Controlled actuation of therapeutic nanoparticles: moving beyond passive delivery modalities
2013; Future Science Ltd; Volume: 4; Issue: 2 Linguagem: Inglês
10.4155/tde.12.141
ISSN2041-6008
AutoresJames B. Delehanty, Igor L. Medintz,
Tópico(s)Microfluidic and Bio-sensing Technologies
ResumoTherapeutic DeliveryVol. 4, No. 2 EditorialFree AccessControlled actuation of therapeutic nanoparticles: moving beyond passive delivery modalitiesJames B Delehanty & Igor L MedintzJames B DelehantyCenter for Bio/Molecular Science & Engineering, US Naval Research Laboratory, Code 6900, Washington DC 20375, USA & Igor L Medintz* Author for correspondenceCenter for Bio/Molecular Science & Engineering, US Naval Research Laboratory, Code 6900, Washington DC 20375, USA. Published Online:23 Jan 2013https://doi.org/10.4155/tde.12.141AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: actuationcontrolled releasedrug deliverynanoparticlestimuli-responsivetheranostictherapeuticNanoparticle actuation: a definitionThe past decade has seen significant advances in the interfacing of nanoparticles (NPs) with living cells for a myriad of applications ranging from the labeling/visualization of cellular structures [1] to the real-time monitoring and sensing of cellular processes [2]. These efforts have been facilitated by steady progress in: ▪ The synthesis of increasingly higher quality NP materials;▪ Methodolgies for rendering NPs biocompatible (stable and inert in biological media);▪ Robust delivery modalities for cellular NP uptake.This has sparked the now rapidly expanding fields of NP-mediated drug delivery and theranostics wherein the primary goals are to utilize NPs' combined small size and large surface area:volume ratio to overcome the inherent limitations of traditional systemic drug delivery and combine diagnostic/therapeutic capabilities on a single NP platform. Paramount to this endeavor is the development of methods for achieving the controlled release or 'actuation' of NP-associated drug (or other effector molecule) cargos with exquisite spatiotemporal control and fidelity. In this Editorial, we provide a brief summary of some emerging themes in the NP cargo actuation arena. We highlight the inherent benefits and liabilities of each approach, and offer a brief forward-looking perspective on how this field can be expected to develop over the next 5–10 years.Emerging themes in NP actuationTo date, a variety of NP actuation themes have emerged that span a continuum of sophistication in their design and functionality. Many of these modalities originate from the field of cancer chemotherapy, where exerting fine control over the release of a drug cargo has been a significant challenge in striking a balance between specific, tumor-directed killing and nonspecific, off-target cell and tissue toxicity. Representative examples of these various actuation themes are highlighted below.▪ Passive cargo actuationThe passive actuation of NP-associated cargos involves the simple release of a drug or other cargo from within the NP core or the NP surface. Examples of this actuation modality include drug-loaded liposomes [3], poly(amidoamine) dendrimers [4] and drug-adsorbed protein NPs [5]. Here, the approach is to incorporate the drug cargo into or on to the NP either during or after NP synthesis. Delivery to targeted, diseased cells or tissues results in the passive efflux of the drug cargo to the tumor environment or the intracellular environment (if the NP is functionalized for cellular internalization). This approach represents the simplest of actuation designs and, accordingly, it offers minimal spatiotemporal control of cargo release. Still, it is worth noting that this passive actuation modality remains the only one to have earnt US FDA approval for use in the clinic. Examples include the chemotherapeutics DOXIL® and Abraxane®, which are NP-based delivery vehicles for the chemotherapeutics doxorubicin and taxol, respectively. DOXIL is a liposomal-encapsulated formulation of doxorubicin that avoids the mononuclear phagocytic system via PEG moieties appended to the liposome surface [6,7]. Abraxane is a human serum albumin conjugate of the naturally occurring diterpene, taxol (or paclitaxel), in which the drug is bound to the human serum albumin protein through hydrophobic interactions. Here, the albumin facilitates the efficient endothelial uptake and transcytosis of the bound drug cargo. Notably, approximately 75% of ongoing clinical trials for a variety of cancer types involve the use of Abraxane or another form of an albumin NP-associated drug [101], a testament to the wide utility of this simple, yet elegant, NP-based drug delivery system.▪ Cellular stimuli-responsive cargo actuationThe actuation of NP-based drug carriers via cell-specific stimuli or microenvironments is another area that has seen significant development. Here, a number of NP-based drug-delivery schemes have been devised that exploit differences in pH, temperature and redox profiles between pathological and healthy tissues. These include: ▪ The lower pH at primary and metastatic tumor sites compared with healthy tissues;▪ The enhanced sensitivity of tumor cells to heat-induced damage relative to normal cells;▪ Alterations in the redox status at the disease site.Lowered pH in the tumor environment has been used to enable the localized degradation of: ▪ Biodegradable cationic polymers (e.g., poly [β-amino ester]) [8];▪ Bethacrylate polymer NPs whose cellular entry is prohibited until pendant, acid-labile PEG chains are cleaved within the tumor interstitium [9];▪ pH-sensitive liposomes that destabilize within endocytic vesicles [10].For taking advantage of the thermal-sensitive nature of cancer cells, amphiphilic polymeric NPs have been developed comprising temperature-sensitive hydrophilic segments grafted to suitable hydrophobic segments. Such block copolymers have been used for the parenteral delivery of paclitaxel [11] and numerous examples are reviewed by Rijcken et al.[12]. Redox-responsive NP drug carriers take advantage of the high redox potential difference (∼102 –103-fold) between the reducing intracellular environment and the oxidizing extracellular space. For example, polyaspartamide polymeric NPs containing disulfide cross-linkages that are susceptible to reduction intracellularly have been used successfully for the reduction-mediated release of electrostatically assembled plasmid DNA [13]. Similarly, disulfide cross-linked liposomes have been reported to efficiently disrupt and deliver encapsulated DNA [14] and doxorubicin [15] intracellularly. Clearly, the ability to differentially modulate NP behavior based on the local cellular environment will be a growing focal area in NP–cargo actuation.▪ Extracellularly triggered cargo actuationA final actuation theme involves exerting control over the NP–cargo assembly from outside the cell upon localization to the diseased tissue site. Approaches utilizing the photoactivation of labile linkages or the radiofrequency ablation of NP-embedded drug cargos allow for the greatest degree of temporal resolution of NP-mediated drug release, as the triggered drug release can be tightly controlled. Here, photosensitive liposomes composed of light-sensitive lipids have been the focus of significant investigation (reviewed in [16]). A similar approach has also been used to mediate the efficient cellular targeting of NP–drug composites coupled with concomitant drug release. Dvir et al. reported an elegant drug-loaded NP system wherein a cell-targeting/uptake peptide on the NP surface was 'caged' by a photolabile protecting group [17]. In a variety of cell types, illumination of cell monolayers in the presence of the caged NPs resulted in efficient localization of the NPs to the cell surface relative to control. Radiofrequency ablation, which utilizes radiowave-induced electrical current to selectively heat a targeted disease site, has been combined with thermosensitive liposomes to efficiently release encapsulated doxorubicin with tight control [18].Future perspectiveClearly, the field of NP actuation for therapeutic drug delivery is an exciting one that has already seen a number of elegant displays illustrating various levels of controlled release of NP-associated drug cargos. Indeed, many of these advances have been demonstrated using liposomal or protein NP platforms. Despite this progress, however, the relatively limited number of FDA-approved NP-mediated drug-delivery platforms points to the need for more basic research and a finer understanding of how to target/control NP–drug constructs in biological systems [19]. Over the next 5–10 years, we anticipate significant advances in a number of key basic research areas. These include: ▪ The development of methods for mediating more efficient endosomal escape as the endocytic pathway continues to the be the primary route of cellular NP internalization;▪ The identification of new biomarker/ligand pairs for efficient targeting of NPs to specific diseased tissue sites;▪ The development of improved, stealthy polymer coatings that not only evade the immune system during systemic or targeted delivery but also play a functional role in drug release;▪ Demonstrations of more complex multifunctional, multilayer constructs that are responsive to multiple, sequential cellular events (e.g., acidic tumor environment acid-labile linkages for cell uptake coupled with intracellular enzyme-sensitive drug release).Financial & competing interests disclosureThe authors acknowledge financial support from the Naval Research Laboratory, Naval Research Laboratory Nanoscience Institute, Defense Advanced Research Project Agency and the Defense Threat Reduction Agency – Joint Science and Technology Office Military Interdepartmental Purchase Request #B112582M. 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.No writing assistance was utilized in the production of this manuscript.References1 Delehanty JB, Mattoussi H, Medintz IL. Delivering quantum dots into cells: strategies, progress and remaining issues. Anal. Bioanal. Chem.393(4),1091–1105 (2009).Crossref, Medline, CAS, Google Scholar2 Delehanty JB, Susumu K, Manthe RL, Algar WR, Medintz IL. Active cellular sensing with quantum dots: transitioning from research tool to reality; a review. Anal. Chim. Acta.750,63–81 (2012).Crossref, Medline, CAS, Google Scholar3 Heneweer C, Gendy SE, Peñate-Medina O. Liposomes and inorganic nanoparticles for drug delivery and cancer imaging. Therapeutic Delivery3(5),645–656 (2012).Link, CAS, Google Scholar4 McNerny DQ, Leroueil PR, Baker JR. 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Drug Del.6(10),1091–1112 (2009).Crossref, Medline, CAS, Google Scholar101 Clinical trials. www.clinicaltrials.govGoogle ScholarFiguresReferencesRelatedDetailsCited ByActive Cellular and Subcellular Targeting of Nanoparticles for Drug Delivery18 October 2019 | Pharmaceutics, Vol. 11, No. 10Neuro‐Nano Interfaces: Utilizing Nano‐Coatings and Nanoparticles to Enable Next‐Generation Electrophysiological Recording, Neural Stimulation, and Biochemical Modulation7 June 2017 | Advanced Functional Materials, Vol. 28, No. 12Multifunctional nanoparticle composites: progress in the use of soft and hard nanoparticles for drug delivery and imaging16 March 2017 | WIREs Nanomedicine and Nanobiotechnology, Vol. 9, No. 6Energy Transfer with Semiconductor Quantum Dot Bioconjugates: A Versatile Platform for Biosensing, Energy Harvesting, and Other Developing Applications30 June 2016 | Chemical Reviews, Vol. 117, No. 2Controlled actuation of therapeutic nanoparticles: an update on recent progressOkhil K Nag, Lauren D Field, YungChia Chen, Ajmeeta Sangtani, Joyce C Breger & James B Delehanty14 April 2016 | Therapeutic Delivery, Vol. 7, No. 5 Vol. 4, No. 2 Follow us on social media for the latest updates Metrics Downloaded 607 times History Published online 23 January 2013 Published in print February 2013 Information© Future Science LtdKeywordsactuationcontrolled releasedrug deliverynanoparticlestimuli-responsivetheranostictherapeuticFinancial & competing interests disclosureThe authors acknowledge financial support from the Naval Research Laboratory, Naval Research Laboratory Nanoscience Institute, Defense Advanced Research Project Agency and the Defense Threat Reduction Agency – Joint Science and Technology Office Military Interdepartmental Purchase Request #B112582M. 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.No writing assistance was utilized in the production of this manuscript.PDF download
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