International Journal of
`Radiation Oncology
`biology
`physics
`
`www.redjournal.org
`
`Biology Contribution
`
`Preclinical Evaluation of Genexol-PM, a Nanoparticle
`Formulation of Paclitaxel, as a Novel Radiosensitizer
`for the Treatment of Non-Small Cell Lung Cancer
`Michael E. Werner, PhD,*,y
`Natalie D. Cummings, BS,*,y
`Manish Sethi, PhD,*,y
`Edina C. Wang, BS,*,y
`Rohit Sukumar, BS,*,y
`z
`Dominic T. Moore, MPH,
`and Andrew Z. Wang, MD*,y
`
`*Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer
`y
`z
`Carolina Center for Cancer Nanotechnology Excellence, and
`Division of Biostatistics and Data Management,
`Center,
`Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
`
`Received Sep 17, 2012, and in revised form Feb 1, 2013. Accepted for publication Feb 6, 2013
`
`Summary
`
`Genexol-PM was evaluated
`preclinically as a radio-
`sensitizer for chemoradiation
`therapy of non-small cell lung
`cancer (NSCLC). Using
`NSCLC cell lines and mouse
`xenograft models of NSCLC,
`we demonstrated that
`Genexol-PM is an effective
`radiosensitizer and is more
`effective than Taxol. We also
`found that Genexol-PM leads
`to lower paclitaxel dose in
`normal lung when compared
`with Taxol. Our findings
`support the clinical evaluation
`
`Purpose: A key research objective in radiation oncology is to identify agents that can improve che-
`moradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as
`preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facil-
`itate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted
`preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with
`a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC)
`as a model disease.
`Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were
`characterized. Genexol-PM’s efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell
`lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver
`after Genexol-PM administration were quantified and compared with that after Taxol administration.
`Results: Genexol-PM has a size of 23.91 0.41 nm and surface charge of8.1 3.1 mV. It releases
`paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer
`showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule coun-
`terpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensi-
`tizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that
`Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postad-
`ministration.
`
`Reprint requests to: Andrew Z. Wang, MD, 101 Manning Dr, Campus
`Box 7512, Chapel Hill, NC 27599. Tel: (919) 445-5208; E-mail: zawang@
`med.unc.edu
`Authors M.E.W. and N.D.C. contributed equally to this work.
`This work was supported by the University Cancer Research Fund
`from the University of North Carolina, a North Carolina Translational and
`Clinical Sciences Institute (NC TraCS) pilot grant, and a Lung Cancer
`Research Foundation Grant. A.Z.W. was supported by National Institutes
`of Health/National Cancer Institute K12 Career Development Award 5-
`K12-CA120780-01-05 and National
`Institutes of Health Center
`for
`
`Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 463e468, 2013
`0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
`http://dx.doi.org/10.1016/j.ijrobp.2013.02.009
`
`Nanotechnology Excellence Grant 1-U54-CA151652-01.
`Conflict of
`interest: A.Z.W.
`is a consultant
`for Samyang Bio-
`pharmaceuticals, Inc.
`Supplementary material
`www.redjournal.org.
`AcknowledgmentsdWe thank the Microscopy Services Laboratory,
`Animal Studies Core, and the Analytical Chemistry Core (School of
`Pharmacy) at the University of North Carolina for their assistance with
`procedures. We also thank E. Claire Dees for advice on this manuscript.
`
`be
`
`found
`
`at
`
`for
`
`this
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`article
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`can
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`464
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`Werner et al.
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`International Journal of Radiation Oncology  Biology  Physics
`
`of Genexol-PM in chemo-
`radiation therapy for NSCLC.
`
`Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensi-
`tizer in the preclinical setting and holds high potential for clinical translation. Our data support the
`clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC. Ó 2013 Elsevier Inc.
`
`Introduction
`
`The concurrent administration of chemotherapy and radiation
`therapy, also called chemoradiation therapy, is an important treat-
`ment paradigm in the curative management of many cancers (1).
`Chemoradiation therapy has not only consistently shown improved
`local tumor control but also improves survival when compared with
`either sequential treatment or sole administration of chemotherapy
`or radiation therapy in some malignancies (1, 2). However, che-
`moradiation therapy is not without limitations. The concurrent use
`of both chemotherapy and radiation therapy has significantly higher
`toxicities compared with either treatment alone or sequential use
`(3). Thus, the development of agents and approaches to further
`improve the therapeutic index of chemoradiation therapy has been
`a major research objective. A key challenge in this effort has been to
`selectively deliver chemotherapeutics to tumors while minimizing
`drug dose to normal tissue. Although traditional drug delivery
`techniques have failed to address this challenge (4), the develop-
`ment of nanoparticle (NP) formulations of chemotherapeutics
`offers an unprecedented opportunity. NP therapeutics possess
`important characteristics that are uniquely suited for chemo-
`radiotherapy. NPs, as macromolecules, preferentially accumulate
`in tumors through the enhanced permeability and retention (EPR)
`effect, leading to high intratumoral drug concentrations (5). NPs are
`also unable to penetrate normal vasculatures and capillaries, thus
`leading to lower drug doses to normal tissues compared with their
`small molecule counterparts. Moreover, NP therapeutics have been
`found to have lower systemic toxicity than small molecules (6).
`Lastly, NP formulations of chemotherapeutics can release their
`cargo in a controlled fashion (5). Such prolonged release can
`increase the synergistic effects of chemotherapy and radiation
`therapy. Indeed, several preclinical studies have demonstrated that
`NP chemotherapeutics can improve the therapeutic efficacy of
`chemoradiotherapy (7, 8). However, there have been no reports
`evaluating NP therapeutics that are clinically approved or under-
`going clinical investigation for use in chemoradiation therapy. Such
`studies are necessary for clinical translation of NP therapeutics in
`chemoradiation therapy. To fill this knowledge gap, we conducted
`a preclinical evaluation of Genexol-PM,
`the only clinically
`approved
`second-generation NP
`chemotherapeutic with
`a controlled drug release profile, in chemoradiation therapy using
`non-small cell lung cancer (NSCLC) as a model disease.
`Genexol-PM is a polymeric NP micelle formulation of pacli-
`taxel that has been approved in South Korea for the treatment of
`breast cancer and NSCLC (9, 10). It
`is composed of low-
`molecular-weight amphiphilic diblock copolymer, monomethoxy
`poly (ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA)
`and paclitaxel (11). Genexol-PM has shown lower toxicity than
`Taxol with its maximum tolerated dose identified as 2 to 3 times
`that of Taxol (9-11). Given that chemoradiation therapy is often
`used for locally advanced and unresectable NSCLC and paclitaxel
`has been shown be an excellent radiosensitizer in NSCLC, we
`chose to study Genexol-PM in chemoradiation therapy using
`NSCLC as a model disease. Moreover, chemoradiation therapy for
`NSCLC has significant toxicities with approximately 5% to 10%
`
`of patients dying from treatment-related pulmonary toxicities (3,
`12). Thus, there is a strong clinical need to improve chemo-
`radiation therapy for NSCLC. In this study, Genexol-PM was
`compared with Taxol in chemoradiation therapy in vitro using
`NSCLC cell lines and in vivo using mouse flank xenograft models
`of NSCLC. We also quantified the paclitaxel dose delivered to
`normal
`lung and liver
`tissues after Genexol-PM and Taxol
`administration.
`
`Methods and Materials
`
`Materials
`
`Genexol-PM was provided by Samyang Biopharmaceuticals
`Corporation (Seoul, Korea) as a gift. Each gram of Genexol-PM
`contains 115 mg of paclitaxel. Genexol-PM was resuspended in
`phosphate buffer saline based on clinical administration protocol
`before use. Taxol 6 mg/mL injectable solution (Teva, Sellersville,
`PA) was purchased from the University of North Carolina Hospital
`pharmacy.
`
`Characterization of Genexol-PM
`
`Genexol-PM size (diameter, nm) and surface charge (z-potential,
`mV) were characterized using a ZetaPALS dynamic light
`scattering detector (Brookhaven Instruments, Holtsville, NY).
`Transmission electron microscopy (TEM) images of Genexol-PM
`were obtained at
`the University of North Carolina (UNC)
`Microscopy Services Laboratory Core Facility. NPs were stained
`using a phosphotungstate stain before TEM imaging.
`
`Paclitaxel release characterization
`
`To measure the release profile of paclitaxel from Genexol-PM, 0.1
`mL of Genexol-PM solution at a concentration of 1 mg/mL was
`aliquot equally into Slide-A-Lyzer MINI dialysis microtubes with
`a molecular weight cut-off of 10 kDa (Pierce, Rockford, IL) and
`subjected to dialysis as described previously (7). Paclitaxel
`content was quantitatively analyzed using an Agilent 1100 HPLC
`(Paolo Alto, CA) equipped with a C18 chromolith flash column
`(Merck, Darmstadt, Germany). Paclitaxel
`absorbance was
`measured by a UV-VIS detector at 227 nm and a retention time of
`8.5 min in 0.25 mL/min gradient (from 0:100 to 100:0) of
`acetonitrile/water.
`
`Cell culture
`
`NSCLC cell lines were acquired from the Lineberger Compre-
`hensive Cancer Center Tissue Culture Facility. A549 cells were
`cultured in Dulbecco’s Modified Eagle Medium (DMEM) (Gibco,
`Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine
`serum (Mediatech, Manassas, VA) and penicillin/streptomycin
`(Mediatech). H460 was cultured in RPMI 1640 (Gibco) with 10%
`
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`
`Preclinical evaluation of Genexol-PM as a radiosensitizer
`
`465
`
`fetal bovine serum (FBS), 2 mM L-glutamine, 1.5 g/L Na
`bicarbonate,
`10 mM HEPES
`(4-(2-hydroxyethyl)-1-piper-
`azineethanesulfonic acid) buffer, 1 mM Na pyruvate, penicillin/
`streptomycin (Mediatech), 4.5 g/L glucose.
`
`a significant difference in AUCs between chemoradiation therapy
`with Genexol-PM compared with chemoradiation therapy with
`Taxol. Statistical analyses were performed using SAS statistical
`software, version 9.2, from the SAS Institute (Cary, NC).
`
`In vitro x-ray irradiation
`
`Quantification of paclitaxel dose in tissue
`
`Mice bearing H460 tumors (5 animals per group) were treated
`intravenously with equivalent paclitaxel dose of Taxol (2.5 mg/kg)
`or Genexol-PM (21.5 mg/kg). Mice were euthanized after 6 h or
`24 h, and organs were collected and weighed. Organs were
`homogenized 4:1 (v/w)
`in chloroform to extract paclitaxel.
`Homogenate was centrifuged, and the organic layer was collected,
`evaporated, and reconstituted in 0.1% acetic acid in methanol for
`analysis via liquid chromatography-mass spectrometry using an
`Applied Biosystems API 4000 triple quadrupole mass spectrom-
`eter with an atmospheric pressure chemical ionization interface.
`
`Results
`
`Characterization of Genexol-PM
`
`Genexol-PM’s physical properties were characterized as these
`properties have not been described in previous publications.
`Genexol-PM has a size of 23.91  0.41 nm by dynamic light scat-
`tering. The NPs are also monodisperse with a polydispersity index of
`0.08  0.02. The NP size and dispersity were confirmed by TEM
`(Fig. 1A). We found that Genexol-PM has a surface charge of 8.1
`
`Radiation therapy was given using a Precision X-RAD 320
`(Precision X-Ray, North Branford, CT) operating at 320 kvp and
`12.5 mA as described previously (7).
`
`Clonogenic survival assay
`
`Cells were seeded at densities ranging from 100 to 200,000 cells
`in 4 mL of culture medium in 25-mL flasks 1 day before treat-
`ment. Cells were treated with IC50 doses of Taxol (1.77 ug/mL for
`A549 and 17.7 ug/mL for H460) or Genexol-PM (15 ug/mL for
`A549 and 150 ug/mL for H460) for 1 hour and washed 3 times
`with fresh media after incubation. Cells were irradiated with 2
`fractions of 0, 1, 2, or 3 Gy separated by 12 hours. Cells were
`incubated and counted as described previously (7). Data were
`analyzed using Origin Pro 8.6 software. Polynomial curve fitting
`was performed using second polynomial order.
`
`In vivo tumor assay
`
`Tumors were established in the upper dorsal region of Nu/Nu mice
`by injecting 1  106 of H460 or A549 cells in a 1:1 RPMI:Ma-
`trigel solution. Tumors were incubated for 10 days (H460) or 14
`days (A549) to reach approximate tumor volume of 100 mm3
`before treatment. Mice (7 per experimental group) were treated
`intravenously with Taxol (2.5 mg/kg) or Genexol-PM (21.5 mg/
`kg) and subsequently irradiated 6 hours postinjection. The mice
`were randomized into experimental groups before treatment. The
`dose rate at a source-subject distance of 70 cm was 50 cGy/min.
`Mice were irradiated with 5 daily fractions of 3 Gy. The head and
`abdomen regions of mice were shielded using 0.5 cm of lead. Only
`the truncal region containing tumor xenograft was irradiated.
`Tumor volumes were calculated by measuring 2 perpendicular
`diameters with a caliper and using the formula of V Z 0.5  a 
`b2 where, a and b are the larger and smaller diameters, respec-
`tively. The tumors were measured every 2 days, and the relative
`percent change in tumor volume was calculated using the relation
`
`100 * (Vi Vo)/Vo, where Vi is the volume calculated and Vo is
`
`the initial volume on day 1.
`Tumor volume was measured every other day until the tumor
`reached 3 times the initial volume or 2 cm in the maximum
`dimension, at which point the animal was euthanized. All animal
`work was approved and monitored by the UNC Animal Care and
`Use Committee.
`
`Statistical methods
`
`We used response features analysis to analyze our serial measures of
`tumor growth (13). This method allows for the comparison of
`individual growth delay profiles by using summary measures. The
`particular summary measure used was the AUC (or area under the
`curve), which was particularly appropriate for the growth-delay
`profiles we encountered. The Wilcoxon 2-group method (using
`Van der Waerden normal scores) was used to test whether there was
`
`Fig. 1.
`Characterization of Genexol-PM. (A) Transmission
`electron microscopy image of Genexol-PM depicting a mono-
`disperse population of particles with a narrow size distribution of
`23.0  4.5. (B) Drug-release curve of Genexol-PM. Genexol-PM
`releases paclitaxel (Ptxl) in a first-order release kinetic. Genexol-
`
`PM was incubated in phosphate buffered saline at 37
`C.
`
`

`

`466
`Werner et al.
` 3.1 mV. We also studied the drug release profile of Genexol-PM.
`Paclitaxel release from the Genexol-PM demonstrated first-order
`controlled release kinetics with w65% drug released at 24 hours
`and 95% drug release at 48 hours (Fig. 1B).
`
`In vitro radiosensitization with Genexol-PM
`
`The therapeutic efficacy of Genexol-PM as a radiosensitizer in vitro
`was evaluated in 2 commonly studied NSCLC cell lines H460 (large
`cell) and A549 (adenocarcinoma). To determine the sensitivity of
`each cell line to Genexol-PM, a dose-response curve was performed
`with no radiation therapy for each cell line (Fig. S1). Radio-
`sensitization experiments were conducted using IC50 concentrations
`as well as equivalent paclitaxel concentrations of Genexol-PM and
`Taxol. Clonogenic survival curves of cells after combined Genexol-
`PM and fractionated radiation therapy were generated for each cell
`line. They were compared to that of fractionated radiation therapy
`alone. We demonstrated that despite the lack of EPR effect in vitro,
`Genexol-PM is an effective radiosensitizer and is more effective
`than Taxol in both cell lines at IC50 doses (Fig. 2). The sensitizer
`enhancement ratio (SER) of Taxol at 10% survival in H460 cells is
`1.03, whereas the SER of Genexol-PM is 1.12. The SER is greater in
`A549 cells at 10%; with Taxol at 1.12 and Genexol-PM at 1.23.
`Also, Genexol-PM was as effective a radiosensitizer as Taxol at
`equivalent paclitaxel doses (Fig. S2). These results confirmed that
`Genexol-PM is an effective radiosensitizer.
`
`In vivo radiosensitization with Genexol-PM
`
`To validate the in vitro result and to evaluate the efficacy of
`Genexol-PM as a radiosensitizer in vivo, we used a murine flank
`xenograft model of NSCLC. Mice bearing either H460 or A549
`cell xenograft tumors were treated with Genexol-PM, Taxol, or
`saline followed by radiation therapy. After treatment with 5 daily
`fractions of 3 Gy, the tumor growth delay curves demonstrated
`that chemoradiation therapy with Genexol-PM leads to signifi-
`cantly longer
`tumor growth delay compared with chemo-
`in H460 cells (PZ.008; Fig. 3A).
`radiotherapy with Taxol
`Although the difference between the 2 treatments does not appear
`as significant in A549 cells (PZ.18; Fig. 3B), the impression
`remains that chemoradiation therapy with Genexol-PM is more
`effective. Since tumors that were treated with chemotherapy only
`(Genexol-PM or Taxol) did not show significant difference in
`the difference between Genexol-PMþXRT and
`growth delay,
`TaxolþXRT is likely due to more effective radiosensitization by
`Genexol-PM (Fig. S3). Our results showed the high potential of
`Genexol-PM in improving chemoradiation therapy.
`
`Evaluation of normal tissue drug exposure
`
`Pulmonary toxicity is the main cause of mortality and morbidity
`from chemoradiation therapy for NSCLC. It is caused by normal
`lung tissue receiving both chemotherapy and radiation therapy. To
`determine whether Genexol-PM can lead to lower normal lung
`paclitaxel exposure, we compared the paclitaxel concentrations in
`mouse lungs after Genexol-PM and Taxol administration. We
`found that Genexol-PM leads to significantly lower lung paclitaxel
`concentration (PZ.01) acutely after injection (6 hours). This
`difference in drug concentration disappeared at 24 hours (Fig. 4).
`Given that NPs are generally cleared through hepatic clearance
`
`International Journal of Radiation Oncology  Biology  Physics
`
`Fig. 2.
`Efficacy of Genexol-PM as a radiosensitizer in non-
`small cell lung cancer cell lines in vitro. Radiation survival curves
`for (A) H460 and (B) A549 non-small cell lung cancer cells treated
`with saline, Taxol, or Genexol-PM. Cells were irradiated with 2
`fractions of indicated doses 12 hours apart. Significant differences
`between Taxol and Genexol-PM at a given dose are indicated
`y
`)
`P<.01,
`P<.05). Error bars correspond to standard error of the
`(
`mean (3 samples per time point). XRT Z radiation therapy.
`
`and the concern over hepatotoxicity, we also compared the
`paclitaxel concentration in mouse liver after Genexol-PM and
`Taxol administration. Although not
`statistically significant,
`Genexol-PM lead to lower paclitaxel exposure to mouse liver than
`paclitaxel at 6 hours (PZ.30). Similar to the drug exposure in the
`lung, there was no difference in liver paclitaxel concentration
`between Genexol-PM and Taxol at 24 hours.
`
`Discussion
`
`Advances in nanomedicine have enabled the development of many
`NP-based chemotherapeutics (14). Although they have been
`
`

`

`Volume 86  Number 3  2013
`
`Fig. 3.
`Efficacy of Genexol-PM as a radiosensitizer in chemo-
`radiation therapy for non-small cell lung cancer cell cell lines
`in vivo. Mice bearing flank tumor xenografts were administered
`(via tail-vein intravenous injection) saline, Taxol, or Genexol-PM
`followed by radiation therapy (XRT). Tumors were irradiated in 5
`daily fractions of 3 Gy beginning at 6 hours after chemotherapy
`injection. Changes in tumor volume were measured and the tumor
`growth delay curves for mice bearing (A) H460 and (B) A549
`tumors were generated.
`
`Preclinical evaluation of Genexol-PM as a radiosensitizer
`
`467
`
`widely used as chemotherapeutics, there has been limited clinical
`evaluation of these drugs in chemoradiation therapy because of
`toxicity concerns (15). Recent nanomedicine clinical translation
`efforts have focused on the development of NP formulation of
`taxanes, a class of chemotherapeutics that is also used in che-
`moradiation. Today, there are 2 clinically approved NP taxane
`formulations, nab-paclitaxel (Abraxane) and Genexol-PM, with
`several
`additional
`therapeutics under
`clinical
`investigation
`(paclitaxel poliglumex [Opaxio], BIND-014 [biologically targeted
`polymeric NP docetaxel]) (5). Among these, Genexol-PM is the
`only NP therapeutic that possesses controlled drug release and is
`approved for clinical use. Furthermore, the only other approved
`NP taxane, nab-paclitaxel (nanoparticle albumin-bound pacli-
`taxel), dissociates upon administration and cannot
`take full
`advantage of the EPR effect (16). Therefore, Genexol-PM is the
`best NP therapeutic candidate for clinical translation in chemo-
`radiation therapy.
`Preclinical studies have shown that the optimal NP physical
`characteristics for tumor targeting are sizes <100 nm with nega-
`tive surface charges (17). Genexol-PM’s properties (23.0  4.5 nm
`and 8.1  3.1 mV) suggest that it is excellent for tumor tar-
`geting. Another advantage of using Genexol-PM in chemo-
`radiotherapy is its controlled drug release. Although previous
`clinical
`investigations have demonstrated that prolonged drug
`exposure can increase the therapeutic efficacy of chemoradiation
`therapy (18), most small molecule chemotherapeutics, including
`taxanes, are too toxic to be administered continuously. NP ther-
`apeutics, conversely, can increase drug exposure time in tumors
`without
`increasing toxicity, both to local healthy tissue and
`systemically. In this study, we found Genexol-PM releases pacli-
`taxel in a controlled and slow fashion, with only 40% drug release
`after 16 hours and >90% of drug release after 48 hours. Such slow
`drug release should lead to increased synergistic effects between
`paclitaxel and radiation therapy, which in turn should result in
`improved therapeutic efficacy.
`The efficacy of Taxol as a radiosensitizer has been evaluated
`previously (19). Our study compared the efficacy of Genexol-PM
`as a radiosensitizer with that of Taxol. At
`the IC50 dose,
`
`Fig. 4. Quantification of paclitaxel dose in mouse lungs after Genexol-PM administration. Mice were administered equivalent paclitaxel
`doses of Taxol and Genexol-PM intravenously. Lungs were harvested at either 6 or 24 hours posttreatment, and paclitaxel dose was
`quantified using liquid chromatography-mass spectrometry.
`
`

`

`468
`
`Werner et al.
`
`Genexol-PM is more effective than Taxol, whereas at the same
`paclitaxel dose, Genexol-PM is as effective as Taxol in vitro.
`The in vitro results reflect the fact that the advantages of NP
`therapeutics
`in chemoradiation therapy are controlled drug
`release and biodistribution but only the effects of controlled drug
`release can be observed in the in vitro setting. Genexol-PM was
`also evaluated in vivo as a radiosensitizer in mouse xenograft
`models of NSCLC. We demonstrated that at equivalent doses of
`paclitaxel, Genexol-PM led to significantly longer tumor growth
`delay than Taxol in mice treated with chemoradiation therapy. It
`is also important to note that we used a relatively low dose of
`paclitaxel in this study. This is shown by the lack of tumor
`growth delay in mice treated with only Taxol or Genexol-PM
`compared with mice that received no treatment. Our findings
`confirm that Genexol-PM is an effective radiosensitizer. On the
`basis of NP biodistribution properties, we also hypothesized that
`Genexol-PM would lead to lower paclitaxel dose to lungs when
`compared with Taxol. Indeed, paclitaxel dose in mouse lungs
`was significantly lower in mice given Genexol-PM than that in
`mice given Taxol at 6 hours after chemotherapy administration.
`Because pulmonary toxicity from chemoradiation therapy is
`related to paclitaxel dose in normal
`lung tissue (20), such
`reduction in paclitaxel dose can result
`in lower pulmonary
`toxicity.
`In summary, we have demonstrated that Genexol-PM holds
`high potential as a radiosensitizer in chemoradiation therapy for
`NSCLC. Our findings provide the preclinical evidence to support
`the clinical evaluation of Genexol-PM as part of the chemo-
`radiation therapy regimen for NSCLC. Genexol-PM can be
`incorporated into existing chemoradiation therapy regimens in
`place of Taxol. Results from this study suggest that substituting
`Taxol with Genexol-PM can improve the therapeutic ratio of
`treatment. More broadly, our report and previously reported
`preclinical studies suggest that NP chemotherapeutics are more
`effective than their
`small-molecule counterparts as
`radio-
`sensitizers. Therefore,
`the clinical development of novel NP
`chemotherapeutics should include clinical evaluations in chemo-
`radiation therapy. Lastly, given the importance of the chemo-
`radiation therapy treatment paradigm, nanomedicine research
`efforts should focus on the development of novel NP therapeutics
`with the primary application of
`improving chemoradiation
`therapy.
`
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