Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers

Abstract

For decades, researchers and medical professionals have aspired to develop mechanisms for noninvasive treatment and monitoring of pathological conditions within the human body. The emergence of nanotechnology has spawned new opportunities for novel drug delivery vehicles capable of concomitant detection, monitoring, and localized treatment of specific disease sites. In turn, researchers have endeavored to develop an imaging moiety that could be functionalized to seek out specific diseased conditions and could be monitored with conventional clinical imaging modalities. Such nanoscale detection systems have the potential to increase early detection of pathophysiological conditions because they can detect abnormal cells before they even develop into diseased tissue or tumors. Ideally, once the diseased cells are detected, clinicians would like to treat those cells simultaneously. This idea led to the concept of multifunctional carriers that could target, detect, and treat diseased cells. The term "theranostics" has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers. Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to execute simultaneous functions at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, imaging contrast agents, and targeting modalities for the development of an all-in-one, localized detection and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles can also be used as thermal therapeutic systems. This Account explores recent advances in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier.

Figure 1

Representative theranostic carrier architecture with key components: targeting moiety, therapeutic agents, detection components for noninvasive imaging, and polymer coating and/or matrix to provide a network for drug loading, impart colloidal stability, and provide functional groups for bioconjugation.

Figure 2

Characterization of SPIO-containing theranostic nanoparticles. (a) TEM of oleate coated iron oxide nanoparticles in hexane. (b) TEM of protein (human serum albumin)-coated iron oxide nanoparticles in water (HSA-IONPs). (c) Hydrodynamic size change of the HSA-IONPs when incubating in PBS at 37 °C for 48 h, monitored by DLS. (d) r2 relaxivity evaluations with HSA-IONPs and Feridex. Reprinted with permission from Ref. .

Figure 3

Optical imaging in a subcutaneous breast adenocarcinoma tumor model. (A) in vivo imaging. The near-IR signal, associated with the tumors compared with surrounding tissue, reflected tumor-specific delivery of EPPT-targeted particles carrying siBIRC5. (B) ex vivo imaging. There was a bright near-IR fluorescence associated with the tumors and limited fluorescence of adjacent muscle tissue. (C) Fluorescence microscopy demonstrating colocalization between green fluorescent EPPT (FITC) and red near-IR magnetic nanoparticle (Cy5.5). This reflects the stability of the theranostic particle after persistence in the circulation. Cell nuclei are depicted in blue (DAPI). Reprinted with permission from Ref. .

Figure 4

Modular construction of multifunctional theranostic agent. PMIDA-coated ultrasmall SPIO (USPIO) nanoparticles are activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) and then reacted with diamine 2,2-(ethylenedioxy)bis(ethylamine) (EDBE) to create an amine-rich surface for bioconjugation. (USPIO–PMIDA-EDBE) served as the base material for T2-weighted magnetic resonance (MR) imaging (A). Next, a fluorescent dye, rhodamine B isothiocyanate (RITC), was conjugated to the USPIO–PMIDA-EDBE surface for fluorescent imaging (B). Third, folic acid (FA) was conjugated to B to provide targeting capabilities (C). Last, methotrexate (MTX) was coupled to the nanoparticle surface through a pH-labile ester linkage created by reaction with D. The particle contains distinct moieties for targeting, multimodal imaging, and cancer treatment (E). Reprinted with permission from Ref. .

Figure 5

Segmentation of the Aortic Wall and Color-Coded Signal Enhancement Before and After Targeted Fumagillin Treatment(Top) Black blood image of the thoracic aorta (arrow) and segmentation of the vessel wall (outlined in yellow) is shown for the week 0 image. The color-coded overlay of signal enhancement (%) shows patchy areas of high angiogenesis. On the week 1 image, the signal enhancement has clearly decreased due to the antiangiogenic effect of targeted fumagillin treatment. (Bottom) The level of signal enhancement gradually increases at weeks 2 and 3 after fumagillin treatment, until week 4, when the level of enhancement is practically identical to the week 0 image. Reprinted with permission from Ref. .