Strategies for using nanoprobes to perceive and treat cancer activity: a review
- Byunghoon Kang†1,
- Aastha Kukreja†1,
- Daesub Song3Email author,
- Yong-Min Huh2Email author and
- Seungjoo Haam1Email author
© The Author(s). 2017
Received: 19 October 2016
Accepted: 19 December 2016
Published: 23 March 2017
Nanomedicine has seen a significant increase in research on stimuli-responsive activatable nanoprobes for tumor-specific delivery and diagnosis. The tumor microenvironment has particular characteristics that can be exploited to implement therapeutic strategies based on disparities between normal tissues and tumor tissues, including differences in pH, oxygenation, enzymatic expression, gene activation/inactivation, and vasculature. The nanocarriers of activatable nanoparticles maintain their structure while circulating in the body and, upon reaching the tumor site, are altered by unique tumoral stimuli, leading to the release of a drug or other agent. This review demonstrates the latest achievements in the use of internal stimuli-responsive, activatable nanoparticles with respect to unique design strategies and applications.
Nanotechnology is a multidisciplinary research field offering exciting possibilities to revolutionize the field of biomedicine through transformative diagnostic and therapeutic tools [1–3]. The past decade has witnessed the successful introduction of a plethora of nanoparticles for cancer diagnosis, imaging, and treatment [4–7]. Nanoparticles have been fabricated with unique physical and chemical properties originating from myriad materials such as organic compounds, inorganic compounds, and hybrid compounds [2, 8, 9].
The early diagnosis of the pathological state of tumors is the mainstay of successful cancer treatment and personalized therapy . Multifunctional nanoparticles, which provide both diagnostic and therapeutic features, have attracted great attention by providing early visualization of tumors and effective delivery of therapeutic agents with minimal side effects [11–15]. Nanoparticles engineered to carry a large payload of drug entities and target specific tumor sites represent an alternative to small-molecule imaging agents or drugs . Targeting can be achieved through antibodies, aptamers, small tumor-specific peptides, polymers, and other molecules. Although targeting factors provide high cancer-cell specificity by binding to specific tumor epitopes, more efficient delivery systems are needed to control the release of the therapeutic cargo (drug, gene, or protein) from the nanocarrier. Such delivery systems must interact minimally with the biological components of the nanoparticle and must prevent the release of the cargo during circulation in the blood stream [16–19].
Irrespective of the presence of highly specific ligands, the heterogeneity of cancer-specific biomarkers among cancer types and organ sites makes it a challenging task to establish a foolproof strategy for cancer diagnosis [6, 15, 20]. To overcome that challenge, many recent studies have established the presence of biomarkers in the tumor microenvironment that are more consistent across a range of cancer types. The metabolism of cancer cells is very distinctive. Angiogenesis, dysregulated glycolysis leading to acidic pH and chronic oxidative stress, proliferative signaling, and the evasion of growth suppressors affecting enzymes and small molecules such as miRNA/DNA are all hallmarks of cancer. The targeting of those tumor hallmarks provides promising strategies for broad tumor detection [2, 15].
Activatable nanoparticles offer a platform to overcome the disadvantages of traditional tumor-targeting techniques by remaining intact before reaching the target. The on-demand activation of nanocarriers, which allows the efficient delivery of therapeutic agents with excellent dosage control, is becoming feasible. That approach requires the careful fabrication of nanoconstructs that are capable of undergoing specific, stimulus-induced changes such as conformational changes, hydrolytic cleavage, or specific protonation. Stimuli-responsive nanoconstructs can be transformed from a passive form to an active form in response to various exogenous or endogenous stimuli. Exogenous stimuli-responsive nanoconstructs take advantage of externally applied stimuli and include thermoresponsive systems, magnetic-responsive systems, ultrasound-triggered systems, light-triggered systems, and electroresponsive systems. Endogenous stimuli-responsive systems take advantage of the tumor microenvironment . For example, at the cellular level, pH variations can be exploited to control drug release in late endosomes or lysosomes or in the generally low pH environment of cancer-specific sites. Also, the glutathione concentration varies between the extracellular environment and the intracellular environment and between tumor tissues and healthy tissues, potentially providing a way to attain redox sensitivity via the cleavage of disulfide bonds [21–23].
In this review, we discuss the most important progress made recently in nanoparticle synthesis. We also describe recent approaches that attempt to overcome the drawbacks of endogenous stimuli-responsive nanosystems for drug or gene delivery, with a particular emphasis on tumor treatment.
Types of nanoparticles
Types of nanoparticles
MFe2O4 (M = Fe, Mn, Co, Zn), MnxOy (1 ≤ x ≤ 3, 1 ≤ y ≤ 4), ZnO
Au, Ag, Pt
CdSe, ZnSe, ZnS, ZnO
Mesoporous Silica, SiO2
Chitosan, Hyaluronic acid
Peptide or Protein Nucleic Acid
Noble metal (gold, silver, and platinum) nanoparticles have unique surface plasmon resonance due to their nanoparticle-sized photon confinement . Among them, gold nanoparticles are the most extensively studied, because their unique phonons make them advantageous for optical and photothermal applications. Several researchers have performed extensive studies to precisely control and tune the optical properties of gold nanostructures by changing the size, shape, and structure of the nanostructures [33–35].
Quantum dots are another example of inorganic nanoparticles that have emerged as versatile tools for biomedical imaging . They are composed of atoms from groups II–VI or III–V of the periodic table. Quantum dots have unique optical and electrical properties due to quantum confinement effects. Recent studies have applied quantum dots in DNA hybridization, immunology, receptor-mediated endocytosis, in vitro and in vivo fluorescence imaging, multiplexed optical coding, and the high-throughput analysis of genes and proteins.
Lipid-based nanocarriers play a major role in cancer therapy . Nanocarriers, such as liposomes, lipid micelles, solid-lipid nanoparticles, nanosuspensions, and nanoemulsions, are commonly made of lipid-based materials, such as cholesterol, phosphatidylcholine, and 1,2-disteardyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG 2000). Liposomes are the lipid-based nanoparticles that have been explored the most for cancer therapies. Liposomes are colloidal vesicles with single or multiple bilayered membrane structures. They are biodegradable and biocompatible and can encapsulate hydrophilic agents in their aqueous core and contain hydrophobic agents within their bilayers. Many clinical studies have shown the successful loading of hydrophobic drugs such as paclitaxel and doxorubicin into liposomes for cancer therapy .
A recent example of a protein-based nanosystem is Abraxane , which was approved by the FDA in 2005 and is now in clinical use. Abraxane is an albumin-bound paclitaxel nanoparticle produced in a high-pressure homogenizer. The drug particle is stabilized by human serum albumin and has an average size of 130 nm, which prevents any risk of capillary obstruction. Preclinical trials conducted in athymic mice with human breast cancer demonstrated that Abraxane has increased antitumor activity and greater penetration into tumor cells compared with an equal dose of standard paclitaxel. A phase I trial confirmed that the maximum tolerated dose of Abraxane is 70% higher than that of the Cremophor EL® paclitaxel formulation. A phase II trial confirmed that Abraxane has antitumor activity in patients with metastatic breast cancer. A phase III trial confirmed the superiority of Abraxane over standard paclitaxel in terms of both the overall response rate and the time to tumor progression.
The development of hybrid nanocomposites, which combine organic and inorganic components, is intended to produce composite materials that retain the beneficial features of both organic compounds and inorganic compounds. Hybrid nanoparticles can be synthesized either by incorporating inorganic particles into a polymer matrix or by forming core/shell structures. Inorganic/organic core/shell structures combine a metal, semiconductor, metal oxide, or silica core with an organic/polymeric shell, which can save the metal core from oxidation and also increase biocompatibility. PEG, dextran, and chitosan have been studied extensively for the coating of various metal cores to improve biocompatibility and increase the number of applications for a single component. For example, Lim et al.  developed a multimodal nanoprobe using the amphiphilic polymer pyrenyl-PEG and superparamagnetic MnFe2O4 nanocrystals. The fluorescent magnetic nanoprobes were biocompatible and had excellent MR sensitivity and optical imaging capabilities .
Organic/inorganic core/shell nanoparticles have a polymer core and an inorganic shell. A metal oxide shell over a polymer can provide increased strength and abrasion resistance. Such systems are also used to synthesize inorganic, hollow nanoparticles .
Types of stimulus response in the tumor microenvironment
Types of stimulus responses in the tumor microenvironment
poly(histidine-co-phenylalanine), 2-(diisopropyl amino) ethyl methacrylate
MT1-MMP, MMP7, secretory phospholipase A2
Hypoxia and oxidative stress
4-nitrobenzyl group (hypoxic trigger), o-hydroxyl E-cinnamic ester (photo-activated group), MnO (glutathione), quaternized chlormethine (H2O2)
Nucleic acid based
Enzymes are key components in all biological processes. The dysregulation of enzyme activity has been observed in many pathological conditions, rendering the detection of enzyme expression a powerful tool for diagnosis [62, 63]. The exceptional efficiency of enzymes in the selective recognition of their substrates makes them a sophisticated tool for producing biologically inspired chemical reactions. That has led to a growing interest in the development of bioresponsive nanoparticle systems, including polymeric nanoparticles, liposomes, metal and semiconducting nanoparticles, and silica nanoparticles, that respond to the catalytic activity of enzymes. Nanoparticles can be rendered enzyme-responsive by the inclusion of moieties that can either be cleaved upon recognition by a biocatalyst or be transformed upon catalytic action by an enzyme . Cancer-associated proteases, esterases, phospholipases, and oxidoreductases are upregulated in tumors and have been utilized to develop enzyme-responsive nanosystems. For example, phospholipase A2 is upregulated in various tumors, including those of the prostate. Enzyme-responsive nanosystems have been explored recently in the search for activatable liposomal drug-delivery systems. Linderoth et al.  developed a novel drug-delivery system that combines lipid-based prodrugs formulated as liposomes with overexpressed secretory phospholipase A2 (sPLA2) as a trigger for activation . As a model drug, they used capsaicin prodrug 8, which forms a uniform bilayer of vesicles directly upon dispersion in a buffer. The ester group at the Sn-2 position of glycerophospholipids is hydrolyzed by sPLA2 , so the researchers synthesized a glycerophospholipid derivative with the drug at the Sn-1 position. When the ester group at the Sn-2 position was hydrolyzed, an OH group was released, which reacted with the ester group at the Sn-1 position to form a lactone and thereby release the drug.
Polymeric nanoparticles are the most widely used nanoplatforms for the development of enzyme-responsive systems.  Chemotherapeutic drugs, proteins, genes, and siRNAs have been delivered using enzyme-responsive polymeric nanoparticles. In a recent study, Li et al.  developed a smart polymeric nanoparticle containing a positively charged dimethylaminoethyl (DMAEMA) corona to package siRNA and also act as a pH-responsive core. They linked the corona to a PEG layer via an MMP-7 cleavage peptide, which shielded the nanoparticles from nonspecific cell interactions. Once the PEG layer was cleaved in an MMP-7-rich environment, the nanoparticles became positively charged, and their rate of internalization increased 2.5-fold because of the negative-positive charge interactions. The pH change following internalization further disrupted the corona, leading to siRNA escape from the endolysosomal pathways.
Hypoxia and oxidative stress
Tumors have inadequate vasculature and therefore rapidly exhaust their blood supply, leading to glucose deprivation and hypoxia. Glucose deprivation prevents the decomposition of endogenous oxygen radicals, causing oxidative stress. Hypoxia and oxidative stress are both present in tumor cells and are interlinked. Angiogenesis within the tumor tissue causes periods of hypoxia due to the uncontrolled blood flow. Hypoxia is known to promote aggressive tumor phenotypes and causes resistance to chemotherapy and radiotherapy. Recently, many studies have applied a hypoxia-activated strategy to release prodrugs, imaging agents, and other functional molecules within tumor cells. Feng at al.  developed a modified gemcitabine (GMC)-based pro-prodrug (GMC-CAE-NO2) with an o-hydroxyl E-cinnamic ester photo-activated group (CAE) and a nitro-benzyl group, which could not be reduced under normal oxygen conditions . Under hypoxic conditions, the GMC-CAE-NO2 was converted to the prodrug GMC-CAE. Subsequently upon UV exposure, alteration of the prodrug led to the formation of fluorescent dye and GMC release. The rate of GMC release increased with decreasing O2 concentration.
Reactive oxygen species (ROS); including hydrogen peroxide (H2O2), hypochlorous acid (HOCl), superoxide (O2 -), singlet oxygen (1O2), and hydroxyl radical (OH-); are abundant in cancer cells. The overproduction of ROS leads to redox imbalance and cellular damage. Li et al.  developed chlormethine (Chl), an H2O2-sensitive quaternized prodrug with an eight-member cyclic boronate ester that could be triggered in the presence of H2O2 . They covalently linked the prodrug to poly(fluorene-co-phenylene; PFP) side chains, creating PFP-Chl, which successfully released the Chl within cancer cells and inhibited cell growth. In another study, Chen at al.  developed H2O2-activatable and O2-evolving photodynamic therapy (PDT) nanoparticles (HAOP NPs). They encapsulated methylene blue (photosensitizer) and catalase (O2-evolving agent) in the aqueous core of a PLGA shell and doped the bilayer of the shell with black-hole quencher-3 (BHQ-3). They further modified the surface of the particles with c(RGDFK), a tumor-targeting peptide. The HAOP NPs were selectively taken up by αvβ3 integrin-rich tumor cells, followed by H2O2 penetration into the core, catalysis by catalase, and O2 generation, causing the rupture of the polymer shell. Thus, the nanoparticles allowed the controlled release of 1O2 within tumor cells, providing high-efficiency in vivo PDT while also overcoming hypoxia-induced drug resistance.
Cancer-specific mRNAs have been utilized to detect tumor progression. Li et al.  utilized multiple mRNA targets to improve the accuracy of cancer detection in single-marker assays . They synthesized a multicolor fluorescent nanoprobe consisting of gold nanoparticles functionalized with three short, dye-terminated reporter sequences via a gold-thiol linkage. The gold nanoparticles quench the fluorescence of the dye. Upon RNA or DNA hybridization with a more stable complementary sequence, the reporter sequence is released, turning the fluorescent signal on. The researchers successfully distinguished between cancer cells and normal cells and reported changes in the expression levels of tumor-related mRNAs.
Limitations of stimuli-responsive nanoparticles
Stimuli-responsive nanosystems have seen tremendous growth in the past few decades. Their efficacy for cancer detection and therapy is undeniable; however, certain challenges still exist that need to be addressed and may vary from one patient to another. The pH-activated nanosystems that disrupt the lysosomal membrane may lead to the release of lysosomal enzymes into the cell cytoplasm, which can cause autophagy and cell death. Also, the release of payload inside the lysosomes may lead to denaturation, causing significant loss of efficacy. Enzyme-activated systems also face various challenges. Enzyme dysregulation in various diseases and at various stages of the same disease needs to be studied extensively for eventual clinical translation. Overlapping substrates between closely related enzymes can cause nonspecific uptake or cleavage, resulting in systemic toxicity. Nucleic acid-activated nanoparticles have a major drawback based on the fact that protein upregulation is not always related to nucleic acid upregulation in cancer, which may lead to untrustworthy conclusions. Hypoxia and oxidative stress is present at elevated levels in all cancer types. However, high levels of ROS may cause activation of various signaling pathways leading to cell death.
Conclusions and perspectives
We reported a general overview of the role of nanoparticles in the efficient delivery of drugs, genes, contrast agents, and other functional molecules for cancer imaging and therapy via specific targeting and selective activation in the cellular niche. Tumor microenvironment-activatable nanosystems with nanocarriers acting as ‘homing devices’ loaded with therapeutic contrast/therapeutic agent and coated with responsive polymers or probes provide new insights into cancer therapy by demonstrating high specificity and sensitivity with minimal degradation or background signal. The successful translation of activatable nanosystems into clinical trials will change the very foundation of tumor theragnostics. Their controlled release, specific targeting, and biocompatibility will make them an important component of personalized therapy in the near future. Nevertheless, some limitations still exist, and more data is needed to translate the results obtained in animal models into applications in humans. The experimental models in humans are not yet standardized and much more heterogeneous than animal models because of high heterogeneity in blood flow, which often makes comparison of results troublesome. In vivo systems are complex, and studies and regulations are essential to ensure the biocompatibility of nanocarriers in humans. We anticipate that many of the current problems will be resolved in the near future, and we expect that much of the current research will be translated into clinical applications.
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (MEST; Grant 2012050077).
Funding information is not available.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the study.
BK, AK, and SH planned the structure of the manuscript, designed the figures, and wrote the manuscript. DS and Y-MH conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript. DS, Y-MH, and SH are co-corresponding authors. BK and AK contributed equally to this work.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The need for ethics approval and consent was waived.
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