Nanoconstructs for Cancer Therapy and Imaging
Published Date: May 29, 2017.
Nanoconstructs for Cancer Therapy and Imaging
Fahima Dilnawaz1*, Zeenat Iqbal2 and Deepak Kumar3
1Laboratory of Nanomedicine, Institute of Life Sciences, Bhubaneswar, Odisha, India
2Hamdard University, New Delhi, India
3University of California, San Diego, San Diego, USA
*Corresponding author: Fahima Dilnawaz, Laboratory of Nanomedicine, Institute of Life Sciences Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha, India, E-mail: firstname.lastname@example.org
Citation: Dilnawaz F, Iqbal Z, Kumar D (2017) Nanoconstructs for Cancer Therapy and Imaging. J Mol Nanot Nanom 1(1): 103.
The complexity of the cancer disease and prevalence of diverse cell populations warrants a highly specific treatment for cancer. The application of nanotechnology towards cancer therapy is one of the advanced approaches to overcome the limitation of conventional chemotherapy. Nanotechnology based carriers are engineered using biomaterials that provide adequate features and surpasses the biological barriers encountered by native drugs rendering controlled release with minimal toxicity. Various nanocarriers are developed for therapy and to have multifunctional effect theranostic nanoconstructs have emerged which integrate anticancer drugs, imaging agents, targeting ligands to cater different types of treatments usually necessary to achieve the highest therapeutic efficiency. This review focuses on recent development of nanoconstructs for the improvement of cancer therapy and imaging.
The peculiar nature of cancer genesis, progression and growth has posed innumerable challenges for its successful amelioration. Advanced research in cancer chemotherapeutics, in the last few years, has relied on the field of nanotechnology and that has taken the advantages of biodegradable polymers which can be tailored and engineered with high specificity for designing various drug delivery platforms such as nanoparticles, nanospheres, nanoliposomes. These nanocarriers are suitably designed to carry drug cargoes at target sites with controlled release for prolonged periods of time thereby executing reduced side effects. Nanoconstructs with their ability to consolidate wide variety of ligands and their amenability towards surface functionalization with various chemistries have emerged as interesting nanotools for both diagnosis and treatment of cancer. Delivery of nanocarriers to the tumor tissues is basically attained by either passive targeting or active targeting. Most of the preferred routes of administration by the clinicians are the intravenous route. Through this route it surpasses multiple obstacles and reaches the tumor site by Enhanced Permeation and Retention (EPR) effect . The passive targeting modes of particle delivery usually take the advantage of unique property of the tumor vasculature and its microenvironment. The architectural design of the tumor mass is highly vascular in nature with aberrant branching along with twists and loops due to which the blood flow behaviour is irregular as well as inconsistent. Moreover, the tumor vessels are leaky with poor lymphatic drainage system. This unique pathophysiologic characteristic encourages EPR effect by which the macromolecules extravasate through the gaps and gets accumulated inside the tumor tissues . To avoid the opsonisation nanocarriers are subjected to various strategies which repels the opsonins and avoids the uptake by MPS leading to increased circulation time in blood . Mostly Polyethyleneglycol (PEG) coating to the nanoparticles is considered to be the better anti-opsonization strategy. Through EPR effect targeting cancer cell in all is not feasible as it is dependent on tumor vascularization. Biological stimuli which can be either internal (physiological, pathological, and patho-chemical conditions) or external (physical: heat, light, magnetic and electrical fields) can be exploited for triggering the delivery of drugs, genes, or diagnostic agents from the nanocarriers .
The solid tumors have peculiar pH feature due to poor vasculature and anaerobic condition and its extracellular pH is more acidic than the systemic pH, to address these issues stimuli responsive materials such as pH responsive polymers, thermosensitive materials offers an alternative to passive and molecular targeting to tumor [3–5]. These nanocarriers can facilitate the release of the payloads near the target compartments either by decomposition or by destabilization. For active targeting, ligands are utilized which can bind to specific molecular signature of the cancer cells, resulting in receptor ligand binding with high precision. The morphological and molecular different feature of tumor blood vessels and tumor lymphatic vessels has been explored and peptides for targeting have been identified for therapy. Using first tumor-penetrating peptide of tumor lymphatics (LyP-1) that richly binds to tumor macrophages uses CendR pathway for successful therapeutics in tumors. iRGD peptide which tend to accumulate extensively into extravascular tumor tissue are used for targeting tumor metastases [6–8]. Usually nanocarriers rely primarily on abnormal leaky vasculature for tumor access, recently a transcytosis transport pathway regulated by neuropilin-1 (NRP-1) has been reported by Liu et al . NRP-1 mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. Liu et al studied the impact of transcytosis by irinotecan-loaded silicasomes with either iRGD conjugation or coadministration in an orthotopic PDAC model . Thus functionalizing ligands over the surface of the nanoparticles facilitates higher cellular uptake in cancer tissues by activating receptor-mediated transport and other related transport mechanisms [10–11].
Nanoconstructs have created a unique stratum in biomedical research platform in recent years. It imbibes certain distinct characteristics such as flexibility in physicochemical modification which makes them appropriate nanomaterial for therapeutic, prognostic as well as diagnostic applications . Nanoconstructs are composed of two components, a core comprising of metal nanoparticle (NP) and a shell made up of ligands. These special structures of nanoconstructs make them suitable for application in the field of cancer diagnostics and treatment [13,14]. The possibility of scaling up due to its simplistic design/geometry makes them an attractive alternative to various nanomaterials . Nanoconstructs offer effective stability and advantage of modulating the release profile of encased therapeutics, targeting ligands functionalization for their improved therapeutic specificity (Figure 1). Nanoconstructs can be grafted with stimuli a sensitive property which allows the encased drugs to remain protected in the core and thereby leading to an appropriate release upon reaching the target sites with a change in local environmental changes such as magnetic fields or pH . Tunable Surface Plasmon Resonance (SPR) of gold nanoconstructs which causers coherent oscillations of electrons in the conduction band leading to photothermal conversion . The two dimensional gold nanoparticle arrays for high malleability are embedded in elastic polydimethylsiloxane (PDMS) membrane. By applying external stress interparticle distance in the gold nanoparticle array can be regulated and the change in distance between each particle will alter the interaction and thereby the frequency is manipulated . Gold nanoconstructs aided phototherapy has emerged as important selections for the treatment of cancer, where the Localized Surface Plasmon Resonance (LSPR) peaks are turned towards the Near-Infrared (NIR) region for better treatment due to the high transparency of the tissues . A number of nanoconstructs such as nanoflares, nanoshells, nanostars have gained much success in biomedical research which is further discussed in detail.
Figure 1: Different form of nanoconstructs used in cancer therapy and imaging.
It is a genetic based approach for invasive cancer research as well as diagnosis in its very initial stage. Nanoflare can be defined as a subtype of nanoconstruct which are typically spherical in shape and proficient in detecting intracellular mRNA levels at single-cell level in live cells . It comprises of spherical gold nanoparticles which are coated or grafted densely with a layer of single-stranded DNA (referred as ssDNA). ssDNA is composed of a segment (3′ thiol) complementary to mRNA for a target gene. Its recognition sequence holds a fluorescent reporter which when attaches or binds with target mRNA, the reporter flare strand is displaced, resulting in a fluorescent readout . Nanoflares are known to enter the cells by employing scavenger receptors which facilitates the process of caveolin-mediated endocytosis . Nanoflares provide a scientific method for detection and isolation of circulating cancer cells from whole blood, when combined with flow cytometry. Additionally it can also be utilized to identify mesenchymal-like cells which can be utilized as a potential tool for isolating and characterizing circulating cancer cells.These properties make the nanoflares well suited for simultaneously labeling, isolating, and genetically characterizing live cancer tumor cells (ctcs) at the single-cell level. Halo, et al  reported the application of nanoflares in the live circulating breast cancer cell lines and subsequent culture as mamosphere in human blood with high recovery using intracellular markers. Vimentin and fibronectin nanoflares were used to identify breast cancer cells seeded in human whole blood as a proxy for the detection of ctcs from. Mcherry cDNA was expressed in MDA MB-231 cells and used for tracking MDA-MB-231 cells in human blood samples. For the analysis the scrambled control, vimentin, fibronectin were incubated at 37°C for 8 h thereafter the samples were analysed for mcherry and nanoflares fluorescence by flow cytometry. The samples treated with vimentin or fibronectin nanoflare ~ 99% of the cells that expressed high mcherry as well as nanoflare fluorescence also they showed 3 to 4 fold fluorescent over non targeting scrambled control nanoflare .
A nanoshell can be defined as a subtype of nanoconstruct, spherical in shape, which consists of spherical nanoparticle made of a dielectric core (usually silica) which is further covered by a thin metallic shell (usually gold). These are usually concentric particles, in which core consists of particles of one material with a thin layer of coating material utilizing specialized formulation processes . Nanoshells hold intrinsic optical as well as chemical properties for biomedical imaging research which makes it a favourable tool for therapeutic applications . As the thickness of shell is in the range of 1–20 nm, hence it is termed as nanoshell. The relative size of the core of nanoparticle and the thickness of the gold shell ultimately decides the optical response of gold nanoshells. When the thickness of the core and shell are proportionately varied, the optical properties of the gold nanoshell can be effectively varied which ranges from visible to near infrared spectral regions. The core materials of nanoshell can be synthesized using a variety of materials which includes metals, insulators and semiconductors. The dielectric materials are more often used owing to its high stability, water solubility and chemical inertness. These intrinsic properties make them suitable for focussed biomedical research. These can also be prepared utilizing various combinations such as dielectric-metal [25,26], dielectric-dielectric [27,28], metal-metal , semiconductor-metal . Many of the researchers have worked on the effective design of gold nanoshells with the desired optical properties and further fabricate the nanoshell with nanoscale dimensions . The formulation steps followed to achieve this includes the growth of silica nanoparticles dispersed in solution, attachment of 1-2 nm sized metal seed onto the surface of nanoparticles which forms a discontinuous metallic colloid layer followed by the growth of additional metal onto the preformed seed metal colloidal adsorbates. This formulation approach has been used widely to grow both gold and silver metallic shells onto preformed silica nanoparticles. These forms of nanoconjugates become highly amenable for targeted bioimaging and therapeutic applications when the specific optical properties of gold nanoshells are maintained. These can also be utilized for photothermal-based therapy applications as well. Hence it can be inferred that bimodal combination of biophotonics and nanotechnology can be utilized in future towards the detection and therapy of cancer.
Nanoformulation in the form of nanoconstructs consisting of polymer and lipid are used for the combined anticancer therapy and anti-inflammatory therapy. Lee, et al  synthesized, spherical polymeric nanoconstructs (spns) consisting of a hydrophobic poly (lacticco-glycolic acid) (PLGA) core stabilized externally by a single phospholipid monolayer, loaded with potent anticancer drug docetaxel and anti-inflammatory drug diclofenac which directly targets cyclooxygenase-2. The co-delivery of drugs exerted efficient in vitro and in vivo anticancer drug and anti-inflammatory activity. Administration of the nanoconstruct in non-orthotopic glioblastoma multiforme tumors demonstrated higher reduction in disease progression as well as dramatic inhibition of COX-2 expression by modulating inflammatory status related to cell death leading to increased survival rate compared to docetaxel nanoconstruct alone. Muhanna, et al  developed a novel multifunctional nanoparticle, porphysome based on porphyrin and lipid molecules. Before the self-assembly the porphyrins are highly fluorescent, but after the self-assembly the porphysome becomes highly absorptive and fluorescence silent due to the dense packing between the prophyrin and lipid. Upon laser exposure conversion of light energy to heat provides a platform for the photothermal and photoacoustic unique property to the organic nanoparticle. Prophysomes serve as potential alternatives for the treatment efficacy in head and neck squamous cell carcinomas (HNSCC) while preserving the anatomical and functional integrity. Muhanna, et al , reported pre-clinical evidence which demonstrated successful fluorescence and photoacoustic image guided detection in HNSCC of buccal mucosa squamous cell carcinoma rabbit model and hamster cheek carcinogenesis model. These porphysomes enabled PTT could be efficiently used as fluorescence and photoacoustic imaging in treatments . Nanoscale vesicles “polymerosomes” which are made of low glass transition temperature “rubbery” polymers and are formed by self-assembly of amphiphilic block copolymers in aqueous media so that they can pass through pores smaller than their diameter. Simon-Gracia et al, recently have demonstrated intrinsic selectivity towards intraperitoneal tumor lesions with pH-sensitive polymersomes. These functionalized plymersomes with RPARPAR (a prototypic cryptic C-end Rule (cendr) peptide, and helps in NRP-1 binding, showed improved efficacy in the treatment of Peritoneal Carcinomatosis (PC). Intraperitoneally administered of above functionalized paclitaxel loaded polymerosomes illustrated greater tumor accumulation, growth inhibition compared to Abraxane in mouse model and in clinical tumor samples . In cancer therapy immune parameters also affects the efficacy indirectly in long term anti-tumor effects. Zhao et al, reported the about the polymeric nanocarrier comprised of monomethoxypoly (ethyleneglycol)-poly (D,L-lactide-co-glycolide) (mpeg-PLGA) with encapsulated Immunogenic Cell Death (ICD) inducer oxaliplatin or non-ICD inducer gemicitabin for the pancreatic cancer treatments. The comparison studies showed that the native gemicitabin nor nanoparticles-encapsulated gemicitabin induce ICD, where as the oxaliplatin(OXA) and oxaliplatin-encapsulated nanoparticles(NP-OXA) released more immune stimulatory damage-associated molecular patterns (damps) which induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Strong therapeutic effects were exhibited by the NP-OXA than OXA and in immune competent mice than in immune deficient mice. Higher proportions of tumor infiltrating activated cytotoxic T-lymphocytes were induced in NP-OXA than OXA treatment. ICD encapsulated in polymeric nanoparticles can significantly enhance anti-tumor effects than the native ICD, and can boost the mode of cancer immunotherapy . Gold nanoparticles (AuNPs), exhibits Surface Plasmon Resonance (SPR) where Near-Infrared (NIR) light photon energy can be transduced into heat by thermal ablation . Due to the weak interaction with Au the anticancer drugs cannot be absorbed onto naked AuNPs surfaces, hence it requires a coating which can be of polymer, mesoporous silica etc. In a study Dreaden, et al  developed multifunctional nanoparticle that is comprised of gold nanostar along with the shell of metal-drug Coordination Polymer (CP) (AuNS@CP) to have the plasmonic photothermal and Two-Photoluminescence (TPL) effect. To which the gadolinium and gemcitabine monophosphate is encapsulated for chemotherapy and MRI imaging. AuNS@CP was applied for imaging and cancer therapy in a breast cancer xenograft model, where it exhibited strong T1 contrast signal. With the help of intravital TPL imaging in vivo monitoring at the microscopic level is possible. The gold nanostructures provide stronger TPL signal than that of organic fluorophores. Mice treated with AuNS@CP showed higher tumor inhibition than that of free drug, whereas the tumor growth in AuNS@CP + laser treated group was the slowest compared to saline + laser group. The combination of photothermal and TPL imaging could be used to monitor the in vivo distribution at the microscopic level .
For conferring diagnostic sensitivity and specificity in vivo, from past decades there have been increased interests in the clinical use of label free Raman spectroscopy for demarcating cancer specimen in situ . Using Raman spectroscopy molecular analysis of chemicals for molecular identification, photostability, and multiplexing can be done which provides molecular imaging Surface Enhanced Raman Scattering (SERS) techniques based on metallic gold are used for augmentation by order of magnitude [40,41]. Gold nanostructures are based on chromophores and adsorbed onto the metallic surface and surface coated with various coating for biocompatibility and used for SERS imaging. For stable SERS probes used for in vitro and in vivo imaging various classes of surface coatings such as poly(ethylene glycol) (PEG) and silica are used [39–42]. Tam, et al  synthesized Raman active phospholipid gold nanoparticles (RAP AuNPs) and reported its first use of porphyrin as reporter molecule for SERS based imaging. Porphyrins have heterocyclic pyrrole structures used for electromagnetic and charge transfer which can exhibit SERS spectra. Gold nanoparticles were combined with porphyrin-phospholipid that can self-assemble into bilayer nanoparticles with subsequent chelation and coating with PEG, exhibits phototherapeutics and imaging function. This porphyrin-lipid stabilized gold nanoparticle is novel SERS probe for cellular imaging. For imaging purpose these porphyrin lipids stabilized gold nanoparticles were incubated with cell line of A549 for imaging by confocal Raman microscope. The cells were exposed to laser illumination and displayed the intensity at 1239 cm-1 the particles were detected both as periphery and inside the cells displaying broadening of specific peaks it may be due to part of molecular changes due to aggregation from endosomal uptake when compared to in solution alone.
Broadly the herbal medicines have been widely used due to the active biological constituents such as flavonoids, tannins, and terpenoids etc. The active biological compounds are highly aqueous soluble, demonstrate low absorption because of inadequacy to cross the lipid molecules of cells resulting decrease in bioavailability and efficacy . Application of nanotechnology to formulate herbal extracts in various forms such as polymeric nanoparticles, solid lipid nanoparticles, liquid crystals, etc. that could potentiate the efficacy. Using biodegradable polymer of PLGA, Das J, et al  formulated polymeric nanoparticles by encapsulating the root extracts of Phytolacca Decandra (PD). Nanoformulation oral dose of 0.3 mg/kg body weight and native PD of 30 mg/kg body weight have demonstrated increased drug bioavailability and better chemo-preventive action against lung cancer in vivo than that of native . Using hydrophobically modified glycol chitosan Watanabe M, et al  formulated nanoparticles from plant alkaloid extract of Camptotheca acuminata Camptothecin (CPT) a potent anticancer drug. The antitumor activity was evaluated in subcutaneous tumor in the back of mouse using MDA-MB-231 human breast cancer cells. The tumor growth was significantly inhibited with both CPT nanoparticles using 10 mg/kg and 30 mg/kg body weight compared to native CPT at dose of 30 mg/kg bodyweight. The CPT-nanoparticles illustrated prolonged circulations in tumors as evaluated from by near infrared (NIR) fluorescence imaging systems demonstrating the efficacy towards the cancer therapy. Watanabe M, et al  used CPT, into pegylated liposomes and coated the surface human serum albumin. The antitumor activity was evaluated against mice bearing colon adenocarcinoma. The tumor growth in mice was inhibited after a single IV injection of nano formulation at 15 mg/kg body weight with better accumulations and stability in 24 h and it was ~ 9.6 times greater than the native CPT solution . The bioactive agent curcumin, found in turmeric has demonstrated potent antitumor properties. Bisht, et al  synthesized a mixture containing curcumin-loaded polymeric nanoparticles, using aggregated structures containing randomly cross linked copolymers of N-isopropylacrylamide, N-vinyl-2-pyrrolidone, and poly (ethylene glycol) monoacrylate. Aqueous dispersible nanocurcumin demonstrated and provided opportunity for better apoptotic activity. Mohanty C, et al  formulated curcumin nannoformulations which demonstrated longer half-life than native curcumin in mice. Moreover, the formulation illustrated potential anticancer activity in various malignant tumors.
Nanoconstructs for Photodynamic Therapy
Nanocarrier platforms such as liposomes, polymeric nanoparticles, micelles have been investigated for their potentiality for photosensiter (PS) based photodynamic therapy (PDT). The PS is encapsulated either by hydrophobic or by chemical conjugation reactions to polymers . In theranostic applications, porphyrins and phthalocyanines molecules which share an aromatic and planar tetrapyrrole backbone ideally suited for intrinsic multifunctional imaging and therapeutic applications. In blood endogenous bright red porphyrins could be considered as the original old theranostic agent, where heme maintains its use in magnetic resonance imaging in for cancer as early as 1980s, phthalocyanines were used for positron emission imaging since 1950s. The porphyrins upon irradiation generate singlet oxygen with exposure to light and are, used for therapeutic applications and have made a clinical mark in the form of PDT . Nanocarrier platforms such as liposomes, polymeric nanoparticles, micelles have been investigated for their potential for photosensiter (PS) based Photodynamic Therapy (PDT). The PS is encapsulated either by hydrophobic or by chemical conjugation reactions to polymers . Bae and Na , synthesized improved polysaccharide-based nanogels from pullulan/folate-pheophorbide-a (Pheo-A) conjugates. In an in vivo study after administration the nanogel illustrated fluorescence activity after 30 minutes and significantly increased till 12 hour and was maintained beyond 3 weeks, whereas, the free Pheo-A showed fluorescence immediately after injection but could not continue for longer period of time. These developed nanogels showed the window of opportunity for PDT with minimal unfavourable phototoxicity. In another study, Oh, et al  synthesized cancer-cell specific photosensitizer pheo-A conjugated Glycol Chitosan (GC) nanoparticle with reducible disulfide bonds (pheo-A-ss-GC) having switchable photoactivity. After the uptake by cancer cells the nanoparticulate structure instantly dissociates by reductive cleavage and disulphide linker with dequencing effect illustrating higher cytotoxicity with light treatment. PLGA nanoparticles encapsulated with Zinc (II) Phthalocyanine illustrated better and stable photophysical behaviour. These nanoparticles showed sustained release activity up to three days with better photocytotoxic activity. In another study, Lee, et al  developed tumor-homing drug carriers using protoporphyrin IX (ppix) GC nanoparticles (ppix-GC-NPs). These nanoparticles illustrated self-quenching effect in an off state with no fluorescence signal and with light exposure phototoxicity. After cellular uptake the compact nanoparticle structure gradually decreased and produced strong fluorescence signal and with irradiation singlet oxygen generation demonstrating the potentiality for synchronous photodynamic imaging and therapy. The ppix-GC-NPs -treated tumor bearing mice showed prolonged blood circulation and improved therapeutic efficiency compared to free ppix-treated mice. Using PEG polymer for cancer photodynamic therapy self-quenchable PS carrier system was developed as bioreducible biarmed mPEG-(ss-PhA)2 conjugate. PhA molecule was conjugated chemically with biarmed linkage at one end of mPEG via disulphide bonds. At the physiological conditions photoactivity of mPEG-(ss-PhA)2 nanoparticles was suppressed due to their self-quenching properties. The bioreducible activation mechanism in cancer cells efficiently showed high cytotoxicity under light exposure with better photodynamic cancer treatment and reduced side effects . Recent development of upconversion nanoparticles (UCNPs) those are capable of converting NIR light into UV-visible light which has aided remarkably to treat inaccessible deep tissues. The PDT based-UCNPs, upon excitation with NIR light the resulting Fluorescence Resonance Energy Transfer (FRET) to the attached PS generates ROS and kills [55,56]. Cui, et al  constituted a photodynamic therapy (PDT) for deep-tissue treatment where FA-modified chitosan (FASOC) coated to UCNPs and loaded with photosensitizer Zinc phthalocyanine (ZnPc), for specific tumor accumulation after NIR irradiation. To examine the nanoconstruct’s ability for biodistribution and tumor targeting, NIR fluorescent dye Indocyanin green (ICG-Der-01) was encapsulated to FASOC-UCNPs. After 24 h of post injection the excised organs showed good fluorescence in vital organs with low uptake in heart and spleen. For tumor selecting ability of the nanoconstruct, mice bearing Bel-7402 tumors (FR positive) were administrated with FASOC-UCNP-ICG and imaged at different time points. After 24 h post injection, the maximum tumor fluorescence was observed and persisted for more than 96 h. These results indicated promising PDT treatment with multifunctional nanoconstruct.
Quantum Dot Nanostructures
The development of specific and high-sensitive probes is highly interest in cell and molecular biology, imaging and medical diagnostics . During the last few years much attention has been devoted to the growth and characterization of self-assembled semiconductor quantum-dots (qds). The qds have unique optical and electronic properties, size- and composition with tunable fluorescence emission from visible to infrared wavelengths. Because of their broad excitation profiles and narrow symmetric emission spectra, high-quality qds are also well suited for optical multiplexing in which multiple colors and intensities are combined to encode genes, proteins and small-molecule libraries. Several groups have reported the use of qds for sensitive bioassays and cellular imaging [60,61]. Highly luminescent qds are covalently coupled with transferrin and are used in cultured Hela cells for nonisotopic detection . Wu, et al  utilized qds with different emission spectra, two cellular targets can be detected with one excitation wavelength. The qds were linked to Immunoglobulin G (IgG) and streptavidin for the detection of the breast cancer marker HER2 on the surface of fixed and live cancer cells. The obtained signals are brighter and considerably more photostable than comparable organic dyes. The qds–peptide conjugates are used to target tumor vasculatures. Akerman, et al  reported the in vivo targeting of zns-capped cdse qdots that was coated with three peptides. One of them was lung-targeting peptide and other two peptides were intended to specifically direct qdots to blood vessels or lymphatic vessels in tumors. After IV administration there was greater accumulation of peptides in lungs and prevents nonselective accumulations in reticuloendothelial tissues. The presence of quantum dots was examined under confocal microscopy image of the lung vasculature and lymphatic vessel. These nanoconstructs demonstrated theranostic capacity. NIR is a promising approach for biomedical imaging in living tissue. In this regard the quantum dots can be tuned into the near infrared and which can be used in major cancer surgery as well as sentinel lymph node mapping [62–64]. Bioconjugated qds probes suitable for in vivo targeting and imaging of human prostate cancer cells growing in mice. Gao et al described the ability of qds based multifunctional nanoparticle probes for cancer targeting and imaging in living animals. Qds were linked with tumor targeting ligands with IV administration to the nude mice it efficiently accumulated by enhanced permeability and along with active recognition of surface markers. To monitor cancer cells subcutaneous injection of QD-tagged cancer cells fluorescence imaging of the cancer cells was achieved in vivo . Qds are used for receptor based signalling. The ErbB/HER family of transmembrane receptor tyrosine kinases (RTKs) mediate cellular responses to Epidermal Growth Factor (EGF) and related ligands. Qds conjugated epidermal growth factor (qds-EGF) bound to erbb1 rapidly internalizes into the endosomes and exhibited active trafficking and extensive fusion in living cells providing the insight of early stages of RTK-dependent signaling in living cells . Ballou, et al  reported the efficacy of qds in tumor imaging in vivo. Injected qds rapidly migrated towards the sentinel lymph nodes and migrated from tumor to the lymphatics to the adjacent nodes which were visualized through the skin. Imaging during the tumor necropsy confirmed the confinement of the qds demonstrating tagging of sentinel nodes for pathology of lymphatic system. In another study Kim et al showed injection of NIR-qds permits Sentinel Lymph Nodes (SLN) imaging in real time. It provides the surgeon the opportunity of visual guidance throughout the SLN imaging and to minimize the dissection inaccuracies during cancer surgery .
In biomedical applications especially magnetic nanoparticles especially, the iron oxide have been exploited for imaging, diagnosis and therapy [68–70]. These magnetic nanoparticles offers significant shorter transverse relaxation of water and used as T2-MRI contrast agent, with an exposure to alternating magnetic field, heat is deployed for hyperthermia and thermal ablation [71–73]. These magnetic nanoparticles are also used for ideal probe for cancer therapy using mesenchymal stem cells due to their tumor-homing behaviour. In a study, Singh, et al  have demonstrated with magnetic nanoparticles better labelling and efficient tracking by MRI illustrated high T2 relaxivity which potentiates its use as a prospective diagnostic tool. These labelled mesenchymal stem cells also illustrated efficient homing ability towards inflammation site in subcutaneous prostate tumor and orthotopic prostate tumor model as revealed by in vivo imaging and histological studies thereby suggesting it’s applicability towards clinical relevancy. Moreover, further the magnetic properties can be modulated with magnetic clusters where the water molecules within and around the cluster is altered by complex spatial organization exhibiting higher transverse relaxivities as compared to the magnetic nanoparticles. In a study Cervadoro, et al  generated magnetic nanoconstructs by confining multiple magnetic nanoparticles in polymeric deoxychitosan matrix, which was further stabilized externally by addition of monolayer of lipids and poly (ethylene glycol) (PEG) chains and the resultant product is named as magnetic nanoflakes. When these magnetic nanoflakes are exposed to alternating magnetic field of 512 khz and 10 kam−1, demonstrated a Specific Absorption Rate (SAR) of ∼75 Wg Fe which is nearly 4–15 times greater than the conventional magnetic nanoparticles, also provides remarkably high transverse relaxivity of ∼ 500 (mms)−1, at 1.41T, proving the ability of an effective theranostic activity. Theranostics approaches deals with different modalities that are embedded into a single nanocarrier without compromising the functionality of each other. In a study theranostic targeted PLGA nanosphere was developed consisting of fluorescent iron oxide nanoparticles, gemicitabine drug and HER-2 antibody. The targeted nanospheres were administered to subcutaneously to human pancreatic cancer xenograft model in SCID mice. After administration the mice was placed in the center of the 440 khz RF frequency coil subjected to Magnetic Hyperthermia (MHT), the temperature in the tumor was increased by 6°C and the body temperature of mice through rectum was normal. The increased intra-tumoral temperature can be attributed to the specific heating caused by the targeted PLGA nanospheres. The tumor inhibition progressed significantly when compared to untreated animal. When the tumor bearing mice was subjected to MRI for evaluating the prognostic potential of targeted PLGA nanospheres, there was a contrast enhancement in groups of without and with MHT. However, with MHT the mice had smaller tumor and increased T2 contrast, confirming the imaging ability in MRI . Using magnetic beads with qds allows multiplex detection in combination with cell separation capabilities. Qds are ideal candidate for fluorescent tags due to narrow emission band and robustness against photo bleaching. As a proof of concept Corato, et al  fabricated multifunctional magnetic-fluorescent nanobeads (MFNBs) using poly (maleic anhydride-alt-1-octadecene) which embeds both manganese iron oxide nanoparticles and core-shell CdSe/ZnS nanocrystals- qds. The multiplex nanoparticles are functionalized with folic acid for biorecognition towards over expressed folate receptors. For their potential biomedical application uptake experiment was conducted in KB cell which over express α1 isoform of the folic acid receptor. The TEM analysis revealed strong contrast with appearance of black spots in time dependent manner. In confocal analysis, there was better fluorescence signal due to uptake of multiplex nanobeads in KB cells. For the cell separation study using the multiplex nanobeads, the doped KB cells were mixed with control cells in defined ratios and kept for specific time, thereafter the cell suspension was removed and the subjected for magnetic separation. The leftover cells (attracted by magnet) was analysed for the recovery of the doped cells. This multiplex nanosystem has significant advantage for it’s used in theranostic as well as cell separation in clinical studies. Huang, et al  made a engineered nanocarriers based on milk protein (casein)-Coated Magnetic Iron Oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. To this platform tumor-targeting Amino-Terminal Fragment (ATF) of urokinase plasminogen activator and anticancer drug cisplatin was engineered. ATF targeted-CNIO-cisplatin nanoparticles illustrated actively targeted delivery of cisplatin into orthotropic pancreatic tumors in mice. The MRI demonstrated better T2-weighted contrast imaging that resulted from specific effective accumulation in the tumor due to the active delivery of ATF targeted-CNIO-cisplatin nanoparticles compared to nontargeted CNIO and free cisplatin treatment suggesting to be an effective theranostic platform.
Conclusions and Future Directions
The continuous and steady insights into the development of nanocarriers over the last decade have depicted a revolutionary shift in cancer treatment, diagnosis and imaging. Although, its translational potential is yet to be assessed clinically but the in vitro and animal studies are pointing to its enormous potential. It has been revealed through researches that optimization of shape, size, composition, drug payloads, biocompatibility, biodegradability and cellular interaction and penetration of the system into the affected tumor tissue remains the mainstay of nanocarriers success as a delivery platform. Nanoconstructs like nanostars, nanoshells, nanoflares, magnetic, polymeric and /or lipidic nanoconstructs have reportedly superseded the earlier nonomedicine systems by proposing “an all-encompassing” cancer therapeutic approach. These systems as comprehensively discussed in the present review with an emphasis on their capacities to cater various aspects of cancer treatment. The strategies varies from engaging with the intracellular organelles and delivering drug and imaging agent at the target sites and capturing its effect by using the sophisticated tools of conversion of irradiated light on to the nanoconstructs to release heat and which in turn cause tumor regression. However, it is understood, that the clinical translation of such technologies could only be realized through fool proof optimization, safety assessment and suitable animal development which could induce confidence in researchers, practitioners and patients alike.
FD gratefully acknowledges Depatment of Science and Technology, Government of India for receiving financial support in the form of women scientist fellowship (SR/WOS-A/LS-524/2013(G). FD thanks Dr Sanjeeb K Sahoo for the encouragement and support.
Conflict of Interest
Authors declared that there is no conflict of interest.
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