Gold nanoparticles: Emerging paradigm for targeted drug delivery

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Oct 27, 2012 - The application of nanotechnology in medicine, known as nanomedicine, ..... Gold nanoparticles as a versatile platform for drug delivery system.
Biotechnology Advances 31 (2013) 593–606

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Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv

Research review paper

Gold nanoparticles: Emerging paradigm for targeted drug delivery system Anil Kumar a, b, 1, Xu Zhang a, 1, Xing-Jie Liang a,⁎ a b

CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11, First North Road, Zhongguancun, Beijing 100190, China Graduate University of Chinese Academy of Science, Beijing, China

a r t i c l e

i n f o

Available online 27 October 2012 Keywords: Targeted drug delivery system Gold nanomaterials Therapeutic mechanism Biological barrier Physiochemical properties Nanoparticles toxicity Nanomedicine

a b s t r a c t The application of nanotechnology in medicine, known as nanomedicine, has introduced a plethora of nanoparticles of variable chemistry and design considerations for cancer diagnosis and treatment. One of the most important field is the design and development of pharmaceutical drugs, based on targeted drug delivery system (TDDS). Being inspired by physio-chemical properties of nanoparticles, TDDS are designed to safely reach their targets and specifically release their cargo at the site of disease for enhanced therapeutic effects, thereby increasing the drug tissue bioavailability. Nanoparticles have the advantage of targeting cancer by simply being accumulated and entrapped in cancer cells. However, even after rapid growth of nanotechnology in nanomedicine, designing an effective targeted drug delivery system is still a challenging task. In this review, we reveal the recent advances in drug delivery approach with a particular focus on gold nanoparticles. We seek to expound on how these nanomaterials communicate in the complex environment to reach the target site, and how to design the effective TDDS for complex environments and simultaneously monitor the toxicity on the basis of designing such delivery complexes. Hence, this review will shed light on the research, opportunities and challenges for engineering nanomaterials with cancer biology and medicine to develop effective TDDS for treatment of cancer. © 2012 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting the nanomaterials with different stages of cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . Cancer metabolism: a novel strategy for targeted drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeted drug delivery system and their therapeutic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gold nanoparticles as a versatile platform for drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Spherical gold nanoparticles in drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Gold nanorods for drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Gold composites and other gold nanoparticles in drug delivery application . . . . . . . . . . . . . . . . . . . 6. How nanoparticles solve the barrier of targeted drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Avoiding reticuloendothelial system (RES) clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Enhancing endothelial penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Blood-brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Blood-tumor barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Nanoparticles by-passing the chaotic blood flow, plasmonic membrane, cellular barriers and multi-drug resistant tumor cells 7. Improving the efficacy of nanomaterials for targeted drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . 8. Evidence for nanomaterials toxicity on the basis of design targeted drug delivery system . . . . . . . . . . . . . . . . 9. Future prospectus of nanomaterials for the biotechnology industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author at: No. 11, First North Road, Zhongguancun, Beijing 100190, PR China. Tel.: +86 1082545569; fax: +86 10 62656765. E-mail address: [email protected] (X.-J. Liang). 1 These authors contributed equally to this work. 0734-9750/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.biotechadv.2012.10.002

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1. Introduction Targeted drug delivery system (TDDS) is the most important research field for the design and development of pharmaceutical drugs. The basic premise of a TDDS is to concentrate the drug in the tissues of interest while reducing the relative concentration of medication in other remaining tissues. As a result, the drug is localized to a greater degree on the targeted site while leaving surrounding tissues unaffected. The ideal drug delivery system delivers drug at rates finely tuned to the biological requirement of the body (Cunliffe et al., 2005; Oppenheim, 1981; Pfister and Hsieh, 1990). Due to their high specificity and efficacy, TDDS are the future in rational drug design and development. The significant advantage with TDDS includes protecting the payload and improving therapeutic index. (Alexis et al., 2008; Cho et al., 2008; Krishnan et al., 2010; Zhang et al., 2008). TDDS has several advantages for the treatment of disease quantitatively (Fig. 1). For instance, drug localization, decreased side effects, reduced dosage, modulated pharmacokinetics, controlled biodistribution, and most importantly, improved patient compliance (Allen and Cullis, 2004; Farokhzad and Langer, 2009). In this context, TDDS, especially gold-based nanoparticles (AuNPs) will be used as a model system in this review. The main objective and basic principle behind the concept of targeting is that, the specific drug receptor is targeted to fit and improve their binding affinity, to the specific receptor that ultimately will trigger the pharmacological activity (NIDA, Research monograph, 1995). There is a wide range of nanomaterial-based therapeutic approaches under development for the treatment of diseases like cancer. Among them AuNPs is also one of the more effective nanomaterials, playing major role for the treatment of cancer (Xia et al., 2011b). AuNPs can be engineered in different ways to detect a stimulus, such as molecular binding events or ionic concentration changes, and respond immediately by releasing cargo into the cells or tissue, degrading or even carrying out the chemical modification of drugs in vitro and in vivo (Dreaden et al., 2011, 2012). In addition to the potential application of nano-based materials to combine multiple therapeutic functions into a single platform, these nanoparticles can also be targeted to specific tissues, thus, reaching sub-cellular compartments or malignant at different stages (Schroeder et al., 2012). In the current era of personalized cancer medicine, nanomaterials can act as suitable platforms for the delivery of modular personalized

therapies. However, the study of the biological cancer treatment with engineered nanomaterials should be taken into account, to fulfill these goals on a long-term basis. Therefore, many critical issues must be addressed in the coming future for nano-based materials for delivery application; particularly their practical applications in biomedicine must be fulfilled before clinical applications. In this review we will emphasize various aspects of nanomaterials based on targeted drug delivery system to design better nano-platforms for medicine and pharmaceutical drug development. 2. Targeting the nanomaterials with different stages of cancer cells Recent research reported the design of nanoparticle therapeutics with various form of carriers, such as small molecule drugs, different cargo or bio-macromolecules (protein, small interfering RNA (siRNA), DNA) (Giljohann et al., 2010; Schroeder et al., 2012) and also several other compounds on the surface of nanoparticles for the diagnosis and therapeutic applications (Wang and Thanou, 2010). Tumor blood vessels are distinct from normal vessels (Minchinton and Tannock, 2006) in that they express numerous cell surface receptors (Table 1) and also extracellular matrix proteins not present in normal vessels. Expression of many of these proteins in tumor blood vessels is associated with angiogenesis (Fig. 2) (Kerbel, 2008; Risau, 1997). Tumors also contain lymphatic vessels, and such tumors also produce several growth factors that stimulate lymph-angiogenesis (e.g., vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, platelet-derived growth factor subunit-B Table 1 Receptors used for targeted drug delivery system and their distributions in different types of tumors. Extracellular receptors

Target tumor

Commonly used Transferrin receptors Folate receptor Integrin

Tissue distributions Most tumors, (Qian et al., 2002) Most tumors, (Ratnam et al., 2003) Most tumors, metastasis (Murphy et al., 2008)

For CNS (Gabathuler, 2010) Transferrin receptors Capillary Insulin receptors Capillary Opioid receptors Capillary Nicotine receptors Capillary Low-density Capillary lipoprotein receptor related proteins 1 and 2 (LRP-1 and 2) For neoplastic and vesicular targeting VEGFR EGFR Vitamin B12 receptor (cobalamin) PSMA Man-6-Phos/ insulin-like receptors LHRH receptors family Nucleolin Immunoglobin receptor (Fcγ receptor) Somastatin receptors Endolin Bombesin receptors

endothelial cells endothelial cells endothelial cells endothelial cells endothelial cells

Target tumor Tumor vesicular endothelial cells (Belting et al., 2005) Epithelial tumor cells (Mamot et al., 2003) Gastric tumors, Neuroendocrine tumors (Andersen et al., 2010) Prostate tumors (Zhao et al., 2012) Breast cancer, pancreatic cancer, gastric cancer, melanoma and hepatocellular carcinoma (Prakash et al., 2010) Breast, ovarian, endometrial, and prostate cancers (Majumdar and Siahaan, 2012) Leukemia, colon cancer, Breast cancer, Melanoma (Belting, Sandgren, 2005) Leukemia (Hymel and Peterson, 2012)

Neuroendocrine tumors (Seon et al., 2011) Vascular and lymphatic endothelium in tumors (Seon, Haba, 2011) Breast, Prostate, Small cell lung, and Pancreatic cancers (Sancho et al., 2011)

Intracellular receptors (Schally et al., 2011) Hormone receptors Sex hormone dependent tumors Fig. 1. Beneficial effects of targeted drug delivery system (TDDS) to improve the efficacy of drug for the treatment of malignant diseases.

CNS; Central Nervous System Delivery, VEGFR; Vascular endothelial growth factor receptor, EGFR; Endothelial growth factor receptor, PSMA; Prostate specific membrane antigen, LHRH; Luteinizing hormone-releasing hormone.

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Fig. 2. Targeting the receptors on different stages of tumor cells. (A) Targeted molecules that recognize exclusively tumor cells provide slight improvement of tumor accumulation. (B) Targeted molecules that recognize tumor vessels accumulate in the tumor, but entry into tumor tissue relies on passive mechanisms. (C) Targeted molecules that recognize both the vessels and tumor cells together combine the (limited) efficiency of the two targeting mechanisms. (D) Targeted molecules can penetrate tumor cells and enter into the nucleus to destroy tumor cells (so far only cell penetrating peptides (CPP) and nuclear localization signal (NLS) with such characteristics are known) which provide a particularly potent tumor targeting system. (E) Targeted molecules recognize the circulating malignant cells in the blood to treat the metastatic cancer.

(PDGF-B), etc.) (Karpanen and Alitalo, 2008). These lymphatic tissues do not show significant role for tumor growth but are important constituents of metastases like tumor blood vessels. These tumor lymphatics also express several molecular markers which can be used as specific target for the cancer treatment (Ruoslahti et al., 2010). As mentioned earlier, tumor endothelial cells express several receptors which are absent in normal cells, making them better target moieties. A primary example is the over-expression of strong affinity and selectivity to the αVβ3 integrin, which is highly expressed by several cancer cell lines (Carreiras et al.,

1995; Freed et al., 1989; Lehmann et al., 1996). Integrins are heterodimeric cell surface receptors that were found in early studies to mediate adhesion between cells and the extracellular matrix (ECM), by binding to ligands with an exposed arginine-glycine-aspartate (RGD) sequence. These receptors also stimulate intracellular signaling and gene expression involved in cell growth, migration, and survival of various types of tumor cells (Cabodi et al., 2010; Zhang and Wang, 2012). Recent evidence report the functional properties of this peptide in

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tumor model (Kim et al., 2011), which has shown highly approachable targeted molecules for cancer treatment (Garanger et al., 2007). Conjugation study of this peptide with nanomaterials such as AuNPs and magnetic nanoparticles hold great promises in the treatment of cancer (Montet et al., 2006). Researchers can potentially use these integrintargeted radiotracers in tumor imaging by single photon emission computed tomography (SPECT) or a positron-emitting radionuclide for positron emission tomography (PET) (Zhou et al., 2011). Integrins are prime targets for synaptic drug delivery and can be functionalized on the surface of AuNPs. cRGD (cyclic RGD peptide) has been modified in a wide variety of RGD-containing peptides depending upon the therapeutic approaches, e.g. RGD iRGD, cyclic RGD, PEG-RGD (Perlin et al., 2008), scrambled RGD peptide (scrRGD) GSSK(Fl)-GGGCDRGC and C-terminal amides (Montet et al., 2006) to make this peptide for theranostic application. There is another class of receptor called NRPs (neuropilins) which act as co-receptors for class 3 semaphorins. NRPs are polypeptides which play a key role in axonal guidance, it is also a member of the vascular endothelial growth factor (VEGF) family of angiogenic cytokines receptor (Bagri et al., 2009; Soker et al., 1998). Neuropilin-1 (NRP-1) is a unique multifunctional and multi-domain transmembrane glycoprotein, 1 and the primary structure of this gene is highly conserved within several vertebrate species. It was first identified in neurons of the developing nervous system, and subsequently considered as a receptor for secreted proteins called semaphorins (i.e., Sema3A, Sema3B, Sema3C and Sema3F) (Stephenson et al., 2002), Semaphorins have an essential role for chemo-repulsion and can mediate various intercellular signals to modulate diverse aspects of physiological and pathophysiologic functions of tumor cells (Bagri et al., 2009). This tumor cell-derived NRP-1 receptor is functionally active and may act as a positive modulator of tumor angiogenesis and a negative regulator of tumor cell apoptosis in presence or absence of VEGF. Additionally, expression of a soluble form of NRP-1 has been identified in prostate cancer (PC-3) cell lines and also in breast cancer (MDA-MB-321) cell lines (Soker et al., 1998), which were recently described as target molecules for cancer therapy and imaging applications (Kumar et al., 2012; Montet et al., 2006). Another example is p32 protein (gC1q receptor, hyaluronic acidbinding protein) which is primarily expressed by mitochondria but also have been found to be expressed by the surface of lymphatic, myeloid, and several tumor tissue (Fogal et al., 2008). This protein is the receptor for the tumor-lymphatic homing peptide (LyP-1), originally discovered using phage display method by Laakkonen et al. (Laakkonen et al., 2002; Laakkonen et al., 2004). These peptides also show penetration behavior into tumor tissue and enter the cell in a cell-type-specific manner. These peptides harbor the ability to concentrate in the target tissue, making them particularly efficient delivery vectors for the targeting of drugs, imaging agents and other therapeutic moieties (Enback and Laakkonen, 2007). The nucleus of a cell is an attractive target organelle, playing a fundamental role in cell-signalling. The nucleus also expresses several receptors on the cancer cell surface which helps in the translocation of drugs or therapeutic molecules inside the nucleus. Nucleolin (Christian et al., 2003), and plectin-1 (Kelly et al., 2008) are found to be present at the cell surface of tumor endothelial cells but not in normal tissues. These nuclear receptors also play a major role in the delivery of drugs and molecules into cells. Recently, 26-nucleotide guanosine-rich (G-rich) DNA sequence (AS1411) aptamer (targeted to nucleolin) functionalized gold and also polymer base nanomaterials has shown significant effects on cancer cells. It demonstrated anti-proliferative activity and subsequently found to bind nucleolin where it inhibit the pro-survival NF-κB signaling pathway and thus blocked DNA-replication and induced cell-cycle arrest and apoptosis (Bates et al., 2009). The aptamer-based design of DNA sequence interacts with the cells surface receptor ultimately delivering the drug into cells or nucleus have paved the way for more promising avenue for the treatment of cancer (Ray and White, 2010). We have

also recently evaluated the effects of this aptamer functionalized with therapeutic drug to formed self-assembled nanoparticles and its effects on the sensitivity and resistance of cancer cells (data unpublished). The potential benefit of loading drugs into nanoparticles (or conjugating of targeting molecules onto their surface) is to deliver the vehicles at the disease site and triggering drug release at specific locations in the body by changing the physiological microenvironment (Fischel-Ghodsian et al., 1988; Timko et al., 2010). Alternatively, external stimuli such as ultrasound (Burks et al., 2011; Dromi et al., 2007; Schroeder et al., 2007), light (Kuruppuarachchi et al., 2011; Lu et al., 2008; Wu et al., 2008) or radio-frequency electromagnetic fields and thermal conductivity (Derfus et al., 2007; Hoare et al., 2011), can be used to trigger local drug release at different stages of tumor proliferation. 3. Cancer metabolism: a novel strategy for targeted drug delivery In addition to the unique characteristic of the vascular structure of cancer cells, altered expression of receptors, and mutated proteins, there is another distinct hallmark of cancer (Hanahan and Weinberg, 2011) the abnormal metabolism. During the 1920's, Otto Warburg discovered that the cancer cells consume glucose more rapidly than normal tissue cells and produce lactic acid even in presence of oxygen (Krebs, 1972). This phenomenon was then recognized as “Warburg effect”. The aberrant metabolism is now considered as a result of “metabolic reprogramming” (Ward and Thompson, 2012). During this transforming process, the input signal is growth factors and nutrient conditions (Pan and Mak, 2007). A series of signal transduction were activated upon stimulation, for example, the PI3K/Akt/mTOR pathway, with transcription factors initiating the changing phase of metabolism, shifting from quiescent to proliferation (Ward and Thompson, 2012). The activation of PI3K/Akt/mTOR pathway played a key role in transformation and the carbon flux was greatly increased afterwards, combined with the glutamine addiction. Instead of forming Acetyl-CoA by pyruvate dehydrogenase (PDH) and join the tricarboxylic acid (TCA) cycle, the pyruvate directly goes to lactic acid production process. Some of the enzymes in TCA cycle are also mutated, for example the aberrant pyruvate kinase isozymes M2 (PKM2), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), etc. Mutations would lead to abnormal oncometabolites, such as 2-HG (Kalinina et al., 2012; McCarthy, 2012; Ward et al., 2012). Also, the lactic acid production often results in low pH environment, which in turn promote cancer cell proliferation and drug resistance (Hu and Zhang, 2009; Montopoli et al., 2011; Tredan et al., 2007). Research is currently focused on molecular therapies (Pathania et al., 2009) and the combination with nanomaterial were still vacant. Potential applications should include the conjugation of such drug molecules with nanoparticles and composite nanomaterials formed by combination of drugs and nanoparticles such as AuNPs. However, it is still possible to collect some useful information about applications of nanomaterials related to intracellular diagnosis, toxicity profile assays and cellular dynamic processes. In vitro studies revealed that some nanoparticles could affect cellular metabolism. Przybytkowski et al. (2009). found that pheochromocytoma derived cancer cells (PC12) treated with CdTe and CdSe/ZnS quantum dots up-regulated HIF-1α and down-regulated β-oxidation of fatty acids, thus increased fatty acids synthesis and accumulation. Carbon nanomaterials (CNMs), such as Carbon nanotubes (CNTs) and graphene could absorb some nutrients and proteins (Guo et al., 2008), leading to nutrient depletion and sometimes elevate oxidative stress (Pumera, 2012). Proteomic study profiling of titanium dioxide (TiO2) nanoparticles treatment on normal human bronchial epithelial cells (BEAS-2B) revealed systematic metabolic alterations and protein expression changes (Ge et al., 2011). These proteins were identified and found that there were some key proteins related to metabolism, cell proliferation and signaling pathways such as insulin-like growth

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factor-1(GF-1), phosphatidylinositol 3-kinases (PI3K) and mitogen activated protein kinases (MAPK) signaling pathway, which were generally considered as carcinogenic (Cairns et al., 2011; Vander Heiden et al., 2009). As a potential medicine candidate, AuNPs usually would not affect the cell viability and gold medication has a long history for treatment of arthritis, epilepsy, rheumatic diseases (Bhattacharyya et al., 2011). Based on this we may hypothesize that the AuNPs could interact with the cellular metabolism while possibly maintaining the cell viability. Earlier studies of biological applications for AuNPs focused mainly on biosafety issues. For example, Ravi Shukla et al. used fluorescein isothiocyanate (FITC)-conjugated AuNPs to monitor the entrance and biodistribution within macrophages. The encapsulation of AuNPs did not trigger cytokine excretion and reduced the cellular reactive oxygen species (ROS) production (Shukla et al., 2005). Interestingly, several reports introduced similar scenario upon addition of chloroauric acid into cell cultures (Anshup et al., 2005) or cyanobacterium (Mishra et al., 2011; Monica et al., 2011). Both eukaryotic and prokaryotic cells can synthesize AuNPs, which indicates the possibility of AuNPs interacting with metabolic processes. The interaction of AuNPs with cellular metabolism has also been explored. Li et al. evaluated addition of 20 nm AuNPs to human lung cancer cell (MRC-5) and discovered enhanced autophagy and oxidative stress (Li et al., 2010), thus leading to genomic instability (Li et al., 2011). Ma et al. used the same system for further illustrating that enhanced autophagy was a result of accumulated autophagosome due to AuNPs uptake and lysosome impairment (Ma et al., 2011). In addition, lysosome was not the only organelle affected by intracellular nanoparticle uptake. Wang et al. found that gold nanorods (AuNRs) can accumulate preferentially within the mitochondria (Wang et al., 2010). B16F10 cells when incubated with 13 nm AuNPs for 20 h resulted in accumulation of nanoparticles within endoplasmic reticulum (ER) and golgi apparatus (Chang et al., 2008). The accumulation of AuNPs within certain cellular compartments could alter normal cell metabolism, but not cell viability. Wang et al. reported that dietary administration of AuNPs (15 nm) to Drosophila larvae, resulted in activation of PI3K/Akt/mTOR signaling pathway and significant lipid accumulation compared to controls (Wang et al., 2012). It is well known that aberrant PI3K signaling could change metabolism and lead to type-2 diabetes and carcinogenesis (Cantley, 2002; Saltiel and Kahn, 2001). Therefore, optimal design of an effective TDDS is needed prior to clinical use. 4. Targeted drug delivery system and their therapeutic mechanisms In order to optimally design a TDDS, it is necessary to elucidate the mechanism of action when a drug is released in the body or disease site. It is vital to understand how and why these targeted nanomaterials transform the signal in complex environment. It is also pertinent to understand how these targeted drug delivery systems communicate in a complex environment or in different stages of a disease when used in therapeutics. The exact communication link between the disease and delivery system provides a better way in complex environment for the vehicles to reach therapeutic materials at the disease site, and these communication link found in the body in the form of chemical signal (protein, heat, and several coagulation factors) (Park et al., 2010; von Maltzahn et al., 2011a). Recently Bhattacharya and her coworkers have extensively investigated the nanoparticles in communication with biological components, wherein signaling modules would first target tumors and then broadcast the tumor location to receive NPs in circulation where the external electromagnetic energy is transferred as heat. The release of heat near to surrounding/local environment disrupts tumor vessels (Fig. 3) and the nanoparticles engineered with human proteins such as tumor-targeted tissue factor (tTF) etc., autonomously survey host vessels for angiogenic tumor receptors and, in their presence, activate the extrinsic coagulation pathways. These coagulation pathways can be found by developing peptide coatings

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that recognize fibrin on the surface of nanomaterials. These peptides act as substrate and target enzyme for the coagulation of transglutamines factor XIII (FXIII) which appears in the form of signal, largely absent in non-targeted molecules (von Maltzahn et al., 2011a). This communication link is not always the same with all types of nanomaterials due to varying physiochemical properties and different functionalized coatings. Thus different materials broadcast the communication signals in different ways to treat and diagnose the disease. Mukherjee and his co-workers investigated a number of targeted moieties present on the surface of nanoparticles having different mechanisms to internalize the cells. In their study, they engineered nanoparticles targeted with same antibody, namely, Cetuximab, targeted to EGFR with two different approaches, one using AuNPs conjugated with complete surface coverage and another AuNPs conjugated with partial surface coverage with the antibody. They observed noticeable difference in the process of internalization when the same antibody (or target molecule) is conjugated with the same material but with a difference in the number/amount present on the surface. The complete surface covering materials clustered in the glycosphingolipid (GSL) domains at the plasma membrane is internalized by dynamin-2 (Dyn-2) dependent caveolar endocytosis, and the partially covered nanoparticles (Au@C225-P; ca. one C225 unit per NP) is internalized by Cdc42-dependent pinocytosis/phagocytosis and requires the polymerization of actin (Bhattacharyya et al., 2012). Therefore, such communication is not only dependent on the characteristic of the materials and properties but is also reliant upon the type and quantum of functionalized ligands on the surface of the delivery system. In our previous study, we explored the concept of designing various conjugations on the surface of ultra-small AuNPs (2 nm). We found that the amount of targeted ligands present on the surface of nanomaterials competes with the receptors expressed by cells, and these receptors ultimately assist therapeutic molecules to deliver into the cells (Kumar et al., 2012; Maus et al., 2010). 5. Gold nanoparticles as a versatile platform for drug delivery system The application of nanotechnology involving diagnosis, monitoring, and control has garnered attention in recent biomedical field. The biomedical use of metallic nanoparticles, especially AuNPs, has peaked interests over the past decade owing to its intrinsic tunable optical properties that can be used directly or indirectly for the treatment and diagnosis of disease (Kumar et al., 2011). Potential applications of AuNPs have been recently studied and administrated in phase I & II clinical trials for cancer treatment (Thakor et al., 2011). The ease of tailoring AuNPs into different size, shape, and decorations with different functionalities encourages the researchers to explore the ultimate potentials of AuNPs for biomedicinal purposes, especially for drug delivery and imaging. The spherical AuNPs size (10 nm) has a characteristic UV absorbance at 520 nm, and the increase or decrease in sizes corresponds to red or blue shifts. As for gold nanorods (AuNRs), the absorbance will skew towards near infra-red range (690 nm–900 nm) (Tong et al., 2009). These intrinsic optical properties provide the opportunity for AuNPs as composite theranostic agents in clinic. 5.1. Spherical gold nanoparticles in drug delivery The first report of successful synthesis of spherical AuNPs was published in 1951 by Dr. Turkevich (Foss et al., 1992). Ever since the 13 nm pivot synthesis, gold nanospheres ranging from 0.8 nm to 200 nm could be obtained by facile one-pot synthesis. Pan, Y.et al. evaluated the cytotoxicity of AuNPs from 0.8 nm to 15 nm in four cell lines, and found that connective tissue fibroblasts, epithelial cells, macrophages, and melanoma cells prove most sensitive to gold particles measuring 1.4 nm, but 15 nm was non-toxic (Pan et al., 2007). Another report conducted by Chen, Y. S.et al. found that, injection of different sized AuNPs into mice could lead to lethal effects if the size was between

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5 nm and 50 nm. (Chen et al., 2009). These studies suggested that with proper size selection, the adverse toxic effect could be eliminated. Recently we also evaluated the initialization properties of small (2 nm) AuNPs conjugated with therapeutic peptide (PMI or p12) and targeted peptide (CRGDK) on surface of AuNPs. Targeting the CRGDK moieties with different concentration onto the surface of AuNPs, the internalization of AuNPs were significantly enhanced. Furthermore, 2 nm AuNPs could penetrate into the cell nucleus, thus greatly promoting the efficacy in treating breast cancer (Kumar et al., 2012). We also evaluated the size-dependent penetration of AuNPs nanoparticles in tumor tissues and found that only particles measuring less than 10 nm were observed within nucleus, while the larger particles were aggregated in the cytoplasm (Huang et al., 2012). Moreover, ultra-small nanoparticles successfully delivered anticancer drugs such as doxorubicin (Dox) into the nucleus of cancer cells and it was found to be an effective delivery system for treatment of resistant cancer cells (Zhang et al., 2011). AuNPs functionalized with cRGD (cyclic RGD) peptide can also be used for imaging of breast cancer cells (Arosio et al., 2011). Taken together, evidence suggests that particle size is an important parameter when considering designing an effective TDDS. 5.2. Gold nanorods for drug delivery Non-spherical nanoparticles may have some advantages beyond the spherical-nanoparticle as a versatile delivery system, and AuNRs are a promising choice. In 1992 the AuNRs was first synthesized by Dr. C. R. Martin (Pérez-Juste et al., 2005). Murfey later optimized the cetyl trimethyl ammonium bromide (CTAB) method in 2001 (Pérez-Juste et al., 2005), which is commonly used for biomedical applications. Gold nanostars, first synthesized by Yamamoto et al. (2005) and Jason H. Hafner in 2006 (Nehl et al., 2006), gained rapid popularity in the field of surface plasmon resonance (SPR) for photothermotherapies. The size (Jiang et al., 2008) and shape (Champion et al., 2007) of nanoparticles play a major role in terms of delivery mechanisms. However, more importantly than size and shape, colloidal dispersion is highly dependent on stability. Although CTAB helps to stabilize the AuNRs, free CTAB is generally recognized as toxic. There were also reports that nanoparticle bounded CTAB did not show acute cytotoxicity (Connor et al., 2005). According to this discovery, one common strategy is surface coating, which can reduce the toxicity and maintain stability. Hongwei Liao et al. developed thiol modified polyethylene glycol (mPEG-SH) coating (Liao and Hafner, 2005), while Wei, Q. S. et al. chose poly(N-isopropylacrylamide (PNIPAAm) polymer (Wei et al., 2008). Most recently Leonid Vigderman et al. even obtained complete exchange of CTAB with a CTAB analogue 16-mercaptohexadecyl trimethylammonium bromide (MTAB), which not only maintained the stability but was also reasonable for biological applications (Vigderman et al., 2012). Based on the above design, Chen, et al. conjugated enhanced green fluorescent protein (EGFP) plasmid DNA with AuNRs, and then treated them with HeLa cells (Chen et al., 2006). Near infrared (NIR) radiation was used as a remote control and only the irradiated cells were successfully transfected by EGFP. These in vitro experiments proved that the appropriate surface coating is an important factor as part of a delivery system design based on AuNRs. After ensuring the colloidal stability, the subsequent consideration for nanomaterial-based targeted drug delivery would be bypassing the biological barriers and reaching to the targeting site. The first challenge comes from the biological fluids and the plasma proteins which are abundantly distributed. These would inevitably bind onto the AuNRs to reticulo-endothelial system (RES) clearance (Yoo et al., 2011). Alkilany et al. mixed plasma proteins with different surface coating of AuNRs, and found that in most cases the plasma protein would bind onto the surface of AuNRs regardless of the surface charge and ligands (Alkilany et al., 2009). These findings suggest that although the absorbed proteins do not affect the stability of well-coated AuNRs, these proteins may interfere with the biodistribution of AuNRs. In another study, Akiyama et al.

evaluated the biodistribution of AuNRs in mice with different level of PEG-grafting and found that higher PEG grafting levels were advantageous for RES clearance avoidance and longer circulation, and most of the AuNRs were distributed in liver, spleen and tumor tissues (Akiyama et al., 2009). Even more challenging work was conducted to evaluate the possibility of AuNRs crossing blood brain barrier (BBB) using an in-vitro model (Bonoiu et al., 2009), and transmigration of AuNRs across BBB was observed. However, another study on the kinetics of transplacenta of PEGylated AuNRs suggested that PEGylated AuNRs of the size 10 nm–30 nm did not cross the perfused human placenta in detectable amounts into the fetal circulation within 6 h (Myllynen et al., 2008), highlighting the ambiguity in trans-barrier studies. A real complement to the development of delivery made by AuNRs was conducted by von Maltzahn, Geoffrey et al. (von Maltzahn et al., 2011b), they reinvented the idea of targeting by turning it from the final goal of the delivery to the amplification process. In this study, AuNRs first located the tumor, and subsequently activated by near infrared region (NIR) to give out signal amplified by coagulation cascade, the effectors part contains anti-tumor drugs receive the signal, selectively localize the signal resource and then release the drug into specific location. 5.3. Gold composites and other gold nanoparticles in drug delivery application Nanotechnology provides a gateway of possibilities for scientists to explore their ideas in the biomedical field. Hybrid nanosystems include AuNRs incorporated microgels (Hain et al., 2008), titanium oxides (Cozzoli et al., 2006), QDs (Costi et al., 2008), among many others. One of the attractive combinations is magneto-AuNRs hybrids system prepared wherein the magneto (Fe3O4) necklace is placed around AuNRs for efficient optical detection, magnetic separation, and thermal ablation of multiple pathogens from a single sample (Wang and Irudayaraj, 2010). Furthermore, Guo et al. used chitosan-AuNRs to deliver cisplatin, which could efficiently enhance the therapy and imaging (Guo et al., 2010). Besides, some core/shell nano-composites were also used in drug delivery applications. Liu et al. developed Dox-loaded, PEGfunctionalized gold nanoshells on silica lattices that could completely remove tumor tissue in mice after NIR laser treatment (Liu et al., 2012). All of these studies showed the promising future of AuNPs based therapies. Some other AuNPs, for instance, gold nanostars, along with gold nano-pyramids and gold nanocages, are members of the growing families of AuNPs. Gold nanostars are more like AuNRs, but with multiplied SPR effect and NIR induced thermo activities. Therefore, recently the main focus on gold nanostars are sensing (Dam et al., 2012) and probing (Barbosa et al., 2010) rather than drug delivery (Dreaden et al., 2012). Due to its shape and enhanced activity, special coatings and surface modifications should be applied to achieve longer blood circulation time (Yoo et al., 2010). Gold nanocages were able to deliver drugs to tumors by conjugating the surface with bioactive molecules (e.g. antibodies) that binds to cancer cell receptors, (Chen et al., 2007) and the interior could serve as a delivery vector (Xia et al., 2011a). 6. How nanoparticles solve the barrier of targeted drug delivery AuNPs are solid metal nanoparticles with enhanced SPR effects, and this intrinsic character makes it an interesting alternative for TDDS. To address the full potentiality of AuNPs based targeted delivery platforms; there are two major challenges to overcome: the RES clearance and the endothelial penetration. Avoiding the RES clearance could achieve long circulation, and enhanced endothelial penetration could help augment targeting and drug accumulation. 6.1. Avoiding reticuloendothelial system (RES) clearance Injection of nanoparticles into the blood may trigger the binding of plasma proteins treating them as foreign particles and, thus, could be

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Fig. 3. Mechanism of targeted nanoparticles to recruit therapeutic nanoparticles in the complex environment (A) Schematic illustration depicting tumor-targeted NPs broadcast signals from the tumour location to other receiving NPs in complex environment. (B) Molecular signaling pathway between the signalling and receiving components. Signaling components comprises of either tumor-targeted plasmonic gold nanorods (AuNRs), which acts through coagulation cascade activation in tumors by photo-thermal mechanism, thus, disrupting tumour vessels and activating the extrinsic and intrinsic coagulation pathways, or tumour-targeted tissue factor proteins, which are latent in circulation and activate the extrinsic coagulation pathway on binding to tumour receptors. Such communication pathways aides in the recruitment of inorganic (iron oxide nanoworms) or organic (drug-loaded LPs) receiving components through activity of the coagulation transglutaminase FXIII or through targeting of polymerized fibrin (adapted from (Von Maltzahn et al., 2011b)).

phagocytized by macrophages and other monocyte-macrophage cells. Conjugating with molecules, such as heparin, dextran, polysaccharides and other hydrophilic macromolecules, could sterically inhibit the binding of plasma protein onto the surface of nanoparticles (Amoozgar and Yeo, 2012; Schneider et al., 2009; Socha et al., 2009). The most common and effective method was by coating the nanoparticles with PEG, termed as “PEGylation” (Goodson and Katre, 1990; Harris and Chess, 2003; Veronese and Pasut, 2005). Qian et al. conjugated single-chain variable fragment (ScFv) antibody on PEGylated AuNPs so they could monitor the nanoparticle accumulation in the tumor tissue by surface enhance Raman scattering (SERS) (Qian et al., 2008). Similar design also can be found in Eck et al. using F19 monoclonal antibody (mAb) to stain pancreatic cancer (Eck et al., 2008). Despite imaging, PEGylated AuNPs also play a role in drug delivery. The efficacy of tamoxifen was increased when it was conjugated to thiol-PEG (Dreaden et al., 2009). Indeed, this very same strategy is already in a phase I clinical trial (Libutti et al., 2010). 6.2. Enhancing endothelial penetration Vascular endothelium is another barrier crucial for targeted drug delivery. Often the endothelial barrier is more susceptible to the disease state. For example, the tight junctions of blood-brain barrier (BBB) could temporarily open when it is injured. (Nielsen et al., 2011). The current available data obtained from the bio-distribution assets has demonstrated that the possibility of AuNPs penetrating the blood-brain barrier

(Dykman and Khlebtsov, 2012; Khlebtsov and Dykman, 2011) is usually less than 1% of the administrated amount in the brain (mice or rat model). As for the tumor, the impaired vascular structure leads to enhanced permeability effect, which benefits targeted drug delivery.

6.2.1. Blood-brain barrier The typical structure of blood-brain barrier (BBB) constitutes two parts: the micro vesicular brain vessels and the astrocytes surrounding around them (Chauhan et al., 2011; Engelhardt, 2011; Naik and Cucullo, 2012). The endothelial cells (EC) lining the vessels are inactive on pinocytosis, and possess a unique trans-membrane transport system to control the transportations of molecules and particles across the vessels. Para-cellular transportations are also absent in the tight conjunctions between endothelial cells (Roney et al., 2005). Besides, the active efflux transport (i.e., P-gps, MRPs) in ECs renders drug delivery a particularly challenging issue as many drugs are substrates for these transporters (Mehdipour and Hamidi, 2009). The early efforts for effective central nervous system (CNS) drug delivery explored the concept of opening a temporal window on the BBB, or to say the blood-brain barrier disruptive (BBBD) strategies (Boado, 1995; Jaspan et al., 1994; Pardridge, 1989, 1994; Stewart, 1994). The disruptive strategies not only enhance the chemotherapy drug penetration, but also aids in the bypassing of the BBB. Mykhaylyk et al. treated the rat by i.v. (intravenous) administration of 130 nm magnetic nanodispersions, and found almost no

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accumulations within the brain unless pretreated with BBBD agents (Mykhaylyk et al., 2001). With regards to the structure and function of BBB, there are two options. First is the increase in the hydrophobicity of drug molecules, and the second is small (less than 20 nm) nanoparticles (Kievit and Zhang, 2011). Some of the researches developed promising pro-drugs followed the first route (Greene et al., 1994; Leon-Carrion et al., 1999; Rubenstein et al., 2001; Shek et al., 1976) and will not be included in detail within this review. However, in the studies for biodistribution of AuNPs, only a small portion of AuNPs could be found within the brain (De Jong et al., 2008), which suggested the possible size that could penetrate the BBB. De Jong et al. was the first to study the biodistribution of 10 nm, 50 nm, 100 nm and 250 nm AuNPs in rat at 24 h after i.v. injection, and only 10 nm was found ubiquitously distributed including brain (De Jong et al., 2008). While G. Sonovane et al. evaluated the 15 nm, 50 nm, 100 nm, 200 nm in mice at 24 h after i.v. injection, and found that the highest accumulation in brain was 15 nm (Sonavane et al., 2008). The reason for the penetration of small sized AuNPs may be dependent on the spaces between the actrocyte end-feet and the capillary endothelium (Pardridge, 1998). However, the low efficiency of passive delivery system hindered further applications, and would occasionally need the assistance from BBBD agents (Alam et al., 2010; Chang et al., 2009). Therefore, the effort for developing active targeting strategy is mainly focused on the receptors presented on the surface of endothelial cells. Despite glucose and peptide receptors, the most exciting part is the discovery of transferrin receptor (TfR) (Chen and Liu, 2012; Moos and Morgan, 2004). Being one of the most well studied receptors, TfR has confirmed a series of success (Recht et al., 1990). Martell, L. A. et al. evaluated the TfR expression on glioma and found it very sensitive to TfR targeted therapy (Martell et al., 1993). Hu et al. developed lactoferrin (Lf)-conjugated PEG-PLA nanoparticles loaded with fluorescence probe coumarin-6 and then intravenously administrated into mice. They found that the fluorescence intensity in the brain of Lf-NP treated mice was nearly 3-folds higher than that of NP treatment, which indicated significant accumulation of NP into the brain (Hu et al., 2009). 6.2.2. Blood-tumor barriers As for anticancer treatment, the concept of tumor microenvironment introduces many advantages in developing drug delivery systems. The blood-tumor barriers, which describe the physiological obstacles around the tumor tissue, form a large part in the genesis of drug resistance (Curti, 1993; Hampton, 2005; Jain, 1994; Radu et al., 2010). Rakesh K. Jain (Jain, 1999) described the four barriers for solid tumor drug delivery: • • • •

Heterogeneous angiogenesis and blood flow in tumors Heterogeneous permeability of tumor vessels Interstitial compartment Cell membrane and cytoplasm

Due to the hyper-permeability effect, it is very difficult for drug molecules to reach the tumor site. Besides, the tumor vascular cell would become more impermeable (Molema et al., 1997). Adenosine triphosphate (ATP) binding cassette (ABC-transporter) were expressed, indicating similar characteristics with BBB. Vascular endothelial growth factor receptor (VEGFR) were also expressed, but not tight junctions. Three strategies were thus proposed: • Angiogenesis targeted • Tumor cell targeted • Cell penetration peptide assisted Tumor needs blood to grow, invade and metastasize, and it would be vital when it reached certain period, normally exceeding 1 mm3. One of the hallmarks was the secretion of VEGF and expression of VEGFR on the surface of tumor blood cells. The VEGF and other cytokines induce angiogenesis and recruit bone marrow derived macrophages, building

up blood vessels towards tumors (Amini et al., 2012; Cantelmo et al., 2010; Garrido-Urbani et al., 2011; Melero-Martin and Dudley, 2011). Kemp, M. M. et al. discovered that the AuNPs could inhibit fibroblast growth factor 2 (FGF-2) induced angiogenesis (Kemp et al., 2009). Ngwa, W et al. utilized tumor vascular-targeted AuNPs as vascular disrupting agents and found it considerably efficient in brachytherapy (also known as internal radiotherapy) (Ngwa et al., 2010). Dongkyu Kim et al. conjugated aptamer to the Dox-loaded AuNPs (Diagaradjane et al., 2008), and found that the intensity of computed tomography (CT) in targeted cells was 4 times higher than non-targeting cells.

6.3. Nanoparticles by-passing the chaotic blood flow, plasmonic membrane, cellular barriers and multi-drug resistant tumor cells As discussed earlier, the above biological barriers, or the “interfaces” disrupted the actual penetration behavior of NPs. In such cases, most of the nanotherapies failed to show their effect (Nel et al., 2009). For example, blood is a complex fluid constituted by numerous serum proteins and blood cells; the very environment which nanoparticles follow and get re-distributed (Paciotti et al., 2006). Some researchers have focused on cardiovascular disease imaging using AuNPs (David et al., 2011), and Wang et al. designed a EGF peptide conjugated AuNPs as bait for circulating tumor cells (CTC) and subsequently CTCs with high sensitivity using SERS (Wang et al., 2011). Evidence suggests that nanoparticles tend to accumulate in the spleen and liver if administrated intravenously (Cuenca et al., 2006; Jain, 1999; Nel et al., 2009). There will be two distinct scenarios: first is known as the rapid clearance and the second is known as passive targeting. Patra et al. summarized recent progress in design of pancreatic tumor targeted therapies based on small AuNPs (Patra et al., 2010). They developed ultrasmall AuNPs (5 nm) conjugated with gemcitabin and cetuximab and this formula could greatly inhibit tumor proliferation both in vitro and in vivo (Patra et al., 2008). Along with these scenarios, A. Verma et al. provided another route for delivery. They synthesized 5 nm AuNPs protected by a monolayer shell of hydrophobic and anionic ligands, and discovered that although these nanoparticles were conjugated with cell penetrating peptides, they could penetrate cells without disrupting the cell membrane structure, which is distinct from previous knowledge about cell penetrating peptide (CPP) nanoparticles (Verma et al., 2008). These so-called “slippery” AuNPs (Xia et al., 2008) indicated that surface engineering is crucial for targeted drug delivery system to tackle with different levels of biological barriers (Mitragotri and Lahann, 2009). Despite these macroscopic biological barriers, the notorious multidrug resistant tumor cells would be the last but the hardest obstacle for tumor treatment. In 2011–2012, one out of four American deaths was due to cancer (Siegel et al., 2012). Although currently there is no official data on deaths due to multidrug resistant cancer, it is believed that cancer patients have to use combined therapy or changing drugs because of drug resistance. Ever since P-glycoprotein (P-gp) was discovered by M.M Gottesman in 1992 (Chin et al., 1992), the mechanism of multidrug resistance has been unveiled. P-gp is responsible for nearly 50% of resistance, and one of the most well studied strategies is to inhibit the P-gp activity (Szakacs et al., 2006). In another way, researchers used nanoparticles as drug delivery platforms to circumvent tumor multidrug resistance by loading more drugs into targeted tumor cells. Gu et al. synthesized doxorubicin (DOX) grafted-PEGylated AuNPs to successfully overcome the DOX resistant cell lines (Gu et al., 2012); Brown et al. grafted oxaliplatin onto PEGylated AuNPs, increased the treatment efficacy and found it could distribute into nucleus (Brown et al., 2010). One alternative strategy is direct use of theranostic nanoparticles. Liang X.J. et al. circumvented cisplatin resistant human prostate cancer cell lines (PC-3) both in vitro and in vivo by a non-toxic metallofullerene [Gd@C82(OH)22]n supplied with cisplatin treatment (Liang et al.,

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2010). These reports all demonstrated the potential of AuNPs in the future treatments of circumventing multidrug resistant tumors. 7. Improving the efficacy of nanomaterials for targeted drug delivery system Spatial and temporal parameters must be considered for design effective therapeutic system. During the transportation of molecules from one site to another, the time interval involved during the delivery process, and understanding the communication of these molecules in the complex environment is of utmost importance. But it would not be an easy task when referring to targeted drug delivery systems due to the complexity of the system which will pose as a restriction for the transport of cargoes, in a living organism. A successful design of drug delivery system implies effectively bringing the drug to the right place in the right time through the chaotic currents (i.e., blood flow) and layers of biological barriers. A tremendous amount of work has been concentrated in the past two decades on the research and development of drugs with improved site-specificity, with particular reference to AuNPs and polymeric nanomaterials due to its ease of preparation and relative optimal loading capacity. Many challenges remain in the designing of an effective drug delivery system, which can sustain longer duration in a highly complex environment. Therefore a range of parameters should be considered for this issue while working within the remit of TDDS. To follow the above principles of TDDS, two main aspects should be taken into consideration: (a) materials used (Fig. 4) and (b) from biological point of view (Fig. 6). Various literature reports have investigated the physical and chemical properties of NMs, primarily based on experiments with cultured cells condition (Oberdörster et al., 2007; Soenen and De Cuyper, 2010). The evaluation of NPs safety has been investigated due to a great variety of findings depending upon personal experience for example: (1) types of NPs, (2) stabilizing/coating or depositing agents, (3) physicochemical parameters of the NPs (diameter, surface charge, surface topography, surface area, and orientation of NMs with cells), (4) incubation conditions (time and concentration), (5) type of cells used, (6) type of assay used, or (7) possible interference of the NPs with the assay readout.(Soenen et al., 2011). Since the majority of literatures explain a limited number of effects of individual nanoparticles on one particular cell type for a specific incubation time period or treatment condition (Buyukhatipoglu and Clyne, 2011; Qiu et al., 2010), a direct comparison of results between different studies is near impossible in real time. As such, the safety of NMs for biomedical applications and their exposure to (cultured) cells remains either unclear or incompletely understood. Receptor targeted drug delivery system is the most popular method used in treatment and diagnosis of disease. However, there are some exceptions to these cases, in such cases, drug toxicity is receptor related and receptor mediated; thus, improving intrinsic drug affinity and activity, as well as receptor binding, does not significantly improve the therapeutic index (NIDA Res Monograph, 1995). Therefore, effective drug targeting cannot be achieved as the receptors alone are not responsible for this case. Due to their high distributional properties, receptor cannot be controlled for all complex processes because at a certain time point the receptors get saturated in the complex environment thus cannot be responsible for selectivity and effective drug targeting (Fig. 5). The quest to design a successful drug delivery system is a multifaceted concept because of the complex interplay of various distributional rates and drug metabolism. Such databases about the characters of barriers and the interaction behaviors of the NMs need to be established at international level that will help to the patient, and should be globally shared by the researchers world-wide. However, a number of important parameters should to be considered to design any kind of delivery system in the physiochemical and

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biological environment (Figs. 4 and 6). These parameters include the following aspects: the nature of biological and cellular membranes, distribution and presence of drug receptors, as well as the enzymes responsible for drug metabolism, time-plasma concentration profiles, local blood flow and the most important one is the nature of disease. However this list is not exhaustive. Furthermore, there might be other different parameters affecting the efficacy of the targeted drug delivery system. In principle, the effective TDDS system can be achieved by maintaining the physical, biological, or molecular systems together that result in high concentrations of the pharmacologically active agent at the patho-physiologically relevant site and at the same time monitored significant reduction in drug toxicity, drug dose and increase treatment efficacy. To sum up, combining all these features in one platform might bring up a biologically active agent of formidable activity for targeted delivery, which would be superior to conventional molecular manipulations aimed at refining the receptor substrate interactions in the complex environment.

8. Evidence for nanomaterials toxicity on the basis of design targeted drug delivery system Evidence suggests that the toxicity of nanoparticles is usually brought upon by inhalation and is also highly dependent on material properties such as size, shape, surface chemistry and mechanical properties (Caldorera-Moore et al., 2010; Oberdörster et al., 2005; Yoo et al., 2011). It is therefore pertinent to discuss the factors that contribute to nanoparticle toxicity. 1. Characteristic properties of nanoparticles are dominant in nature and these particles associated with small size and large surface area per unit mass. Their shape, size, roughness, surface chemistry, coatings and functionalization molecules on the materials have different bio-interfacial activity. Here the particle toxicology suggests that, more particle surface reactivity equates to more toxicity (CaldoreraMoore et al., 2010). 2. The quantitative and qualitative loading of drug molecules on the surface of nanomaterials; highly tight and compact binding or deposition of molecules result in the greater toxicity (Baselga et al., 2000).

Fig. 4. Design of effective targeted drug delivery system according to materials point of view. There are three main aspects from material side to combine in one platform to design successful drug delivery system, where a number of major steps in drug development that activated the field of drug targeting.

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Fig. 5. Saturation of receptors at the certain time point which lose their binding specificity in complex environment. Once the receptors of the homing peptide have been saturated, the specificity of the targeting molecules declines immediately, and results in failure of targeting system to reach the specific site (adapted from experimental data in Kranenborg et al., 1998 and reprinted with the permission of the Journal of Cell Biology, Ruoslahti et al., 2010). au, arbitrary units.

3. During enzymatic reactions in the body, chemical and structural modifications in the molecule would result in a change in its biological activity. In many instances, some of the metabolites become biologically more active or will possess a different type of pharmacological activity. 4. In some of cases during the oxidative processes result in the production of epoxides and free radicals will lead to short-lived, highly reactive intermediates. All these will contribute to the apparent toxicity. 5. Metabolism of the administered nanomaterials might produce several types of intermediate compounds with similar activity, but with different pharmacokinetic (PK) properties. This might lead to unfavorable effects on selectivity or PK properties. 6. The different status of pathological site has different enzymatic response for the targeted molecules. During some of the enzymatic process, the materials and targeted molecules do not follow the exact behavior to interact with the relevant site. Therefore, in such cases, the materials change their different PK properties which result in toxicity. 9. Future prospectus of nanomaterials for the biotechnology industry If we took a look back at history, the concept of drug targeting was inspired by histochemical staining in late 19th century. In 1911 Paul Ehrlich published the seminal article “Aus Theorie und Praxis der Chemotherapie” that converges chemistry, biology, and medicine. After the discovery of receptors, Prof. Paul Ehrlich developed the prototype of targeted drug delivery and called it the “Magic bullet”. Ever since 1911 the concept of drug targeting has been evolving through onco-protein specific drugs to onco-targeted drugs (usually a chimera of anticancer drug and antibody) (Strebhardt and Ullrich, 2008), and now into the era of nanoparticle-based targeted drug delivery. A century later, this magic bullet has metamorphosized into a multi-functional magic bullet, with the aid of nanotechnology multiple drug-loading and multi-targeting could be achieved simultaneously. In the near future, there is possibility that microchips could be introduced into the TDDS making it programmable (Freitas, 2006), and it might be also possible that combine more than one nanomaterial (different characteristic property) in one platform to make highly robust and advanced materials as third generation delivery system and also designed for theranostic purposes (Dufort et al., 2012). The biomedical application of gold stretches back to almost five millennia. NPs have opened new avenues for biotechnology industry, for instance, how to design a better and effective diagnostic and

Fig. 6. There are a number of important parameters to be considered for designing any kind of effective drug targeting system and these parameters are not limited. Also, there might be other different parameters affecting the efficacy of the targeted drug delivery system.

therapeutic product for biomedical applications. Furthermore, and many of these nano-based drugs are already in clinical trials (Table 2) with some approved by the US Food Drug Administration (FDA). Special progress has been made by biotechnology industry in the field of tumor targeting where by AuNPs can specifically target and deliver anti-cancer drugs directly into cancerous cells, with the added advantage of being simple and cost-effective. Research is currently underway to improve the therapeutic effects of nano-based pharmaceutical drugs based upon engineering of biophysical and chemical process, while simultaneously limiting the toxicity. It is also foreseeable that close collaboration between academia and industry would drive the new wave of innovations in nanotechnology-based therapeutics. On the basis of compositions of TDDS, a draft for future TDDS is as listed below: 1. Selecting the right drugs. A drug candidate for optimized TDDS should be effective. A drug with high specificity is preferred, thus reducing side effects. 2. Selecting the right materials as carriers. Here, nanotechnology is the preferred treatment of choice because cellular interactions and communications are often in the nanoscale region (Mann, 2008). And we also believe that AuNPs are promising candidates because its production can be easily controlled, characterized, and manipulated. AuNPs are relatively chemically negative in the physiological environment (Khlebtsov and Dykman, 2011; Lasagna-Reeves et al., 2010; Sung et al., 2011; Zhang et al., 2010). 3. Selecting the right targeting moieties. It is important for a TDDS to choose the best-fitting ligands, and to put it onto the surface of carriers into the optimal configuration. 4. Manufacturing the optimized TDDS according to the physical characteristics and chemical behaviors (Bae and Park, 2011). This is of vital importance because without sophisticated tailoring the TDDS would not be able to perform its prescribed biological functions. Abbreviations 2-HG Abnormal onco-metabolites ABC ATP binding cassette Akt Protein Kinase B (PKB) ATP Adenosine triphosphate AuNPs Gold nanoparticles AuNRs Gold nanorods BBB Blood brain barrier BBBD Blood-brain barrier disruptive

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Table 2 Examples of gold based nanomaterials in therapeutics use approved by FDA. Product/brand name

Component/active ingredient

Delivery route

Target

Company

Current status

Verigene Aurimmune

Gold Colloidal gold nanoparticles coupled to TNF-α and PEG-Thiol (~27 nm) Gold coated silica nanoparticles (~150 nm) Iron oxide nanoparticles (17–20 nm)

In-vitro diagnostic Intravenous

Genetics Solid tumor

Nanosphere Cyt-Immune Sciences

FDA-approved Phase-II

Intravenous Intravenous

Solid tumor Tumor Imaging

Nanospectra Biosciences Advance Magnetics

Phase-I NDA field

AuroShell Combidex (Ferumoxtran-10)

Cdc42 Cell division control protein 42 homolog CdSe/ZnS Cadmium selenide/Zinc sulfide CdTe Cadmium telluride CNMs Carbon nanomaterials CNS Central nervous system CNTs Carbon nanotubes CPP Cell penetrating peptide cRGD Cyclic RGD CT Computed tomography CTAB Cetyl trimethyl ammonium bromide CTC Circulating tumor cells DDS Drug delivery system DNA Deoxyribonucleic acid Dox Doxorubicin Dyn-2 Dynamin-2 EC Endothelial cells ECM Extracellular matrix EGFP Enhance green fluorescent protein EGFR Epithelial growth factor receptor ER Endoplasmic reticulum FDA Food and drug administration FGF-2 Fibroblast growth factor 2 FITC Fluorescein isothiocyanate FXIII Trans-glutamines factor XIII gC1q G-protein coupled complementary receptor GSL Glycosphingolipid HIF Hypoxia induced factor IDH1 Isocitrate dehydrogenase-1 IDH2 Isocitrate dehydrogenase 2 IGF-1 Insulin-like growth factor-1 iRGD Disulfide-based cyclic RGD peptide, c(CRGDKGPDC) Lf Lactoferrin LyP-1 Tumor-lymphatic homing peptide mAb Monoclonal antibody MAPK Mitogen activated protein kinases MDA-MB-321 Breast cancer cell line mPEG-SH Thiol modified polyethylene glycol MRP Multidrug resistant associated protein MTAB 16-mercaptohexadecyl trimethylammonium bromide mTOR Mammalian target of rapamacin NIR Near infrared region NRP-1 Neuropilin-1 NRPs Neuropilins p32 protein gC1q receptor; hyaluronic acid–binding protein PC Prostate Cancer PC12 pheochromocytoma derived cancer cells PDGF-B Platelet-derived growth factor subunit-B PDH Pyruvate dehydrogenase PET Positron emission tomography P-gp P-glycoprotein PI3K Phosphatidylinositol 3-kinases PK Pharmacokinetic PKM2 Pyruvate kinase isozymes M2 PNIPAAm Poly (N-isopropylacrylamide) RES Reticulo-endothelial system RGD Arginine-glycine-aspartate

RNA ROS ScFv ScrRGD Sema SERS SPECT SPR TCA TDDS TfR TiO2 tTF VEGF VEGFR

Ribonucleic acid Reactive oxygen species Single-chain variable fragment Scrambled RGD Semaphorins; (Sema 3A, Sema3B, Sema3C and Sema3F) Surface enhance Raman scattering Single photon emission computed tomography Surface plasmon resonance Tricarboxylic acid cycle Targeted drug delivery system Transferrin receptor Titanium dioxide Tumor-targeted tissue factor Vesicular epithelial growth factor (C, D) Vascular endothelial growth factor receptor

Declaration of interest The authors do not have any conflicts of interest to declare. Acknowledgment This work was supported in part by the Chinese Natural Science Foundation project (No. 30970784 and 81171455), National Key Basic Research Program of China (2009CB930200), Chinese Academy of Sciences (CAS) “Hundred Talents Program” (07165111ZX) and CAS Knowledge Innovation Program. The authors would also like to thank Aaron Tan (University College London) for his valuable suggestions and comments in preparing this entry. References Akiyama Y, Mori T, Katayama Y, Niidome T. The effects of PEG grafting level and injection dose on gold nanorod biodistribution in the tumor-bearing mice. J Control Release 2009;139:81–4. Alam MI, Beg S, Samad A, Baboota S, Kohli K, Ali J, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci 2010;40:385–403. Alexis F, Basto P, Levy-Nissenbaum E, Radovic-Moreno AF, Zhang L, Pridgen E, et al. HER-2-targeted nanoparticle-affibody bioconjugates for cancer therapy. ChemMedChem 2008;3:1839–43. Alkilany AM, Nagaria PK, Hexel CR, Shaw TJ, Murphy CJ, Wyatt MD. Cellular uptake and cytotoxicity of gold nanorods: molecular origin of cytotoxicity and surface effects. Small 2009;5:701–8. Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science 2004;303: 1818–22. Amini A, Moghaddam SM, Morris DL, Pourgholami MH. The critical role of vascular endothelial growth factor in tumor angiogenesis. Curr Cancer Drug Targets 2012;12: 23–43. Amoozgar Z, Yeo Y. Recent advances in stealth coating of nanoparticle drug delivery systems. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012;4:219–33. Anshup A, Venkataraman JS, Subramaniam C, Kumar RR, Priya S, Kumar TR, et al. Growth of gold nanoparticles in human cells. Langmuir 2005;21:11562–7. Andersen CBF, Madsen M, Storm T, Moestrup SK, Andersen GR. Structural basis for receptor recognition of vitamin-B12-intrinsic factor complexes. Nature 2010;464: 445–8. Arosio D, Manzoni L, Araldi EM, Scolastico C. Cyclic RGD functionalized gold nanoparticles for tumor targeting. Bioconjug Chem 2011;22:664–72. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 2011;153:198–205. Bagri A, Tessier-Lavigne M, Watts RJ. Neuropilins in tumor biology. Clin Cancer Res 2009;15:1860–4.

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