Editorial For reprint orders, please contact: [email protected]
Nanomedicine for treatment of cancer stem cells “Nanomedicine for the targeting of cancer stem cells may provide a practical solution to actually cure cancer at its earliest stage … owing to its sustained, controlled and targeted delivery of therapeutics, high efficiency for drug transportation across the cell membrane as well as the various drug barriers, and preferable pharmacokinetics and biodistribution.” KEYWORDS: cancer nanotechnology n drug targeting n multiple drug resistance n intracellular autophagy n nanotheranostic n pharmaceutical nanotechnology
Cancer stem cells (CSCs) are cancer cells that possess properties similar to that of normal stem cells, such as the ability to give rise to all cell types found in a particular cancer tissue. As such, CSCs are supposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement in survival and quality of life of cancer patients, especially for sufferers of metastatic disease [1]. Conventional therapies can kill bulky cancer cells, but are often unable to eliminate CSCs [2]. It is, therefore, a challenge to develop CSC-specific reagents to cure the cancer at its earliest stage, however, their application is limited by low selectivity and poor response [3,4]. Nanomed icine may be defined as the application and further development of nanotechnology to solve problems in medicine, specifically to diagnose, treat and prevent diseases [5]. Nanomedicine for the targeting of CSCs may provide a practical solution to actually cure cancer at its earliest stage (i.e., to cure cancer before a tumor forms) owing to its sustained, controlled and targeted delivery of therapeutics, high efficiency for drug transportation across the cell membrane as well as the various drug barriers, and preferable pharmacokinetics and biodistribution [6–9].
non-CSCs based on CSC phenotypes, however, no universal CSCs phenotypes exist; rather, CSCs phenotypes are thought to be cancer specific. Recent studies in CSCs phenotypes have raised several challenges: CSC phenotypes can vary between patients for any type of cancer; the CSC phenotypes between primary cancer specimens and their corresponding xenograft may be substantially different; multiple CSC pools exist within individual tumors [12]. Thus, CSC phenotypes could be variable, and it will be imperative to target all CSC subsets within the cancer to prevent relapse. In fact, the status of CSCs is also variable, and CSCs can be converted from non-CSCs [13]. Thus, both non-CSCs and CSCs should be eradicated to cure cancer. CSCs exhibit the following unique characteristics: quiescence, which makes CSCs insensitive to conventional therapeutics; self-renewal signaling pathways, including the Wnt, Hedgehog and Notch pathways; high levels of drug efflux pumps, which confers the drug resistance of CSCs; enhanced DNA repair ability; high levels of antiapoptotic molecules; and CSC niches, which support the unique characteristics of CSCs [3].
Cancer stem cells CSCs represent a small subpopulation of cancer cells that exhibit many unique characteristics including quiescence, self-renewal and pluripotency [10]. CSCs from acute myeloid leukemia were first isolated by Bonnet et al. in 1997 [11]. Theoretically, CSCs could be distinguished from
Conventional strategies against CSCs Conventional strategies against CSCs include blocking self-renewal signalling, inhibiting survival mechanisms, inhibiting DNA damage responses, targeting CSC phenotypes, and applying differentiating therapy; and targeting CSC niches [1–4]. Conventional anti-CSC drugs include small molecule inhibitors, chemotherapy, and gene and protein drugs. Small molecule inhibitors against the Wnt, Hedgehog and Notch pathways make up the major part of anti-CSC
10.2217/NNM.13.195 © 2014 Future Medicine Ltd
Nanomedicine (2014) 9(2), 181–184
Jie Gao International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China
Si-Shen Feng Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, Engineering Drive 4, 117576, Singapore
Yajun Guo Author for correspondence: International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China Tel.: +86 21 81870801 Fax: +86 21 81870810 [email protected]
part of
ISSN 1743-5889
181
Editorial
Gao, Feng & Guo
drugs [4]. Although efficient, anti-CSC drugs have many disadvantages, which include unfavorable pharmaceutical properties, undesired damages to normal stem cells and difficulty to achieve combined therapy. For elimination of CSCs, combined therapy is necessary since targeting multiple CSC pathways are more effective than inhibiting a single pathway and both nonCSCs and CSCs must be eradicated. However, achieving combined therapy is not as easy in vivo as in vitro, since a major challenge in combined therapy is to transfer the benefits of the synergistic effects observed in vitro to the in vivo setting as each drug has its own pharmacokinetics and biodistribution.
Nanomedicine for treatment of CSCs Nanomedicine can improve the therapeutic index of conventional therapeutics owing to its manner for sustained, controlled and targeted delivery. It can extend the range of existing anticancer strategies and can, therefore, be useful in targeting CSCs. Nanomedicines targeting CSCs include prodrugs, micelles, liposomes, dendrimers, nanohydrogels, solid lipid nanoparticles and nanoparticles of biodegradable polymers. Here we highlight five potential mechanisms underlying the superiority of nanomedicine in targeting CSCs.
“Although efficient, anticancer stem cell
drugs have many disadvantages, which include unfavorable pharmaceutical properties, undesired damages to normal stem cells and difficulty to achieve combined therapy.” First, the unfavorable pharmaceutical properties of anti-CSC drugs could be greatly overcome by nanomedicine. For example, curcumin shows anti-CSC activity, but its efficacy is limited by its poor bioavailability. Compared with free curcumin, curcumin-loaded nanomedicine showed enhanced stability, bioavailability and antitumor effects [14]. Cyclopamine, an inhibitor of the Hedgehog pathway, could inhibit CSCs. The clinical use of cyclopamine is hampered by its high hydrophobicity, systemic toxicity and poor pharmacokinetics. Zhou et al. developed an N-(2-hydroxypropyl) methacrylamide-based cyclopamine conjugate to overcome these drawbacks [15]. The conjugate demonstrated selective killing of prostate CSCs and the bioactivity of cyclopamine was retained after conjugation to the polymer. Advanced molecular biomaterials, such as natural or synthesized polymers, could 182
Nanomedicine (2014) 9(2)
be used to develop stimuli-responsive nanomedicine, and thus further enhance the specific accumulation of the formulated therapeutics among cancer cells and CSCs. Second, CSC phenotypes could serve as candidate targets. Nanomedicine could be modified with CSC phenotype-specific ligands, such as CSC antigens, which could improve the specific targeting of nanomedicines to CSCs. An example is the single-walled carbon nanotubes (SWNTs) conjugated with CD133 antibodies (anti-CD133–SWNTs) developed by Wang et al. [16]. The in vitro tumorigenicity of glioblastoma CD133+ cells were selectively blocked after treatment with anti-CD133–SWNTs under irradiation with near-infrared laser light. Third, nanomedicine could combine chemotherapy with other physical therapies, such as hyperthermia therapy, for synergistic effects. These physical approaches could be employed to target both CSCs and bulky cancer cells. This strategy includes the local delivery of the nanomedicine and subsequent body irradiation or ultrasound. Burkeet et al. demonstrated that although breast CSCs are resistant to traditional hyperthermia, they are indeed sensitive to multiwalled carbon nanotube-mediated hyperthermia and lose their long-term proliferative capacity following treatment [17]. Fourth, nanomedicine overcomes drug resistance mainly through two mechanisms: intrinsic properties (bypassing or inhibiting the efflux pump) and codelivery of efflux pump inhibitors. Nanomedicines could bypass and/or inhibit the efflux pump and achieve higher intracellular accumulation, whereas free drugs are often internalized by diffusion across the cell membrane, making them vulnerable to efflux pumps [18–20]. In addition, nanomedicines that codeliver chemotherapeutics and efflux pump inhibitors further strengthen the activity of nanomedicines in overcoming drug resistance. Finally, nanomedicines can be engineered to achieve multifunctional and multimodality treatment strategies that offer the feasibility to codeliver chemotherapy drugs and anti-CSC drugs. Recently, multifunctional liposomes have been developed, either in the form of a single liposome or combination of two separate liposomes, which have achieved superior activity against CSCs and bulky cancer cells [21]. The strategy of a single liposome is complicated. However, it is easy to be applied since it uses a single-dosage protocol and thus can achieve a synergistic effect of the two for drugs formulated in the same vehicle. The strategy of combination of two separate future science group
Nanomedicine for treatment of cancer stem cells
liposomes is simple and flexible although the synergistic effects of the two liposomes may not be easily achieved in vivo, as each liposome may have its own pharmacokinetics and biodistribution. It is therefore imperative to compare the two strategies in the same experimental setup in further studies. It should be pointed out that the development of nanomedicine targeting CSCs is still at an early stage but it is rapidly evolving. More proofof-concept experimental data should be obtained to confirm the targeting activities and anti-CSC mechanisms of nanomedicines.
Difficulties & challenges Although significant advances have been achieved, many challenges still remain for nanomedicines that target CSCs: The molecular mechanism of how CSCs form tumors still remains unclear. Elucidating the molecular mechanism of CSCs would greatly contribute to the development of CSC-targeted nanomedicines; Nanomedicines are is still far from perfect. They suffer from several drawbacks such as intracellular autophagy and possible nanotoxicity. Conjugating targeting ligands to nano medicines may not improve their accumulation in cancer, but instead, there is evidence that high binding affinity can decrease the penetration of nanomedicines owing to a ‘binding-site barrier’; Coformulation of multiple therapeutics, including chemotherapy drugs and anti-CSC drugs, in one nanomedicine may have technical difficulties as a high payload of both hydrophobic and hydrophilic drugs in one nanomedicine has to be achieved. Furthermore, coordinated release of both chemotherapy drugs and anti-CSC drugs in one nanomedicine may be necessary for their synergistic effects. However, it is difficult to normalize the drug release rate of both drugs and maintain a desired drug:drug ratio;
1
2
3
Reya T, Morrison SJ, Clarke MF et al. Stem cells, cancer, and cancer stem cells. Nature 414(6859), 105–111 (2001). Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5(4), 275–284 (2005). Zhou BB, Zhang H, Damelin M et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery.
future science group
The safety of CSC-targeted nanomedicines deserves attention. CSCs share many of the properties of normal stem cells. Thus, the potential therapeutic window of CSC-targeted nanomedicines, and the choice of anti-CSC drugs, drug combination and dosing regimen should be optimized.
Future perspective Looking forward to the future for CSC-targeted nanomedicines, we have a number of points that are particularly promising but require further study, which include: Continued study of the molecular mechanisms of CSCs; Nanomedicines for the detection of CSCs and in cancer theranostics; Nanomedicines for the multimodality treatment of CSCs; Nanoimmunotherapy (development of nanotechnology to solve immunotherapy problems) for CSCs; Safety issues in nanomedicine. Financial & competing interests disclosure This work was supported in part by the grants from the National Natural Science Foundation of China, Shanghai Commission of Science & Technology, Ministry of Science & Technology of China (973 & 863 program projects), Pudong Commission of Science & Technology of Shanghai, a special grant from Ministry of Education of China (Key Laboratory), the Shanghai Commission of Education and the National Special Projects for New Drug Development & Infectious Diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Nat. Rev. Drug Discov. 8(10), 806–823 (2009).
References 4
5
Editorial
Shigdar S, Lin J, Li Y et al. Cancer stem cell targeting: the next generation of cancer therapy and molecular imaging. Ther. Deliv. 3(2), 227–244 (2012). Feng SS. New-concept chemotherapy by nanoparticles of biodegradable polymers: where are we now? Nanomedicine (Lond.) 1(3), 297–309 (2006).
www.futuremedicine.com
6
Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. 7(4), 597–615 (2012).
7
Wang K, Wu X, Wang J et al. Cancer stem cell theory: therapeutic implications for nanomedicine. Int. J. Nanomedicine 8, 899–908 (2013).
8
Dong X, Mumper RJ. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress. Nanomedicine 5(4), 597–615 (2010).
183
Editorial 9
Gao, Feng & Guo
Shapira A, Livney YD, Broxterman HJ et al. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist. Updat. 14(3), 150–163 (2011).
10 Dean M, Fojo T, Bates S et al. Tumour stem
cells and drug resistance. Nat. Rev. Cancer 5(4), 275–284 (2005). 11 Bonnet D, Dick JE. Human acute myeloid
leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3(7), 730–737 (1997). 12 Visvader JE, Lindeman GJ. Cancer stem
cells: current status and evolving complexities. Cell Stem Cell 10(6), 717–728 (2012). 13 Chaffer CL, Marjanovic ND, Lee T et al.
Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154(1), 61–74 (2013).
184
14 Mimeault M, Batra SK. Potential
applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy. Chin. Med. 6, 31 (2011). 15 Zhou Y, Yang J, Rhim JS et al. HPMA
copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects. J. Control. Release 172(3), 946–953 (2013). 16 Wang CH, Chiou SH, Chou CP et al.
Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine 7(1), 69–79 (2011). 17 Burke AR, Singh RN, Carroll DL et al.
The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated
Nanomedicine (2014) 9(2)
photothermal therapy. Biomaterials 33(10), 2961–2970 (2012). 18 Parhi P, Mohanty C, Sahoo SK et al.
Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov. Today 17(17–18), 1044–1052 (2012). 19 Gao J, Feng SS, Guo Y. Nanomedicine
against multidrug resistance in cancer treatment. Nanomedicine 7(4), 465–468 (2012). 20 Zhang Z, Tan S, Feng SS. Vitamin E TPGS
as a molecular biomaterial for drug delivery. Biomaterials 33(19), 4889–4906 (2012). 21 Zhang L, Yao HJ, Yu Y et al. Mitochondrial
targeting liposomes incorporating daunorubicin and quinacrine for treatment of relapsed breast cancer arising from cancer stem cells. Biomaterials 33(2), 565–582 (2012).
future science group
Nanomedicine for treatment of cancer stem cells “Nanomedicine for the targeting of cancer stem cells may provide a practical solution to actually cure cancer at its earliest stage … owing to its sustained, controlled and targeted delivery of therapeutics, high efficiency for drug transportation across the cell membrane as well as the various drug barriers, and preferable pharmacokinetics and biodistribution.” KEYWORDS: cancer nanotechnology n drug targeting n multiple drug resistance n intracellular autophagy n nanotheranostic n pharmaceutical nanotechnology
Cancer stem cells (CSCs) are cancer cells that possess properties similar to that of normal stem cells, such as the ability to give rise to all cell types found in a particular cancer tissue. As such, CSCs are supposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement in survival and quality of life of cancer patients, especially for sufferers of metastatic disease [1]. Conventional therapies can kill bulky cancer cells, but are often unable to eliminate CSCs [2]. It is, therefore, a challenge to develop CSC-specific reagents to cure the cancer at its earliest stage, however, their application is limited by low selectivity and poor response [3,4]. Nanomed icine may be defined as the application and further development of nanotechnology to solve problems in medicine, specifically to diagnose, treat and prevent diseases [5]. Nanomedicine for the targeting of CSCs may provide a practical solution to actually cure cancer at its earliest stage (i.e., to cure cancer before a tumor forms) owing to its sustained, controlled and targeted delivery of therapeutics, high efficiency for drug transportation across the cell membrane as well as the various drug barriers, and preferable pharmacokinetics and biodistribution [6–9].
non-CSCs based on CSC phenotypes, however, no universal CSCs phenotypes exist; rather, CSCs phenotypes are thought to be cancer specific. Recent studies in CSCs phenotypes have raised several challenges: CSC phenotypes can vary between patients for any type of cancer; the CSC phenotypes between primary cancer specimens and their corresponding xenograft may be substantially different; multiple CSC pools exist within individual tumors [12]. Thus, CSC phenotypes could be variable, and it will be imperative to target all CSC subsets within the cancer to prevent relapse. In fact, the status of CSCs is also variable, and CSCs can be converted from non-CSCs [13]. Thus, both non-CSCs and CSCs should be eradicated to cure cancer. CSCs exhibit the following unique characteristics: quiescence, which makes CSCs insensitive to conventional therapeutics; self-renewal signaling pathways, including the Wnt, Hedgehog and Notch pathways; high levels of drug efflux pumps, which confers the drug resistance of CSCs; enhanced DNA repair ability; high levels of antiapoptotic molecules; and CSC niches, which support the unique characteristics of CSCs [3].
Cancer stem cells CSCs represent a small subpopulation of cancer cells that exhibit many unique characteristics including quiescence, self-renewal and pluripotency [10]. CSCs from acute myeloid leukemia were first isolated by Bonnet et al. in 1997 [11]. Theoretically, CSCs could be distinguished from
Conventional strategies against CSCs Conventional strategies against CSCs include blocking self-renewal signalling, inhibiting survival mechanisms, inhibiting DNA damage responses, targeting CSC phenotypes, and applying differentiating therapy; and targeting CSC niches [1–4]. Conventional anti-CSC drugs include small molecule inhibitors, chemotherapy, and gene and protein drugs. Small molecule inhibitors against the Wnt, Hedgehog and Notch pathways make up the major part of anti-CSC
10.2217/NNM.13.195 © 2014 Future Medicine Ltd
Nanomedicine (2014) 9(2), 181–184
Jie Gao International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China
Si-Shen Feng Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, Engineering Drive 4, 117576, Singapore
Yajun Guo Author for correspondence: International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China Tel.: +86 21 81870801 Fax: +86 21 81870810 [email protected]
part of
ISSN 1743-5889
181
Editorial
Gao, Feng & Guo
drugs [4]. Although efficient, anti-CSC drugs have many disadvantages, which include unfavorable pharmaceutical properties, undesired damages to normal stem cells and difficulty to achieve combined therapy. For elimination of CSCs, combined therapy is necessary since targeting multiple CSC pathways are more effective than inhibiting a single pathway and both nonCSCs and CSCs must be eradicated. However, achieving combined therapy is not as easy in vivo as in vitro, since a major challenge in combined therapy is to transfer the benefits of the synergistic effects observed in vitro to the in vivo setting as each drug has its own pharmacokinetics and biodistribution.
Nanomedicine for treatment of CSCs Nanomedicine can improve the therapeutic index of conventional therapeutics owing to its manner for sustained, controlled and targeted delivery. It can extend the range of existing anticancer strategies and can, therefore, be useful in targeting CSCs. Nanomedicines targeting CSCs include prodrugs, micelles, liposomes, dendrimers, nanohydrogels, solid lipid nanoparticles and nanoparticles of biodegradable polymers. Here we highlight five potential mechanisms underlying the superiority of nanomedicine in targeting CSCs.
“Although efficient, anticancer stem cell
drugs have many disadvantages, which include unfavorable pharmaceutical properties, undesired damages to normal stem cells and difficulty to achieve combined therapy.” First, the unfavorable pharmaceutical properties of anti-CSC drugs could be greatly overcome by nanomedicine. For example, curcumin shows anti-CSC activity, but its efficacy is limited by its poor bioavailability. Compared with free curcumin, curcumin-loaded nanomedicine showed enhanced stability, bioavailability and antitumor effects [14]. Cyclopamine, an inhibitor of the Hedgehog pathway, could inhibit CSCs. The clinical use of cyclopamine is hampered by its high hydrophobicity, systemic toxicity and poor pharmacokinetics. Zhou et al. developed an N-(2-hydroxypropyl) methacrylamide-based cyclopamine conjugate to overcome these drawbacks [15]. The conjugate demonstrated selective killing of prostate CSCs and the bioactivity of cyclopamine was retained after conjugation to the polymer. Advanced molecular biomaterials, such as natural or synthesized polymers, could 182
Nanomedicine (2014) 9(2)
be used to develop stimuli-responsive nanomedicine, and thus further enhance the specific accumulation of the formulated therapeutics among cancer cells and CSCs. Second, CSC phenotypes could serve as candidate targets. Nanomedicine could be modified with CSC phenotype-specific ligands, such as CSC antigens, which could improve the specific targeting of nanomedicines to CSCs. An example is the single-walled carbon nanotubes (SWNTs) conjugated with CD133 antibodies (anti-CD133–SWNTs) developed by Wang et al. [16]. The in vitro tumorigenicity of glioblastoma CD133+ cells were selectively blocked after treatment with anti-CD133–SWNTs under irradiation with near-infrared laser light. Third, nanomedicine could combine chemotherapy with other physical therapies, such as hyperthermia therapy, for synergistic effects. These physical approaches could be employed to target both CSCs and bulky cancer cells. This strategy includes the local delivery of the nanomedicine and subsequent body irradiation or ultrasound. Burkeet et al. demonstrated that although breast CSCs are resistant to traditional hyperthermia, they are indeed sensitive to multiwalled carbon nanotube-mediated hyperthermia and lose their long-term proliferative capacity following treatment [17]. Fourth, nanomedicine overcomes drug resistance mainly through two mechanisms: intrinsic properties (bypassing or inhibiting the efflux pump) and codelivery of efflux pump inhibitors. Nanomedicines could bypass and/or inhibit the efflux pump and achieve higher intracellular accumulation, whereas free drugs are often internalized by diffusion across the cell membrane, making them vulnerable to efflux pumps [18–20]. In addition, nanomedicines that codeliver chemotherapeutics and efflux pump inhibitors further strengthen the activity of nanomedicines in overcoming drug resistance. Finally, nanomedicines can be engineered to achieve multifunctional and multimodality treatment strategies that offer the feasibility to codeliver chemotherapy drugs and anti-CSC drugs. Recently, multifunctional liposomes have been developed, either in the form of a single liposome or combination of two separate liposomes, which have achieved superior activity against CSCs and bulky cancer cells [21]. The strategy of a single liposome is complicated. However, it is easy to be applied since it uses a single-dosage protocol and thus can achieve a synergistic effect of the two for drugs formulated in the same vehicle. The strategy of combination of two separate future science group
Nanomedicine for treatment of cancer stem cells
liposomes is simple and flexible although the synergistic effects of the two liposomes may not be easily achieved in vivo, as each liposome may have its own pharmacokinetics and biodistribution. It is therefore imperative to compare the two strategies in the same experimental setup in further studies. It should be pointed out that the development of nanomedicine targeting CSCs is still at an early stage but it is rapidly evolving. More proofof-concept experimental data should be obtained to confirm the targeting activities and anti-CSC mechanisms of nanomedicines.
Difficulties & challenges Although significant advances have been achieved, many challenges still remain for nanomedicines that target CSCs: The molecular mechanism of how CSCs form tumors still remains unclear. Elucidating the molecular mechanism of CSCs would greatly contribute to the development of CSC-targeted nanomedicines; Nanomedicines are is still far from perfect. They suffer from several drawbacks such as intracellular autophagy and possible nanotoxicity. Conjugating targeting ligands to nano medicines may not improve their accumulation in cancer, but instead, there is evidence that high binding affinity can decrease the penetration of nanomedicines owing to a ‘binding-site barrier’; Coformulation of multiple therapeutics, including chemotherapy drugs and anti-CSC drugs, in one nanomedicine may have technical difficulties as a high payload of both hydrophobic and hydrophilic drugs in one nanomedicine has to be achieved. Furthermore, coordinated release of both chemotherapy drugs and anti-CSC drugs in one nanomedicine may be necessary for their synergistic effects. However, it is difficult to normalize the drug release rate of both drugs and maintain a desired drug:drug ratio;
1
2
3
Reya T, Morrison SJ, Clarke MF et al. Stem cells, cancer, and cancer stem cells. Nature 414(6859), 105–111 (2001). Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5(4), 275–284 (2005). Zhou BB, Zhang H, Damelin M et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery.
future science group
The safety of CSC-targeted nanomedicines deserves attention. CSCs share many of the properties of normal stem cells. Thus, the potential therapeutic window of CSC-targeted nanomedicines, and the choice of anti-CSC drugs, drug combination and dosing regimen should be optimized.
Future perspective Looking forward to the future for CSC-targeted nanomedicines, we have a number of points that are particularly promising but require further study, which include: Continued study of the molecular mechanisms of CSCs; Nanomedicines for the detection of CSCs and in cancer theranostics; Nanomedicines for the multimodality treatment of CSCs; Nanoimmunotherapy (development of nanotechnology to solve immunotherapy problems) for CSCs; Safety issues in nanomedicine. Financial & competing interests disclosure This work was supported in part by the grants from the National Natural Science Foundation of China, Shanghai Commission of Science & Technology, Ministry of Science & Technology of China (973 & 863 program projects), Pudong Commission of Science & Technology of Shanghai, a special grant from Ministry of Education of China (Key Laboratory), the Shanghai Commission of Education and the National Special Projects for New Drug Development & Infectious Diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Nat. Rev. Drug Discov. 8(10), 806–823 (2009).
References 4
5
Editorial
Shigdar S, Lin J, Li Y et al. Cancer stem cell targeting: the next generation of cancer therapy and molecular imaging. Ther. Deliv. 3(2), 227–244 (2012). Feng SS. New-concept chemotherapy by nanoparticles of biodegradable polymers: where are we now? Nanomedicine (Lond.) 1(3), 297–309 (2006).
www.futuremedicine.com
6
Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. 7(4), 597–615 (2012).
7
Wang K, Wu X, Wang J et al. Cancer stem cell theory: therapeutic implications for nanomedicine. Int. J. Nanomedicine 8, 899–908 (2013).
8
Dong X, Mumper RJ. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress. Nanomedicine 5(4), 597–615 (2010).
183
Editorial 9
Gao, Feng & Guo
Shapira A, Livney YD, Broxterman HJ et al. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist. Updat. 14(3), 150–163 (2011).
10 Dean M, Fojo T, Bates S et al. Tumour stem
cells and drug resistance. Nat. Rev. Cancer 5(4), 275–284 (2005). 11 Bonnet D, Dick JE. Human acute myeloid
leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3(7), 730–737 (1997). 12 Visvader JE, Lindeman GJ. Cancer stem
cells: current status and evolving complexities. Cell Stem Cell 10(6), 717–728 (2012). 13 Chaffer CL, Marjanovic ND, Lee T et al.
Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154(1), 61–74 (2013).
184
14 Mimeault M, Batra SK. Potential
applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy. Chin. Med. 6, 31 (2011). 15 Zhou Y, Yang J, Rhim JS et al. HPMA
copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects. J. Control. Release 172(3), 946–953 (2013). 16 Wang CH, Chiou SH, Chou CP et al.
Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine 7(1), 69–79 (2011). 17 Burke AR, Singh RN, Carroll DL et al.
The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated
Nanomedicine (2014) 9(2)
photothermal therapy. Biomaterials 33(10), 2961–2970 (2012). 18 Parhi P, Mohanty C, Sahoo SK et al.
Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov. Today 17(17–18), 1044–1052 (2012). 19 Gao J, Feng SS, Guo Y. Nanomedicine
against multidrug resistance in cancer treatment. Nanomedicine 7(4), 465–468 (2012). 20 Zhang Z, Tan S, Feng SS. Vitamin E TPGS
as a molecular biomaterial for drug delivery. Biomaterials 33(19), 4889–4906 (2012). 21 Zhang L, Yao HJ, Yu Y et al. Mitochondrial
targeting liposomes incorporating daunorubicin and quinacrine for treatment of relapsed breast cancer arising from cancer stem cells. Biomaterials 33(2), 565–582 (2012).
future science group
