The term “theranostics”, portmanteau of therapeutics and diagnostics, represent a new class of materials and treatment options that allows both therapy and diagnostics to patients. 1,2 It is a concept that provides a transition from conventional medicine to personalized medicine. The goal is providing targeted individualized treatment options for various pathologies using a single agent creating a new therapeutic paradigm involving diagnosis, drug delivery and monitoring of treatment response. This approach leads to better survival statistics and quality of life by enhancing treatment while reducing toxic effects, especially in cancer therapy application. Cancer theranostics involves early diagnosis, accurate molecular imaging, precise treatment (right timing and proper dose) followed by real-time monitoring of treatment efficacy that can intelligently and effectively remove the diseased tissue with limited negative effect to the patient and minimize the chance of cancer recurrence. This approach is not only ideal but could make an immediate impact in the clinic.
Theranostic nanoplatforms with multiple modalities for multimodal imaging and therapy, integrated with a remote-triggering mechanism offer great advantages in cancer therapy. In designing theranostic nanoplatforms, it is important to focus on parameters such as adequate circulation time, specific delivery to cancerous tissue, evasion of normal tissue and prevention of accumulation in the organs, lack of an immune response, and noninvasive monitoring. 3 Remotely triggered theranostic nanoparticles that permit simultaneous cancer diagnosis and therapy have been designed, fabricated, and evaluated in various in vitro and in vivo models of cancer. 4-6 Smart systems that release drugs or induce a toxic effect in response to an externally controlled stimulus in contrast with conventional systems that release their cargo passively or are activated internally have been made and evaluated. 7-9 Externally controlled triggers include ultrasound, electric or magnetic fields, X-rays, and visible or near-infrared (NIR) light. This remote-triggering approach allows treatment options that minimize damage to otherwise healthy living tissue through non-invasive triggering and spatiotemporal release of drug or therapeutic molecule.
The objective of this review is to discuss some major advances in the field of theranostic nanoparticles, specifically photo-triggering mechanisms used in cancer therapy by briefly summarizing their development and delineating the challenges that must be overcome for successful clinical implementation.
Nanotheranostics has been a rapidly growing field, developing nanoparticles capable of simultaneously monitoring drug distribution, drug release, and evaluate therapeutic efficacy through a single nanoscale carrier (Fig. 1). 10-12 Nanoparticles (1–100 nm) which are approximately 100,000 times smaller than the normal human cells have shown stronger interactions with biomolecules, such as receptors, antibodies, and enzymes, present inside or outside the cells. 13 Nanoparticles are versatile as they can be made into different forms and modified to incorporate varying moieties for precise detection and therapy. 14,15 Several nanosized delivery vehicles have been studied for theranostic applications (Fig. 2). For example, carbon nanotubes, gold nanoparticles, magnetic nanoparticles, 16 and quantum dots. 17,18 Chemotherapeutic agents have also been conjugated onto these nanoparticles with or without inherent fluorescence utilized for image-guided therapies. 19,20 However, these types of nanoparticles have been found to have elevated risks of toxicity, immunogenicity, and slow excretion kinetics from the body, which need to be thoroughly examined prior to clinical test in human. 21,22 Single-walled carbon nanotubes, for example, can cause oxidative stress and trigger apoptosis, 23 and magnetic nanoparticles can induce cell death through membrane damage. 24 As such, the potential of theranostic polymer-based nanomaterials have been explored.
Polymeric nanoparticles are perhaps the simplest form of soft materials for nanomedicine applications owing to their facile synthesis methods and versatility. Polymer-based theranostic nanomaterials possess excellent biocompatibility, biodegradability, and structural versatility. 25,26 Biopolymers naturally degrade into safe materials over time in the body and are typically nontoxic except at extremely high concentrations. Polymers that have been explored as theranostic nanoplatforms are, polyethylene glycol (PEG), poly(lactic acid), poly(glycolic acid), and poly(ε-caprolactone), which have been approved for clinical use in macroformulations. 27 Polymer-based nanomedicine usually fall into one of two categories, which are polymer-drug conjugates with increased drug half-life and bioavailability, and degradable polymer architectures for controlled release applications. Many of the components required and architecture can be designed and controlled through organic synthesis methods. Polymer components can be synthetic, pseudo-synthetic or those that arise from natural sources. Polymeric nanoparticles in cancer treatment are able to accumulate at specific disease sites through passive targeting by the enhanced permeability and retention (EPR) effect, or through active targeting by the incorporation of targeting moieties specific for a receptor or cell surface ligand at the region of interest. 28,29 However, the application of biodegradable polymeric nanoparticles are still currently limited by their nonspecific distribution, short half-lives and toxicity.
Polymeric micelles consist of self-assembled polymeric amphiphiles tailored for controlled delivery of hydrophobic drugs. Through the careful design of the hydrophobic or hydrophilic moieties in the amphiphile, the size and morphology of the assembled micelles can be controlled. For example, the hydrophobic core can be used to encapsulate drugs that have poor water solubility, whereas polar surfaces can be tailored to allow dissolution in aqueous solution. 30 Several micelle formulations are in late-stage clinical trials. However, traditional micellar formulation of estradiol (EstrasorbTM; Novavax Inc., Malvern, PA, USA) is the only Food and Drug Administration (FDA)-approved micelle to date, which is indicated as a topical treatment for moderate to severe vasomotor symptoms of menopause.
Another class of theranostic nanoparticles developed are liposomal platforms. The stabilizing nature and improved biodistribution of liposomes in circulation allow for the delivery of drugs with high toxicity or low bioavailability. Liposome nanoparticles are self-assembling that can integrate established targeting ligands into already approved liposome drug carriers creating new potential combinations to improve therapeutic delivery. They have amphipathic domains surrounding an aqueous core that chemically allows for the rapid integration of multiple molecules with different physico-chemical properties. Advances incorporate active targeting through cell surface receptor ligands conjugation to the liposome surface. These materials are currently in various phases of clinical trials.
A well-studied field in nanotheranostics and the center of this review, is inorganic nanoparticles. Several inorganic platforms are being investigated for therapeutic and imaging treatments. As such, iron oxide nanoparticles have undergone a number of clinical trials. To date there are only three particles that have completed FDA approval (Feraheme®, Feridex®, and GastroMARKTM), but two of which have been later withdrawn from the market. Iron oxide nanoparticles have an emerging research profile as contrast enhancement reagents for magnetic resonance imaging, however the majority of FDA-approved materials are indicated as iron replacement therapies. Some nanoparticle design is composed of an iron oxide core, coated with hydrophilic polymers (e.g. dextran, sucrose), which provide slow dissolution of the iron following intravenous injection. This allows rapid administration of large doses without increasing free iron in the blood to a level which causes toxicity. 31 Despite a number of similar superparamagnetic iron oxide nanoparticles (SPIONs) being granted FDA approval, they have since been discontinued for reasons that remain unclear. In 2010 there was EU-wide regulatory approval for NanothermTM, which consists of aminosilane-coated SPIONs designed for tumor therapy (glioblastoma) using local tissue hyperthermia (temperatures reach 40-45°C, leading to programmed and nonprogrammed cell death). NanothermTM is in late-stage clinical trials in the US, and FDA approval is pending. Gold has also been utilized as a nanomedicine in clinical trials due to its unique combination of optical properties, thermal properties, and tunable size, shape, and surface chemistry. 32 However, there are few gold nanoparticles being actively investigated in clinical trials, and there are no gold-based nanomedicines that have been approved to date by the FDA. Different changes in gene expression have been shown for acute and chronic exposure to gold nanoparticles. 33 Particles that have been placed into clinical trials recently have incorporated a biocompatible coating. In one study, recombinant human tumor necrosis factor (rhTNF) bound to colloidal gold using a PEG linker was studied for solid tumor. 34 It was found that the dose of rhTNF administered after immobilization to gold could be 3 times higher than native rhTNF without causing toxic effects. The PEG layer aided in accumulation in tumor masses via the EPR effect. In another example developed by Nanobiotix, NBTXR3 is a novel radio enhancer utilizing a high electron density metal oxide (hafnium oxide) nanoparticle to increase radiotherapy efficacy without increasing the surrounding tissue dose. 35 Entering phase I clinical trials in 2011, it has since reached phase II/III for treatment of soft tissue sarcoma. Phase I trials have also begun for indications including head and neck cancer and have been completed for rectal cancer in conjunction with PharmaEngine under the name of PEP503.
Upconversion nanoparticles (UCNPs) are particles that can emit high-energy photons under NIR excitation, resulting from a nonlinear optical upconversion process wherein the sequential absorption of two or more photons leads to the emission of a single photon at the shorter wavelength. Upconversion is mainly divided into three mechanisms: (i) excited state absorption, (ii) energy transfer upconversion, and (iii) photo avalanche. 36 With the development of nanotechnology, several methods have been developed to synthesize different kinds of UCNPs, many of which are lanthanide-doped nanocrystals with crystalline structures and controlled sizes. 37-39 In contrast with down conversion fluorescent organic dyes and quantum dots, UCNPs have a number of advantages such as sharp emission bandwidth, long lifetime, tunable emission, high photostability, low cytotoxicity, and importantly, little background auto-fluorescence, making them attractive contrast agents in optical biomedical imaging. In the past few years, several groups have investigated the potential applications of UCNPs in biomedicine. Targeting ligands have also been conjugated to UCNPs, wherein Li and coworkers 40 achieved efficient in vivo tumor targeting and imaging. In addition, UCNPs could be engineered to be contrasts agents in magnetic resonance (MR) imaging, positron emission tomography (PET), and computer tomography (CT), for in vitro and in vivo multimodal imaging, as demonstrated by a number of groups. 41,42 UCNPs may also be combined with anti-cancer drugs, 43 photosensitizers 44,45 or gold nanostructures 46 for potential therapeutic applications including chemotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT). Upconversion nanoparticles have several advantages that allow for specialized, targeted, and safe applications in biomedicine. However, it is still in its early developmental stages and has yet to be assessed for long-term toxicity and optimized prior to clinical trials. Some clinically approved nanoparticles with their material description and application are shown in Table 1.
Light-sensitive multifunctional nanoparticles have the advantage of locating cancer in a patient using different imaging modalities or optical imaging. Using an external light source as a trigger, nanoparticles can be used for targeted and controlled drug release at the cancer sites. Such photo-triggered theranostics result in better treatments that eradicate the possibility of under or overdosing, reduce the requirement for multiple rounds of administrations, and lead to improved patient compliance. This section will focus on PDT and phototriggered chemotherapeutic release.
At present, PDT is clinically approved for cancer treatment, while PTT and phototriggered chemotherapeutic release are still in clinical trials for cancer treatment. Remotely triggered theranostics allows for early recognition of the disease with controlled and image-guided release of a therapeutic agent. By using contrast agents and imaging techniques (MRI, optical imaging, ultrasound, X-ray) the location of the disease can be targeted using these remote triggers, allowing for control of the location of drug release and subsequent cell death. With more information about the tumor, there is a reduced potential for over and under dosing. This gives better control over the quantity of drug released. Remotely triggered therapies can also provide control over when the treatment occurs and the treatment duration, which is not possible with most conventional approaches. Using remotely triggered theranostics, treatments can either be turned “on” or “off” depending on a variety of factors, including whether or not the nanoparticle has reached the tumor sites. This ability to turn treatments “on” or “off”, compared to a treatment always being “on”, reduces toxicity in noncancerous or normal tissue. They are also advantageous regardless of the type of treatment due to their non-invasive nature, which is desirable for clinical translation. The non-invasive nature is a characteristic of many remote-triggering systems (NIR light, electric/magnetic fields, and ultrasound) that possess the ability to penetrate through skin, and in some cases through tissue, to induce a treatment.
Photo-triggering mechanisms in nanoparticles can involve photoisomerization and photocleavage-induced drug activation and release, oscillation of conduction electrons in noble metals or semi-conductors, formation of photo-induced whole-electron pairs in metaloxides, etc. 47,48 Nevertheless, few photo-triggered nanoparticles have been developed and studied thus far. Although potential is high for precision medicine in cancer therapy.
Precision medicine has been recognized as one of the future directions in cancer research and development. It is becoming more and more evident that the incidence and status of a cancerous disease in one patient can be very different to that in other patients. Thus, the response to any treatment would vary as well. The development of photo-triggered nanotheranostic particles is one of the strategies in the realization of precision medicine that presents a feasible means to convert current “one fits all” treatments into personalized approaches. The imaging modality allows the detection of disease sites and predicts whether the patient will benefit from the treatment, while the photo-triggered therapeutic modality could be localized in and around the diseased tissue without resulting in any significant off-target toxicity. The nanotheranostic system could also be used to monitor the outcome of the therapy, and the second treatment could be initiated or adjusted accordingly. Many great advances have been achieved in the development of photo-triggered nanotheranostic particles for cancer therapy within the past few years, with both their diagnosis and therapeutic capabilities validated on tumor-bearing animal models. Currently, several photo-triggered therapies are already in clinical use for the treatment of some superficial cancers that have achieved good therapeutic effect but require more comprehensive evaluation in terms of toxicity. Taking advantage of the advances in nanotechnology, it can be foreseen that the limitations currently hampering the application of these treatment types will be overcome, and that the clinical translation is highly expected.