ABSTRACT
3. Smart Materials for Cancer Diagnosis and Treatment 1 Lung Cancer
Lung cancer is the most common cancer worldwide and the most frequent cancer among men. The mortality of lung cancer ranks as the fi rst of overall cancer death and is over 2-fold higher than the second (liver cancer).
According to GLOBOCAN report, for 2012, approximately 1.82 million new cases of lung cancer were reported globally, representing 13.0% of the total number of all new cancer cases (Ferlay et al. 2015). In the same year, lung cancer caused 1.59 million deaths, representing 19.4% of all cancer deaths (Ferlay et al. 2015). For 2015, in the U.S. alone, the American Cancer Society estimates about 221,200 new cases and 158,040 deaths of lung cancer (Siegel et al. 2015).
There are three main types of lung cancers. (i) Non-small cell lung cancer (NSCLC). NSCLC is an umbrella term for squamous cell carcinoma, adenocarcinoma and large cell carcinoma. NSCLC is the most common type of lung cancers, representing approximately 85% of all lung cancers, relatively insensitive to chemotherapy. The overall fi ve year survival rate of NSCLC is between 11% and 17%. (ii) Small cell lung cancer (SCLC, or oat cell cancer). SCLC accounts for about 10%–15% of all lung cancers, which is generally more aggressive and metastatic than other types of lung cancers, leading to a poorer prognosis. The overall fi ve year survival rate of SCLC is 5%. (iii) Lung carcinoid tumor (or lung neuroendocrine tumor). Lung carcinoid tumor is a less malignant lung cancer, representing fewer than 5% of all lung cancers. The overall fi ve year survival rate of lung carcinoid tumor ranges between 50% and 90%. Tobacco smoking is usually considered as one of the major causes of lung cancer, which gives rise to about 86%
of new lung cancer cases (Ganti 2006), resulting from the carcinogens,
Figure 1. Schematic illustration of smart medicine for cancer diagnosis and treatment.
including nitrosamines and polycyclic aromatic hydrocarbons, exist in tobacco smoke. The incidence of SCLCs has been found highly correlated with tobacco smoking.
Six common targeted therapeutics for lung cancer are being used clinically (as seen in Table 1). They are Bevacizumab (Avastin) (Sandler et al. 2006), Ramucirumab (Cyramza) (Garon et al. 2012), Erlotinib (Tarceva) (Shepherd et al. 2005), Afatinib (Gilotrif) (Miller et al. 2012), Crizotinib (Xalkori) (Shaw et al. 2013), and Ceritinib (Zykadia) (Shaw et al. 2014). Bevacizumab is a humanized anti-vascular endothelial growth
Table 1. Summary of clinical targeted therapeutics for cancer therapy.
factor (VEGF)-A monoclonal antibody. It functions as an angiogenesis inhibitor by blocking VEGF-A and inhibiting new blood vessel formation toward tumors (Sandler et al. 2006). Ramucirumab is another angiogenesis inhibitor, which is a humanized anti-VEGFR2 monoclonal antibody, and functions by neutralizing a certain type of receptor for VEGF via antibody blockade (Garon et al. 2012). Erlotinib and Afatinib are tyrosine kinase inhibitors, and function by blocking the signaling pathway of epidermal growth factor receptor (EGFR) overexpressed on lung cancer cells (Miller et al. 2012, Shepherd et al. 2005). Crizotinib and Ceritinib are small molecular inhibitors that function by targeting ALK gene mutations, which has been found in about 5% of all NSCLCs (Shaw et al. 2013, Shaw et al. 2014).
Common lung cancer molecular targets used for smart nanomedicines include EGFR, integrin αvβ6, folate receptor and sigma receptor (as seen in Table 2). EGFR is a cell surface receptor for epidermal growth factor (EGF) that has been found upregulated in a variety of tumor cells, including lung cancer cells. Thus, EGFR has been widely used in smart nanomedicine for lung cancer specifi c affi nity. In 2007, Tseng et al. reported EGF-conjugated gelatin nanoparticles could specifi cally bind with EGFR expressing lung cancer cells via in vivo aerosol administration (Tseng et al. 2008, 2007). Later in 2009, Tseng et al. further used their EGF-conjugated gelatin nanoparticles as lung tumor-targeted drug delivery systems to deliver cisplatin specifi cally via aerosol inhalation (Tseng et al. 2009). This EGFR-targeted constructs can inhibit the in vivo lung tumor growth by about 70%. In 2011, Peng et al. reported the development of single-chain variable fragment anti-EGFR antibody-conjugated heparin nanoparticles to deliver cisplatin specifi cally to lung tumor, in comparison with full-length EGFR antibody conjugated ones (Peng et al. 2011). Single-chain variable fragment EGFR antibody has a lower molecular weight by removing Fc regions, which showed better tumor penetration function with less non-specifi c interaction with Fc receptors on normal tissues.
EGFR has also been used in inorganic smart nanomedicine for cancer diagnostic and ablation applications. In 2008, Qian et al. used single- chain variable fragment anti-EGFR antibody-conjugated pegylated gold nanoparticle to facilitate a lung tumor specifi c detection via surface-enhanced Raman scattering (Qian et al. 2008). In 2011, Yokoyama et al. developed EGFR-targeted hybrid plasmonic magnetic nanoparticles to synergistically induce autophagy and apoptosis in NSCLC cells (Yokoyama et al. 2011).
In 2013, Sadhukha et al. reported EGFR-targeted superparamagnetic iron oxide (SPIO) nanoparticles could be administered via aerosol inhalation and specifi cally bind with NSCLCs (Sadhukha et al. 2013). The therapeutic studies further demonstrated that the EGFR-targeted SPIO nanoparticles could facilitate effi cient hyperthermia therapy and signifi cantly inhibited in vivo NSCLC tumor growth.
Table 2. Summary of common molecular targets for cancer diagnosis and treatment.
Table 2. contd....
Table 2. contd.
Table 2. contd....
Integrin αvβ6 is a transmembrane receptor presenting on lung cancer cells, and can be targeted by engineered RGD peptides. In 2009, Sundaram et al. reported the development an RGD peptide-conjugated polymeric nanoparticle to deliver anti-VEGF intraceptor (Flt23k) specifi cally to lung cancer cells (Sundaram et al. 2009). In 2010, Guthi et al. developed an integrin αvβ6-targeted micelle to co-deliver magnetic resonance imaging (MRI) contrast agent iron oxide nanoparticle (IONP) and chemotherapeutic doxorubicin (Dox) specifi cally to lung cancer cells (Guthi et al. 2010, Huang et al. 2009). The integrin αvβ6-targeted constructs increased the cancer cell uptake by 3-fold, compared with non-specifi c counterparts, demonstrating potential application for image-guided, target-specifi c treatment of lung cancer.
Folate receptor is a cell surface glycoprotein that binds folate specifi cally and reduce folic acid derivatives. Folate receptor has been reported overexpressing in a variety of tumor cells including lung cancer cells, fi t to be used as a molecular target for smart nanomedicine. In 2009, Santra et al. reported tumor-targeted multifunctional folate-conjugated polyacrylic acid-coated IONPs, composed of an anti-cancer drug paclitaxel (PTX), a near infrared (NIR) dye DiR and a MRI contrast agent IONP for lung
Table 2. contd.
cancer-targeted treatment (Santra et al. 2009). In 2012, Yoo et al. demonstrated that folic acid-conjugated, PEGylated SPIO nanoparticles could facilitate a lung tumor-specifi c MR imaging for in vivo tumor detection (Yoo et al. 2012).
Sigma receptor is another lung cancer molecular target. In 2006, Huang et al. developed sigma receptor-targeted liposome-polycation-DNA nanoparticles for a lung tumor specifi c antisense oligodeoxynucleotide or siRNA delivery (Li and Huang 2006). The anisamide ligand increased cellular uptake for 4 to 7-folds by the sigma receptor overexpressing cells, producing strong antisense effi cacies to down-regulate survivin mRNA and protein levels in lung cancer cells. Later in 2012, Yang et al. developed a sigma receptor-targeted lipid/calcium/phosphate nanoparticle to co-deliver MDM2, c-myc and VEGF siRNAs specifi cally to lung metastases.
The sigma receptor-targeted constructs could signifi cantly prolong the lung tumor bearing animal survival time by 27.8% without any systematic toxicity (Yang et al. 2012). In 2013, Zhang et al. further used sigma receptor targeted lipid/calcium/phosphate nanoparticles to co-deliver siRNA targeting VEGFs and gemcitabine (Gem) monophosphate specifi cally to NSCLCs. A synergy of anti-angiogenesis therapy and chemotherapy has been observed, and the tumor growth was reduced effectively by 70% in orthotopic lung tumor model (Zhang et al. 2013).
3.2 Breast Cancer
Breast cancer is the second most common cancer worldwide and the most frequent cancer among women. The mortality rate of breast cancer ranks the fi fth of overall cancer death and the second of cancer death in women exceeded only by lung cancer. According to the GLOBOCAN report, for 2012, approximately 1.68 million new cases of breast cancer were reported globally, representing 25% of the total number of new women’s cancer cases (Ferlay et al. 2015). In the same year, breast cancer caused 522,000 deaths, representing 14.7% of women’s cancer deaths. For 2015, in the U.S. alone, the American Cancer Society estimates about 234,190 new cases and 40,730 deaths of breast cancer (Siegel et al. 2015).
There are three common types of breast cancers: (i) estrogen receptor/
progesterone receptor (ER/PR) positive breast cancer. ER/PR positive breast cancer is the most common type of all breast cancers, representing approximately 70% of all breast cancers. ER/PR positive breast cancer patients respond to hormone therapy, and have a fi ve year survival rate of over 95%. (ii) Human epidermal growth factor receptor 2 (HER2) positive breast cancer. HER2 positive breast cancer is defi ned by the overexpression of HER2 on breast cancer cell membranes, and represents about 20% to 25% of all breast cancers. HER2 positive breast cancer patients are usually treated with HER2 targeted therapeutics, and have a fi ve year survival
rate of over 87%. (iii) Triple negative breast cancer. Triple negative breast cancer is defi ned by the lack of expression of ER, PR, and HER2 in breast cancer cells, and represents about 15–20% of all breast cancers. Currently there is no clinical targeted therapeutic for triple negative breast cancers.
About 50% of triple negative breast cancer patients respond to adjuvant chemotherapy, but triple negative breast cancer cells are generally more proliferative and aggressive than the other types of breast cancers. Together with limited therapeutic approaches, triple negative breast cancer has a signifi cant poorer prognosis than other types of breast cancers, which has a fi ve year survival rate less than 74.5%.
Six targeted therapeutics are being used clinically for breast cancer (as seen in Table 1) including Trastuzumab (Herceptin) (Romond et al. 2005), Pertuzumab (Perjeta) (Baselga et al. 2012b), Ado-trastuzumab emtansine (Kadcyla) (Verma et al. 2012), Lapatinib (Tykerb) (Geyer et al. 2006), Palbociclib (Ibrance) (Finn et al. 2015) and Everolimus (Afi nitor) (Baselga et al. 2012a). Trastuzumab and Pertuzumab are anti-HER2 monoclonal antibodies. They function by neutralizing HER2 signaling cascades on HER2 positive breast cancer cells via antibody blockade (Baselga et al.
2012b, Romond et al. 2005). Ado-trastuzumab emtansine is a monoclonal antibody-chemotherapeutic drug conjugate, which is used to treat advanced HER2 positive breast cancer with resistance to trastuzumab (Verma et al. 2012). Lapatinib is a dual tyrosine kinase inhibitor. It functions by interrupting both HER2 and EGFR signaling pathways in HER2 positive breast cancers (Geyer et al. 2006). Palbociclib is an aromatase inhibitor.
It functions by blocking cyclin-dependent kinase (CDK) 4 and CDK6 to inhibit cancer cell proliferation in ER/PR positive breast cancers (Finn et al. 2015). Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that functions by blocking mTOR in ER/PR positive breast cancers.
mTOR is a protein that promotes breast cancer cells growth and division and using Everolimus to block mTOR along with a hormone therapy, can prevent tumor growth in advanced ER/PR positive breast cancer patients (Baselga et al. 2012a).
The common breast cancer molecular targets include HER2, EGFR, urokinase-type plasminogen activator receptor (uPAR), and p32 cell surface receptor (as seen in Table 2). HER2, also known as Receptor tyrosine- protein kinase erbB-2 (ERBB2), is a clinically approved biomarker and molecular target for HER2 positive breast cancers. A variety of targeted nanomedicines have been developed to target HER2 via monoclonal antibodies. For example, in 2008, Sun et al. developed a poly(d,l-lactide- co-glycolide)/montmorillonite nanoparticle decorated by Trastuzumab for targeted chemotherapy of breast cancer overexpression HER2 (Sun et al. 2008). Their fi ndings demonstrated that the half maximal inhibitory concentration (IC50) of their targeted nanomedicine is over
13-fold more effi cient than free PTX. In 2011, Stuchinskaya developed HER2-targeted PEGylated gold nanoparticles that can produce cytotoxic singlet oxygen under visible light illumination. Their fi ndings showed that this nanoparticle can selectively target HER2 positive breast cancer to facilitate effective photodynamic therapy (PDT) (Stuchinskaya et al. 2011).
In 2009, Kikumori et al. developed a HER2-targeted magnetite nanoparticle- loaded immunoliposomes to treat breast cancer via hyperthermia. It showed that hyperthermia using magnetic nanoparticle is an effective and specifi c therapy for breast cancer overexpressing HER2 (Kikumori et al. 2009).
In 2007, Lee et al. engineered a HER2-targeted magnetism-engineered iron oxide nanoprobe that can show enhanced MRI sensitivity for the in vivo detection of HER2 overexpressing breast tumors (Lee et al. 2007).
In 2002, Wu et al. reported that HER2 antibody-conjugated quantum dots (QDs) could be used to specifi cally stain actin and microtubule fi bers in the cytoplasm, and to detect nuclear antigens inside the nucleus. But the application of QD for in vivo imaging is signifi cantly limited by QD’s safety issues (Wu et al. 2003). Single-walled carbon nanotube (SWNT) is a novel nanomaterial with potential applications in cancer detection and imaging, owing to its two unique optical properties: SWNTs have a strong Raman signal for cancer cell detection, and also demonstrate strong NIR absorbance for selective photothermal ablation of tumors. In 2009, Xiao et al. functionalized SWNTs with anti-HER2 antibodies, and used them for both detection and selective photothermal ablation of HER2 positive breast cancer cells without the need of internalization by the cells (Xiao et al. 2009).
EGFR is another common molecular target that highly expresses on breast cancer cells. In 2009, Acharya et al. reported that anti-EGFR antibody- conjugated, Rapamycin encapsulating PLGA nanoparticle can effi ciently deliver anticancer drugs specifi cally to breast cancer cells, and signifi cantly inhibit breast cancer cell proliferation (Acharya et al. 2009). uPAR has also been investigated as a molecular target for breast cancer. In 2009, Yang et al.
explored the uPAR as a novel breast cancer molecular target and conjugated amino-terminal fragment of uPAR to IONPs for in vivo MR imaging of breast cancers. Their fi ndings also showed that uPAR-targeted nanoparticles have a lower accumulation in mouse liver and spleen compared with their non-targeted counterparts (Yang et al. 2009).
Other breast cancer targets, such as p32 cell surface receptor, have also been investigated to provide high breast cancer specifi city. In 2011, Kinsella et al. reported the synthesis of a LyP–1 peptide conjugated Bi2S3 nanoparticle as a new class of X-ray contrast agents (Kinsella et al. 2011). These NPs can produce quantitative, high fi delity CT images of breast tumors, and last for more than one week. Notably, these nanoparticles appear to undergo clearance from the mice via a fecal route during this time period. Although limiting the period of imaging, it provides a safe mechanism for nanoparticle clearance.
3.3 Colorectal Cancer
Colorectal cancer includes colon cancer and rectal cancer, and is the third most common cancer worldwide. The mortality of colorectal cancer ranks the fourth of overall cancer deaths following lung, liver and stomach cancers. According to the GLOBOCAN report, for 2012, approximately 1.36 million new cases of colorectal cancer were reported globally, representing 9.6% of the total number of all new cancer cases (Ferlay et al. 2015). In the same year, colorectal cancer caused 694,000 deaths, representing 8.5% of all cancer deaths. For 2015, in the U.S. alone, the American Cancer Society estimates about 132,700 new cases and 49,700 deaths of colorectal cancer (Siegel et al. 2015).
There are fi ve common types of colorectal cancers: (i) Adenocarcinoma.
More than 95% of colorectal cancers are adenocarcinomas originated from glands that make mucus to lubricate the inside of colon and rectum.
Colon adenocarcinoma has an overall fi ve year survival rate of 65.2%.
(ii) Carcinoid tumor. Carcinoid tumors originated from specialized hormone- producing cells in the intestine, representing about 1% of cancers of the gastrointestinal tract. The fi ve year survival rate of carcinoid cancer ranges from 65% to 90% based on carcinoid tumor location. (iii) Gastrointestinal stromal tumor (GIST). GIST originates from specialized cells in the wall of the colon called the interstitial cells of Cajal, representing less than 1%
of all gastrointestinal tumors. But it is the most common mesenchymal tumors of the gastrointestinal (GI) tract. GISTs have a fi ve year survival rate of 35%. (iv) Lymphoma. Primary colorectal lymphoma is a rare tumor of the GI tract, and the most common variety of colonic lymphoma is non-Hodgkin’s lymphoma (NHL). The fi ve year survival rate of primary colorectal lymphoma patient is approximately 40%. (v) Colorectal sarcoma.
Colorectal sarcoma is also a rare GI tract cancer originating from muscle and connective tissue in the wall of the colon and rectum. The fi ve year survival rate of colorectal sarcoma patient is approximately 51%.
There are fi ve common clinical targeted therapeutics for colorectal cancer (as seen in Table 1). They are Bevacizumab (Avastin) (Hurwitz et al. 2004), Ziv-afl ibercept (Zaltrap) (Sun and Patel 2013), Cetuximab (Erbitux) (Cunningham et al. 2004), Panitumumab (Vectibix) (Amado et al. 2008) and Regorafenib (Stivarga) (Grothey et al. 2013). Bevacizumab is anti-VEGF-A monoclonal antibody, and its therapeutic function is effi ciently inhibiting tumor angiogenesis by blocking VEGF-A signaling pathways (Hurwitz et al. 2004). See more information about Bevacizumab in lung cancer section. Ziv-afl ibercept is a recombinant fusion protein with VEGF-binding portions (Sun and Patel 2013). Cetuximab and Panitumumab are both anti-EGFR monoclonal antibodies that function by neutralizing EGFR signaling pathways in EGFR overexpressing cells via antibody
blockade (Amado et al. 2008, Cunningham et al. 2004). Regorafenib is a kinase inhibitor, and can block several important kinase proteins that promote tumor growth and angiogenesis (Grothey et al. 2013).
Common colorectal cancer molecular targets include EGFR, VEGF, CD44, and folate receptor (as seen in Table 2). EGFR is a colorectal cancer target protein highly overexpressed in about 80.0% human colorectal tumor tissues. In 2010, Cho et al. developed Cetuximab-conjugated magneto-fl uorescent silica nanoparticles and used them for in vivo colon cancer targeting and MR imaging. Their findings indicated that the potential application of Cetuximab as a nanomedicine targeting ligand for the detection of EGFR-expressing colon cancer using in vivo imaging approaches (Cho et al. 2010). In 2011, Löw et al. reported the development of the Cetuximab-modifi ed human serum albumin (HSA) nanoparticles as a colon cancer-targeted drug delivery carrier (Löw et al. 2011). Their nanoparticles can signifi cantly improve cellular binding and intracellular accumulation with EGFR overexpressing colon cancer cells.
VEGF is a colorectal cancer target detected in about 64.0% human colorectal tumor tissues. In 2012, Hsieh et al. reported the development of anti-VEGF antibody-conjugated SPIO nanoparticles for colon cancer specifi c MR imaging (Hsieh et al. 2012). Their fi ndings demonstrated that VEGF is an effective colon cancer target for in vivo tumor targeting and effi cient accumulation of nanoparticles in tumor tissues after systemic delivery in a colon cancer animal model.
CD44 is detected in 54% of colorectal tumor tissues. In 2010, Jain et al. developed a hyaluronic acid-coupled chitosan nanoparticles bearing oxaliplatin for targeted treatment of colon tumors (Jain et al. 2010).
They demonstrated using hyaluronic acid to target CD44 expressing colon tumor in murine model which can achieve high local drug concentration within the colonic tumors with prolonged exposure time, indicating a potential for enhanced antitumor effi cacy with low systematic toxicity.
Folate receptor was detected positive in about 33% of primaries and 44%
of metastases of colorectal tumor tissues. In 2005, Zheng et al. developed folic acid-conjugated lipoprotein-based nanoplatform to targeted folate receptor overexpressing prostate cancer cells and their fi ndings indicated that folic acid conjugation to the Lys side-chain amino groups can block binding to the normal LDL receptor and reroute the resulting conjugate to cancer cells through their folate receptors (Zheng et al. 2005). In 2010, Yang et al. demonstrated that folic acid-conjugated chitosan nanoparticles enhanced protoporphyrin IX accumulation in colorectal cancer cells, as an ideal vector for colorectal-specifi c delivery of 5-ALA for fl uorescent endoscopic detection (Yang et al. 2010).