R.S. Kerbel, B.A. Kamen, The anti-angiogenic basis of metronomic chemotherapy, Nat. Rev. Cancer 4 (2004) 423e436. [7] E. Pasquier, M. Kavallaris, N. Andre, Metronomic chemotherapy: new rationale for new directions, Nat. Rev. Clin. Oncol. 7 (2010) 455e465. [8] T. Tagami, A.S. Abu Lila, M. Matsunaga, N. Moriyoshi, H. Nakamura, K. Nakamura, et al., Improved intratumoral delivery of PEG-coated siRNAlipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model, Drug Deliv. Transl. Res. 2 (2012) 77e86. [9] K. Nakamura, A.S. Abu Lila, M. Matsunaga, Y. Doi, T. Ishida, H. Kiwada, A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA, Mol. Ther. 19 (2011) 2040e2047. [10] X. Luan, Y.Y. Guan, J.F. Lovell, M. Zhao, Q. Lu, Y.R. Liu, et al., Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel, Biomaterials 95 (2016) 60e73. [11] C. Li, H. Wang, F. Lin, H. Li, T. Wen, H. Qian, et al., Bioinformatic exploration of MTA1-regulated gene networks in colon cancer, Front. Med. 10 (2016) 178e182. [12] T. Ichise, S. Adachi, M. Ohishi, M. Ikawa, M. Okabe, R. Iwamoto, et al., Humanized gene replacement in mice reveals the contribution of cancer stroma-derived HB-EGF to tumor growth, Cell Struct. Funct. 35 (2010) 3e13. [13] T. Browder, C.E. Butterfield, B.M. Kraling, B. Shi, B. Marshall, M.S. O'Reilly, et al., Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer, Cancer Res. 60 (2000) 1878e1886. [14] T. Torimura, H. Iwamoto, T. Nakamura, H. Koga, T. Ueno, R.S. Kerbel, et al., Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma, Transl. Oncol. 6 (2013) 511e519. [15] O.G. Scharovsky, L.E. Mainetti, V.R. Rozados, Metronomic chemotherapy: changing the paradigm that more is better, Curr. Oncol. 16 (2009) 7e15.

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