Home

Search

Collections

Journals

About

Contact us

My IOPscience

Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

This content has been downloaded from IOPscience. Please scroll down to see the full text. 2014 Nanotechnology 25 445101 (http://iopscience.iop.org/0957-4484/25/44/445101) View the table of contents for this issue, or go to the journal homepage for more

Download details: IP Address: 128.122.253.212 This content was downloaded on 15/02/2015 at 14:42

Please note that terms and conditions apply.

Nanotechnology Nanotechnology 25 (2014) 445101 (7pp)

doi:10.1088/0957-4484/25/44/445101

Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery Ambarish Pandey1,3, Sasmit Sarangi2,3, Kelly Chien1, Poulomi Sengupta2, Anne-Laure Papa2, Sudipta Basu2 and Shiladitya Sengupta2 1 2

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Laboratory of Nanomedicine, Brigham and Women’s Hospital, Boston, MA, USA

E-mail: [email protected] Received 6 July 2014, revised 26 August 2014 Accepted for publication 9 September 2014 Published 10 October 2014 Abstract

Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to selfassembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics. Keywords: nanoparticles, drug delivery, cisplatin, clopidogrel (Some figures may appear in colour only in the online journal) Abbreviations

EPR

enhanced permeability and retention

OCT DAPI

optimum cutting temperature 4′,6-diamidino-2-phenylindole

SACN

self-assembling cisplatin nanoparticles

Nanoparticles have been identified as an extremely important aid in improving drug delivery and consequently, could be vital for future improvements in cancer chemotherapy [1]. Clinically approved cancer nanoparticles have to date been very effective in reducing therapeutic side effects, however there has been a distinct lack of nanoparticles which have been shown to effectively improve patient survival in clinical settings [2]. One of the reasons that has been identified to hamstrung several diverse cancer nanotherapeutics, has been the observation that many solid organ tumors develop several impediments to drug penetration and delivery, particularly in the core of the tumor [2, 3]. It has been observed that chemotherapy often accumulates around the vasculature of the tumor and deeper penetration is significantly lower due to the very high interstitial pressures observed in solid tumors [4].

1. Introduction Enhancing drug delivery to tumors continues to be an extremely important challenge in the field of oncology. 3

Contributed equally to the manuscript.

0957-4484/14/445101+07$33.00

1

© 2014 IOP Publishing Ltd Printed in the UK

Nanotechnology 25 (2014) 445101

A Pandey et al

These observations of inadequate tumor core penetration have been independently verified using particles of progressively increasing sizes as well [5]. Patients with cancer often develop thrombocytosis and their platelets frequently show exaggerated activity. This is considered to be one of the reasons for cancer associated thrombosis and has been historically considered to be an important sign of occult cancer [6]. Platelets have been implicated in supporting cancer cells in a wide variety of ways, including but not limited to increasing metastasis [7], angiogenesis [8] and tumor proliferation [9]. Several studies have provided clear evidence that a reduction in the number of platelets exerts anti-cancer activity and maybe synergistic with chemotherapy [10]. Recently, platelets have been demonstrated to be actively preventing intra-tumoral hemorrhage by secretion of granule contents [11]. Functional inhibition of platelets, with drugs like aspirin and clopidogrel, has been utilized as one of the cornerstones of secondary prevention of ischemic events in cardiology. The effects of platelet inhibition in cancer have been poorly explored. Our group has recently shown in vitro evidence that anti-platelet drugs could be synergistically increasing the cytotoxic effect of chemotherapy by direct effects on cancer cells [12]. In this current study, we investigated the effect of the platelet P2Y12 inhibitor, clopidogrel on drug delivery in a murine breast cancer model. The primary hypothesis was that clopidogrel would inhibit granule secretion from activated platelets and this could increase specific drug delivery to the tumor.

2.2. Estimation of fluorescent particle delivery

The frozen tumor sections were allowed to warm up to room temperature and then coverslipped with Vectashield hardset mounting media with DAPI (Vector Labs). After hardsetting, they were imaged with a Nikon eclipse Ti microscope. Random areas of the sections were used to manually count the number of particles seen in any particular field. All pictures were taken at a magnification of 40X. 2.3. Particle to vessel ratio estimation

The tumor sections were fixed in −20 °C acetone, blocked with 10% goat serum before incubation in a primary antibody solution against Von Willebrand Factor (1 : 200 polyclonal rabbit, Dako) for 90 min. The samples were then probed with Alexa fluor-conjugated anti-rabbit secondary antibody at room temperature for 2 h. Nuclei was counterstained with DAPI. Images were captured with an immunofluorescence microscope (Nikon Eclipse) at 10× and 40× magnification. 40X images were captured of random fields and then were quantified for number of particles and vessels by two independent observers. 2.4. Nanoparticle synthesis

The detailed methodology on synthesis of self-assembled cisplatin nanoparticles (SACNs) has been reported previously [13, 14]. Briefly, L-α-Phosphatidylcholine, Pt(II)-cholesterol conjugate and 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino (Polyethylene Glycol)2000] (2 : 1 : 0.2 weight ratio) were dissolved in DCM, evaporated into a thin and uniform film and subsequently hydrated to form light yellow to whitish appearing hydrated liposomes with viscous texture. It was passed though Sephadex G-25 column and extruded at 65 °C. A measured amount of the extruded liposome was heated at 100 °C in 1.6 mg mL−1 concentration of 1,2-Phenylenediamine in DMF for 2 h. Pt (II) amount was calculated using UV Spectrophotometry (Shimadzu 2450). The release profile of cisplatin liposomes was evaluated at 37 °C in neutral and acidic (tumor like) pH in triplicates. The % release was plotted against time. The results show significant difference in acidic and neutral pH, which favors the controlled release of cancer drug in tumorous microenvironment (figure 1).

2. Materials and methods 2.1. In vivo fluorescent particle delivery study

Red Fluorescent (580/605) FluoSpheres (Life Technologies) at three different sizes (100 nm, 200 nm and 500 nm) were used in this study. 1 × 106 4T1 breast cancer cells (obtained from American Type Culture Collection and used within six months of resuscitation of frozen stock) were implanted subcutaneously in the flanks of four-week-old BALB/c female mice (weighing 16 g, Charles River Laboratories). The fluorescent particles were injected intravenously on day 10 when the tumors reached approximately 300–400 mm3 in volume. The approximate numbers of particles injected/animal are as follows: 100 nm—3.6 × 1010, 200 nm—2.3 × 109 and 500 nm—1.5 × 109. All three sizes of particles were injected both with and without intraperitoneal clopidogrel pretreatment (10 mg kg−1), in at least three animals per treatment group. All the animals were sacrificed at 48 h after the administration of the particles and the tumors were harvested by necropsy. The tumors were placed in molds with OCT compound and flash frozen by contact with liquid nitrogen. The frozen tumors were then stored at −80 °C until they were sectioned by an ultramicrotome, at a thickness of 5 μM. The tumor sections were then mounted on slides and again stored at −80 °C.

2.5. Drug accumulation study

4T1 tumors were implanted as mentioned above for the fluorescent particle study. The treatment groups for this study were free cisplatin (5 mg kg−1), SACN (5 mg kg−1), Clopidogrel + Free cisplatin, Clopidogrel + SACN. For the combination therapy groups, the mice were pretreated with intraperitoneal clopidogrel (10 mg kg−1), 3 h before free cisplatin/SACNs were administered via tail vein injection on day 10. Each group consisted of three animals. All the mice were sacrificed at 24 h post drug injection and their tumors were removed after a necropsy. The tumor tissues were then processed using standard protocol and the platinum content of the solution was measured by flameless atomic absorption spectrometry. 2

Nanotechnology 25 (2014) 445101

A Pandey et al

A

B DSPE-PEG Cholesterol Cisplatin Conjugate Phosphatidylcholine

Size Distriction by Number

40

% Release

Number (%)

30

20

10

30 acidic 20 neutral 10

0

0 1

10

C

100

1000

0

D

Size (d.nm)

10 20

30 40

50 60 70 80 90 100 110 120 Time (hours)

Figure 1. Self-assembling cisplatin nanoparticle (SACN) synthesis and characterization as previously reported. (A) Bioconjugation of

Cisplatin to cholesterol. (B) Schematic representation of SACN. (C) Dynamic Light Scattering (DLS) of SACN showing the size distribution. (D) Release kinetics plot of SACN in acidic and neutral pH.

was no significant difference in the observed absolute numbers with larger fluorescent particles of 200 nm and 500 nm (figure 2(B)). Vasculature was subsequently labeled with an antibody for Von Willebrand factor and particle vessel ratio was then calculated as an indirect measure of the level of particle penetration from the vasculature. A ratio significantly higher or lower than 1, implied a lack of co-localization of vasculature and the particles. A lack of particle penetration would manifest as a linear association between vasculature and the particles and the particle vessel ratio would be closer to 1. In all three sizes, the addition of clopidogrel significantly altered the particle vessel ratio away from 1 (figure 2(C)). It was evident from this analysis that even when clopidogrel did not increase the number of particles delivered to the tumor, it still managed to induce a deeper penetration of the particle into the tumor.

2.6. In vivo tumor growth and survival study 5

4T1 breast cancer cells (3 × 10 ) were implanted subcutaneously in the flanks of four-week-old BALB/c female mice (weighing 20 g, Charles River Laboratories). The drug therapy was started on day 8 when the tumors reached approximately 100 mm3 in volume. The treatment groups in the study were: control; free cisplatin only (0.5 mg kg−1); clopidogrel only (10 mg kg−1); SACNs only (0.5 mg kg−1); clopidogrel (10 mg kg−1) + free cisplatin (0.5 mg kg−1); clopidogrel (10 mg kg−1) + SACN (0.5 mg kg−1). For the combination therapy groups (clopidogrel + free cisplatin/SACN), the mice were pretreated with intraperitoneal clopidogrel 3 h before cisplatin based chemotherapy was administered via tail vein injection. Drug administration was done every third day and a total of three doses were given for each drug on day 8, 11, 14. In the control groups, the animals received PBS instead of the drug at the same volume. All the six groups consisted of eight animals each. The tumor volumes, calculated using formula L × B2, and body weights were monitored on a daily basis. The primary end point of the study was animal death due to tumor burden or tumor ulceration through the skin. The Harvard Institutional Use and Care of Animals Committee approved all animal procedures.

3.2. Clopidogrel increases intra-tumoral delivery of cisplatin

The above-mentioned findings were further validated in the same tumor model by utilizing free cisplatin and a recently developed SACN. In a separate study of intra-tumoral drug accumulation, the amount of platinum delivered to the tumors was assessed after 48 h of treatment with a single dose of either cisplatin or SACN. As expected, use of SACN was associated with 2 folds greater accumulation of platinum in tumor tissue as compared to free cisplatin only. Furthermore, use of SACN with clopidogrel resulted in a 4 fold greater accumulation of platinum as compared to SACN alone. In contrast, use of free cisplatin with clopidogrel resulted in a 2–2.5 fold greater accumulation of platinum in the tumor tissues as compared to cisplatin alone (figure 3).

3. Results 3.1. Clopidogrel improves the intra-tumoral penetration of nanospheres

Clopidogrel pretreatment in a subcutaneous 4T1 tumor model increased the number of 100 nm fluorescent particles observed on high power fields (figures 2(A) and (B)). There 3

Nanotechnology 25 (2014) 445101

A Pandey et al

Figure 2. (A) Comparison of the relative intra-tumoral delivery of 100 nm particles, with and without clopidogrel, as quantified by the distribution of the number of particles per high power field. (B) Representative images of tumor sections from BALB/c mice with ten day old 4T1 tumors, given I.V injections of three sizes of red fluorescent nanospheres, with and without clopidogrel. The tumors were harvested at 48 h (post I.V injection) and then cryosectioned for imaging. Insets show magnified images of selected area. All the sections were counterstained with DAPI for nuclear staining. (C) Scatter plot showing the distribution of nanoparticle/blood vessel density ratio in high power fields as seen in clopidogrel treated (left) and control groups. The ratio represents the concentration of nanospheres with respect to blood vessel density in a particular high power-field and has been used as a marker of degree of nanoparticle penetration in tumor tissue. A ratio close to 1 represents that nanosphere concentration is linearly associated with blood vessel density with increased concentration in regions of high blood vessel density (e.g. tumor surface with high blood vessel density) and low concentration in the regions with low vessel density (e.g. tumor core with low blood vessel density). A ratio ≫1 or ≪1 represents increased concentration of the nanospheres in regions with low blood vessel density and vice-versa signifying an increased tumor penetration. As seen in the scatter plots there is a strong segregation of the data points close to 1 representing a vessel density dependent distribution of nanospheres in control samples. Whereas, in clopidogrel treated groups the data points are scattered ≫1 or ≪1 representing increased tumor penetration and nanosphere concentration in regions with much lower vessel density (tumor core).

4

Nanotechnology 25 (2014) 445101

A Pandey et al

(A) 500

(B) 500

SACN

400

% relative platinum concentration

% relative platinum concentration

Cisplatin SACN+ clopidogrel

300 200 100

Cisplatin+Clopidogrel

400 300 200 100

0 SACN

0

SACN+ clopidogrel

Cisplatin Cisplatin+Clopidog

Treatment groups

Treatment groups

Figure 3. Effect of clopidogrel on intra-tumor delivery of cisplatin. 4T1 subcutaneous tumor bearing BALB/c mice were pre-treated with

clopidogrel (10 mg kg−1) followed by high dose free cisplatin (5 mg kg−1) in one group and high dose SACN (5 mg kg−1) in the other group. The tumor samples were harvested 48 h after treatment and relative platinum content/unit weight in dissected solubilized whole tumors was estimated using by flameless atomic absorption spectrometry. Each graph represents the relative concentration of platinum in the combination therapy group normalized to that in chemotherapy only (SACN only in (A) and free cisplatin only in (B)) groups (* p value < 0.05 by ANOVA).

therapeutic delivery to the tumor can often be the difference between non-responders and patients who display a complete pathological response. It has been shown that a strong pathological response at the outset of therapy can often make a dramatic difference in the expected prognosis and life span of a patient [15]. Nanoparticles have been heralded as a potential solution to this persistent problem as appropriately sized particles display preferential delivery to tumors by utilizing the enhanced permeability and retention (EPR) effect. Briefly, vascular abnormalities as seen in tumor vasculature can enhance permeability of macromolecules and defective lymphatics in the tumor cause subsequent retention. This leads to a preferential accumulation at the site of the tumor and can increase circulation time of the active agent as well [16]. However, it is being increasingly appreciated that the magnitude of the EPR effect can be variable and is often offset by the opposing force of the increased interstitial pressures seen in solid tumors [2, 17]. Tumor vasculature is drastically different in structure and organization in comparison to normal vasculature. This is primarily a consequence of the rapid and disorganized growth of vasculature that is need in tumors, to keep up with their high metabolic demands. Platelets have been shown to play an essential role in maintaining the dysfunctional tumor vasculature and their granule secretion has been shown to continuously prevent intra-tumoral hemorrhage [11]. It was also recently demonstrated that depletion of platelets with an antibody can increase the delivery of paclitaxel to tumors [18]. A near complete platelet depletion would be difficult to translate to clinical practice as a consequence of the very high risk of life threatening bleeding. Clopidogrel is a suitable candidate for a more clinically achievable approach as it inhibits the secretion of alpha granules specifically [19]. This property along with their generalized suppression of platelet activity could be explanations for the observed size dependent delivery enhancement seen here. Intra-tumoral hemorrhage could also be assisting delivery deeper from the vasculature

3.3. Clopidogrel enhances the efficacy of cisplatin based chemotherapeutic agents

Synergistic effect of clopidogrel in combination with cisplatin based chemotherapeutic agents was tested in a 4T1 murine subcutaneous breast cancer model. Clopidogrel was used in combination with free cisplatin and SACN. The combination of cisplatin and clopidogrel was more efficacious than cisplatin alone, in reducing the growth of tumors and improving survival (figure 2(A)). Our group has previously shown that the SACNs are more effective than cisplatin on both tumor growth studies as well as in survival studies [14]. The addition of clopidogrel pretreatment with SACNs caused a significant additional therapeutic benefit in comparison to SACNs alone with a significant reduction in tumor growth rate as well as an increased survival as seen in the Kaplan–Meyer survival analysis (figure 4). Thus, clopidogrel significantly enhanced the efficacy of both free cisplatin as well as cisplatin based nanoformulation.

4. Discussion We observe several important findings in this study. First, clopidogrel increases the permeability of leaky tumor vessels thereby rendering it more susceptible to penetration by foreign agents such as chemotherapeutic drug molecules. Second, this property of clopidogrel can be used to enhance the intra-tumoral delivery of cisplatin based chemotherapeutic agents. Finally, clopidogrel can be used synergistically with cisplatin-based nanoformulations to reduce tumor growth and improve survival. Taken together, these findings highlight the potential of antiplatelet agents such as clopidogrel as an adjuvant to preferentially target chemotherapeutic agents against tumor tissues. The therapy of aggressive cancers is often limited by an inadequate tumor response to chemotherapy. A lack of 5

Nanotechnology 25 (2014) 445101

A Pandey et al

Figure 4. (A) Effect of pretreatment with clopidogrel (10 mg kg−1), 3 h before I.V cisplatin (0.5 mg kg−1) in murine syngenic 4T1 breast

tumor model BALB/c mice. There were four different treatment groups as indicated (n = 8 in each group). Kaplan–Meier survival curves (left) indicate the increase in survival with clopidogrel and cisplatin in comparison to other groups. Daily tumor volumes growth curves (right) indicated a significantly lower growth rate with clopidogrel and cisplatin. (B) Equivalent experiments and data plots utilizing Cisplatin nanoparticles (Cis NP), instead of cisplatin. The nanoparticles were used at exactly the same doses as cisplatin in the previous experiment.

by countering the high interstitial pressures in the tumor. It is important to note here that this increased delivery and penetration observed with clopidogrel may not necessarily extend to other anti-platelet drugs. For example, aspirin may not show this effect due to a lack of suppression of platelet granule secretion [20]. The larger size of a nanoparticle could be a significant impediment for it to pass through the pores of the tumor vasculature and could be a possible reason for the greater delivery enhancement observed with nanoparticles in this study. The importance of combating high intra-tumoral interstitial fluid pressures has been increasingly appreciated for nanoparticles [21]. It is not enough for nanoparticles to be passively targeted to the tumor with the EPR effect as this phenomenon can lead to uneven drug distribution particularly to the core of the tumor [22]. Several approaches are currently being pursued to lower intra-tumoral pressures and increase nanoparticle delivery [23]. It has been suggested that normalization of tumor vasculature using anti-angiogenic agents can lower interstitial pressures and can improve the penetration of nanoparticles, particularly around the size of 12 nm [24]. However, it is generally considered that to specifically

accumulate at the tumor using the EPR effect, a nanoparticle should be in the size range of 10–100 nm [25]. Thus, delivery enhancement using tumor vessel normalization would require a very tightly controlled size so as to achieve both selective accumulation and deeper penetration. This current strategy of using functional platelet inhibition is essentially an alternative approach to the same problem and it can make the tumor vasculature more permeable and increase the vascular abnormalities. In a way it is akin to the concept of ‘synthetic lethality’ and ‘stress overload’ as seen in the development of novel targeted cancer therapies [26]. In short, a specific abnormality in cancer cells is identified and this makes the cancer uniquely sensitive to a particular targeted drug. New strategies are absolutely essential to combat the inherent resistance of tumors to therapeutic drug delivery and improve survival in metastatic and aggressive forms of cancer. This current anti-platelet strategy could be extremely important for maintaining high levels of nanoparticle delivery deep into the tumor core and consequently producing better efficacy with nanoparticle based drug delivery systems. The robust enhancement in survival following the administration of clopidogrel with both cisplatin and SACNs is a clear 6

Nanotechnology 25 (2014) 445101

A Pandey et al

indication of the potential inherent in this novel approach. This study shows evidence for a clinically relevant technique for enhancing drug delivery in breast cancer. In our knowledge, this is the first report of utilizing pharmacological platelet inhibition to augment intratumoral delivery of cancer chemotherapy. Further studies are warranted at this point to elucidate the mechanism of this increased delivery and to isolate specific granule constituents that could be involved in this process of enhanced drug delivery and vascular penetration. Furthermore, future studies are needed to determine the optimal degree of platelet inhibition and its timing in relation to the chemotherapy that is required to maximally augment tumor drug delivery without predisposing the animal to significant bleeding risks. This approach of using a safe clinically approved drug to act as a delivery adjuvant has the potential to improve clinical outcomes and begin an era where nanotherapeutics could move beyond equivalence, to clinical superiority.

[11] Ho-Tin-Noe B, Goerge T, Cifuni S M, Duerschmied D and Wagner D D Platelet granule secretion continuously prevents intratumor hemorrhage Cancer Res. 2008 68 6851–8 [12] Sarangi S et al 2013 P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer Med. Oncol. 30 567 [13] Pandey A et al 2014 Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy Cancer Res. 74 675–85 [14] Sengupta P et al 2012 Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity Proc. Natl. Acad. Sci. USA 109 11294 [15] Kuerer H M et al 1999 Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy J. Clin. Oncol. 17 460–9 [16] Fang J, Nakamura H and Maeda H 2011 The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect Adv. Drug Deliv. Rev. 63 136–51 [17] Nichols J W and Bae Y H 2014 EPR: Evidence and fallacy Journal of Control Release 90C 451–64 [18] Demers M, Ho-Tin-Noe B, Schatzberg D, Yang J J and Wagner D D 2011 Increased efficacy of breast cancer chemotherapy in thrombocytopenic mice Cancer Res. 71 1540–9 [19] Muller I et al 2001 Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement Heart 85 92–3 [20] Rinder C S, Student L A, Bonan J L, Rinder H M and Smith B R 1993 Aspirin does not inhibit adenosine diphosphate-induced platelet alpha-granule release Blood 82 505–12 [21] Jain R K and Stylianopoulos T 2010 Delivering nanomedicine to solid tumors Nat. Rev. Clin. Oncol. 7 653–64 [22] Yuan F, Leunig M, Huang S K, Berk D A, Papahadjopoulos D and Jain R K 1994 Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft Cancer Res. 54 3352–6 [23] Holback H and Yeo Y 2011 Intratumoral drug delivery with nanoparticulate carriers Pharmaceutical Res. 28 1819–30 [24] Chauhan V P et al 2012 Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner Nat. Nanotechnology 7 383–8 [25] Petros R A and DeSimone J M 2010 Strategies in the design of nanoparticles for therapeutic applications Nat. Rev. Drug Discovery 9 615–27 [26] Luo J, Solimini N L and Elledge S J 2009 Principles of cancer therapy: oncogene and non-oncogene addiction Cell 136 823–37

References [1] Schroeder A et al 2012 Treating metastatic cancer with nanotechnology Nat. Rev. Cancer 12 39–50 [2] Prabhakar U et al 2013 Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology Cancer Res. 73 2412–7 [3] Jain R K 2001 Delivery of molecular and cellular medicine to solid tumors Adv. Drug Deliv. Rev. 46 149–68 [4] Heldin C H, Rubin K, Pietras K and Ostman A 2004 High interstitial fluid pressure—an obstacle in cancer therapy Nat. Rev. Cancer 4 806–13 [5] Dreher M R, Liu W, Michelich C R, Dewhirst M W, Yuan F and Chilkoti A 2006 Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers J. Natl. Cancer Inst. 98 335–44 [6] Young A, Chapman O, Connor C, Poole C, Rose P and Kakkar A K 2012 Thrombosis and cancer Nat. Rev. Clin. Oncol. 9 437–49 [7] Erpenbeck L et al 2010 Constitutive and functionally relevant expression of JAM-C on platelets Thrombosis Haemostasis 103 857–9 [8] Bambace N M and Holmes C E 2011 The platelet contribution to cancer progression J. Thrombosis Haemostasis 9 237–49 [9] Cho M S et al 2012 Platelets increase the proliferation of ovarian cancer cells Blood 120 4869–72 [10] Stone R L et al 2012 Paraneoplastic thrombocytosis in ovarian cancer New England J. Med. 366 610–8

7

Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery.

Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based ch...
1MB Sizes 1 Downloads 7 Views