With continued advancements in nanoparticle (NP) synthesis and in the interfacing of NPs with biological systems has come the exponential growth in the use of NPs for therapeutic drug delivery and imaging applications. In recent years, the advent of NP multifunctionality-the ability to perform multiple, disparate functions on a single NP platform-has garnered much excitement for the potential realization of highly functional NP-mediated drug delivery for use in the clinical setting. This Overview will survey the current state of the art (reports published within the last 5 years) of multifunctional NPs for therapeutic drug delivery, imaging or a combination thereof. We provide extensive examples of both soft (micelles, liposomes, polymeric NPs) and hard (noble metals, quantum dots, metal oxides) NP formulations that have been used for multimodal drug delivery and imaging. The criteria for inclusion, herein, is that there must be at least two therapeutic drug cargos or imaging agents or a combination of the two. We next offer an assessment of the cytotoxicity of therapeutic NP constructs in biological systems. We then conclude with a forward-looking perspective on how we expect this field to develop in the coming years. WIREs Nanomed Nanobiotechnol 2017, 9:e1466. doi: 10.1002/wnan.1466 For further resources related to this article, please visit the WIREs website.
Nanoparticle (NP)-mediated drug delivery (NMDD) has emerged as a novel method to overcome the limitations of traditional systemic delivery of therapeutics, including the controlled release of the NP-associated drug cargo. Currently, our most advanced understanding of how to control NP-associated cargos is in the context of soft nanoparticles (e.g., liposomes), but less is known about controlling the release of cargos from the surface of hard NPs (e.g., gold NPs). Here we employ a semiconductor quantum dot (QD) as a prototypical hard NP platform and use intracellularly triggered actuation to achieve spatiotemporal control of drug release and modulation of drug efficacy. Conjugated to the QD are two peptides: (1) a cell-penetrating peptide (CPP) that facilitates uptake of the conjugate into the endocytic pathway and (2) a display peptide conjugated to doxorubicin (DOX) via three different linkages (ester, disulfide, and hydrazone) that are responsive to enzymatic cleavage, reducing conditions, and low pH, respectively. Formation of the QD-[peptide-DOX]-CPP complex is driven by self-assembly that allows control over both the ratio of each peptide species conjugated to the QD and the eventual drug dose delivered to cells. Förster resonance energy transfer assays confirmed successful assembly of the QD-peptide complexes and functionality of the linkages. Confocal microscopy was employed to visualize residence of the QD-[peptide-DOX]-CPP complexes in the endocytic pathway, and distinct differences in DOX localization were noted for the ester linkage, which showed clear signs of nuclear delivery versus the hydrazone, disulfide, and amide control. Finally, delivery of the QD-[peptide-DOX]-CPP conjugate resulted in cytotoxicity for the ester linkage that was comparable to free DOX. Attachment of DOX via the hydrazone linkage facilitated intermediary toxicity, while the disulfide and amide control linkages showed minimal toxicity. Our data demonstrate the utility of hard NP-peptide bioconjugates to function as multifunctional scaffolds for simultaneous control over cellular drug uptake and toxicity and the vital role played by the nature of the chemical linkage that appends the drug to the NP carrier.
Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection. In this paper, we describe a NP–peptide–drug bioconjugate that achieves significant cell killing in MDR-positive cancer cells without the need for additional drugs. We use a quantum dot (QD) as a central scaffold to append two species of peptide, a cell-uptake peptide to facilitate endocytic internalization and a peptide–drug conjugate that is susceptible to cleavage by esterases found within the endocytic pathway. This approach relies on spatiotemporal control over drug release, where endosomes traffic drug away from membrane-resident pumps and release it closer to the nucleus. Cellular internalization studies showed high uptake of the NP–drug complex and nuclear localization of the drug after 48 h in MDR-positive cells. Additionally, cellular proliferation assays demonstrated a 40% decrease in cell viability for the NP–drug bioconjugate compared to free drug, confirming the utility of this system in overcoming MDR in cancer cells.
A primary envisioned use for nanoparticles (NPs) in a cellular context is for controlled drug delivery where the full benefit of NP attributes (small size, large drug cargo loading capacity) can improve the pharmacokinetics of the drug cargo. This requires the ability to controllably manipulate the release of the drug cargo from the NP vehicle or 'controlled actuation'. In this review, we highlight new developments in this field from 2013 to 2015. The number and breadth of reports are a testament to the significant advancements made in this field over this time period. We conclude with a perspective of how we envision this field to continue to develop in the years to come.
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