The future of quantum dots in drug discovery

Abstract

The rapid development of drug discovery today is inseparable from the interaction of advanced particle technologies and new drug synthesis protocols. Quantum dots (QDs) are regarded as a unique class of fluorescent labels, with unique optical properties such as high brightness and long-term colloidal and optical stability; these are suitable for optical imaging, drug delivery and optical tracking, fluorescence immunoassay and other medicinal applications. More importantly, QD possesses a rich surface chemistry property that is useful for incorporating various drug molecules, targeting ligands, and additional contrast agents (e.g., MRI, PET, etc.) onto the nanoparticle surface for achieving targeted and traceable drug delivery therapy at both cellular and systemic levels. In recent times, the advancement of QD technology has promoted the use of functionalized nanocrystals for in vivo applications. Such research is paving the way for drug discovery using various bioconjugated QD formulations. In this editorial, the authors highlight the current research progress and future applications of QDs in drug discovery.

Keywords::

• drug delivery
• drug discovery
• drug screening
• quantum dot

1. Introduction

The sensitivity analysis and detection of protein, nucleic acids, peptides and other important biological markers in patient’s biological fluids are the critical challenges in life science [1]. Quantum dots (QDs) are semiconductor nanocrystals with unique optical properties, such as high photochemical stability, broad excitation wavelength, narrow emission bandwidth and long fluorescent lifetime, and they have been widely used in many areas of life sciences [2-4]. In the late 1970s, QDs have attracted widespread attention from chemists, physicists and engineers where many of them are using QDs as a model to understand the theory of quantum confinement effect on nanomaterials. In 1998, Nie’s and Alivisatos’s groups independently reported the use of QDs for imaging of cells and tissues and these studies have sparked the research growth of QD applications in life science [5,6]. In more recent years, bioconjugated QDs are being applied for detecting DNA, peptide, protein, traceable drug delivery therapy, and small animal fluorescence imaging [7,8]. Many researchers are very hopeful that QDs can be translated for clinical medicine applications in the near future. However, the potential threat of QD toxicity has significantly delayed the progress of employing QDs in animals for drug discovery usage. Tremendous research efforts have been devoted in developing new QD surface modification strategies to enhance biocompatibility and reduce toxicity of the nanocrystal formulation. For example, Li et al. synthesized near-infrared (NIR)-emitting CdTe QDs coated with the tumor-specific ligands for imaging of tumor in vivo without observing any toxicity effects [9]. Hu et al. demonstrated the use of micelle-encapsulated NIR-emitting lead sulfide QDs for imaging of cancer cells and small animals and no adverse effects were observed at the cellular and tissue levels [10]. Such result has suggested that QDs can be potentially engineered and used as drug nanocarriers or nanoprobes for traceable and targeted therapy of diseases in vitro and in vivo [3,4,11]. Due to the unique optical property and rich surface chemistries of QDs, we envision that QDs will have a great application prospect in drug discovery such as target detection, drug delivery and screening.

2. Why use nanoparticles for drug discovery?

Current drug discovery approaches suffer from major challenges such as low reliability of biological targets, tedious drug-screening workload, inefficient drug delivery and off-target side effects. Nanoparticles (NPs) such as micelles, liposomes, gold colloids and polymers have emerged as attractive materials in drug discovery because they can address the challenges mentioned above. For example, Lee et al. reported that the effective tumor uptake of i.v. administered dendrimer–doxorubicin nanoformulation reached up to ninefold much higher than that of the free doxorubicin at 48 h in BALB/c mice and this was achieved through the use of enhanced permeation and retention effect strategy [12]. Linemann et al. demonstrated that lipid-encapsulated chitosan-coated magnetic NPs are able to escape from capturing by reticuloendothelial system [13]. Thus, NPs provide many advantages for drug discovery purpose. However, many of the NPs described above do not allow one to detect or even real-time monitor them with high-resolution imaging signals when they are introduced into the body. For example, the currently used medical technique MRI is not capable of providing specific chemical and dynamic information (changes happening in real-time response to a treatment or a stimulus) of the examined areas. Optical imaging overcomes these drawbacks as encountered by MRI. Optical imaging uses the spatial variation in the optical properties of a biological sample, whether a cell, a tissue, an organ or an entire living object. By further incorporating bioconjugated QDs into the optical imaging techniques, one can obtain information on cellular processes and tissue chemistry by spectrally resolved and dynamic imaging with resolution as low as 100 nm. To address this limitation, QDs can be used as high-resolution contrast agent and a nanoscaffold platform for assembling multifunctional and multimodal biomolecular probes in achieving QD-based drug testing, detection, diagnosis and therapy applications.

3. The application of QDs in drug discovery

3.1 The application of QDs in drug target study

The successful development of innovative drugs for diseases therapy relies heavily on the discovery and validation of new drug targets. Functionalizing specific ligands such as antibody, peptide and amino acid on the QD surface will allow one to engineer traceable optical probes for real-time monitoring and understanding the dynamic interaction between biomolecules within a cell. For instance, different emission colors of QDs can be used simultaneously to observe the chain reaction process of multiple target molecules in/on living cells. In recent years, a variety of specific molecular biomarkers of tumors have been conjugated on the QD surface for achieving diagnosis of tumor in vivo. For example, Cai et al. reported the targeted imaging of tumor vasculature in vivo using arginine–glycine–aspartic acid (RGD) peptide-attached QDs [14]. They have attached the RGD peptide on CdTe/ZnS QDs and subsequently the prepared formulation is injected into athymic nude mice bearing subcutaneous U87MG human glioblastoma tumors. The study shows that tumor fluorescence intensity reached maximum at 6 h post-injection. Using such similar approach, for drugs with unknown targets, a number of drugs can be conjugated with different emission colors of QDs to identify their possible corresponding targets by quantitative analysis of fluorescence emissions in the various sets of target molecule-conjugated QD arrays.

3.2 Applications of QDs in drug delivery

To meet the high-standard requirements of using drugs for clinical applications, researchers have to devote tremendous efforts in developing new methods and approaches for targeted delivery of drugs into the body with minimum toxicity and side effects. Currently, biomedical and biotechnological researchers are paying great attention on the applications of employing QDs in drug delivery [3,12]. In some sense, QDs possess unique features that combine the best of both worlds from the prospective of imaging and drug delivery. On one hand, QDs themselves can be used as a nanocarrier for drug delivery. On the other hand, QDs can be utilized as a multimodal probe to monitor the biodistribution of the drug delivery system such as liposomes, cationic polymer nanocapsules, micelle nanostructures and chitosan NPs. In general, functional molecules such as thioglycolic acid or heterobifunctional PEG can be used as the surface coating materials and subsequently they can be further modified with drug molecules to form QD theranostic nanoprobes. Yezhelyev et al. demonstrated the use of both QDs and proton-absorbing polymeric coating (proton sponges) to design multifunctional NPs for delivering short-interfering RNA in vitro. The QD–siRNA nanoformulation has a higher transfection efficiency rate of 10 – 20-fold in cells compared to the existing transfection agents and such formulation allows one for real-time tracking and studying the ultrastructural localization of the biomolecules such as drugs [15]. In addition, the delivery of drugs to specific parts of the body can be enhanced by linking these nanocarriers with targeted ligands [14,16]. Also, Boeneman et al. undertook an iterative structure–activity relationship analysis of JB577 peptide to elucidate residues required for endosomal escape by modifying key motifs including charge, length, fatty acid content and domain order. They have evaluated these analogs within a comparative and semiquantitative assay, to define the key elements within the peptide sequences, which must be conserved for cytosolic delivery applications with additional QD formulations [17].

3.3 The applications of QDs in drug screening

The unique optical property of QDs has a far-reaching impact on drug screening in the near future. Nie’s group embedded different emission colors of QDs into polymer microbeads at various controlled concentration ratios of QDs, thereby forming microspheres with distinguished spectral characteristic and luminescence characteristic and they can be used for identifying and differentiating biological molecules [18]. They reported that > 30,000 types of encoded QD microspheres can be prepared by using only 6 types of QD emission colors. Such discovery can be further developed in engineering QD-based drug-screening platform such as fluorescence resonance energy transfer, immunoassay and pharmacological assay for monitoring the molecular details (e.g., the location and track of targets, the interaction between targets and unknown substrates, etc.) of biological processes during the drug-screening process. For example, Zhang et al. reported that single QD-based nanosensor can be used for screening of new anti-HIV drugs by quantifying the sequence-specific interaction between the regulatory protein Rev and env gene that is critical for HIV-1 replication [16]. Choi et al. developed a novel enzymatic assay using fluorogenic QD–gold NP assembly via Ni–His interaction to screen the α-secretase1 activity in living cells [7]. Ku et al. developed an antimalarial drug-screening assay by using QDs as probes where they have been labeled with plasmodium falciparum-infected erythrocytes. This new assay can offer a rapid and robust platform for screening and discovering new classes of antimalarial drugs [19]. These examples clearly show the potential of QDs for future drug-testing applications in vitro and in vivo.

4. Expert opinion

To date, QDs have been applied in research areas ranging from optics to life sciences. With the development of new approaches of utilizing QDs in life sciences, some challenges that we are facing currently in clinical research can be overcome. For example, the unique optical property of QDs allows one to investigate the real-time dynamic events in living cells and such events include interaction between intracellular proteins, the mechanisms of intracellular signal transmission and cell growth. In addition to this basic research, QDs have also been applied for clinical applications such as diagnosis of disease and labeling of pathological tissue specimens. By further optimizing the surface chemistries of QD formulations, QDs can be used as a powerful tool for mass screening of drugs and they are expected to provide effective methods to study the efficacy of different drug types, especially NIR QDs, and they provide a promising future in the application of traceable therapy of tumor since the emission wavelength of these particles is in a region of the spectrum where blood and tissue absorb minimally and tissue penetration reaches maximum. However, there are some limitations yet to be resolved for their use in the drug discovery studies, namely, size variation, aggregation, toxicity and attachment of multiple drugs onto a single QD. Currently, many active and distinguished researchers worldwide are creating novel approaches to address the shortcomings of QDs listed above and we are very hopeful that these problems can be overcome in the near future thereby shortening the time needed to translate the use of QDs in clinical drug discovery and testing.

Declaration of interest

The authors’ research in the area of quantum dots for biological applications is supported by their universities and the Singapore Ministry of Education. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.