Radiolabeled Human Protein-Functionalized Upconversion Nanoparticles for Multimodal Cancer Imaging

Abstract

Multimodal imaging removes the intrinsic limitations of individual modalities, while the multipurpose nanoagents reduce the toxicity associated with the use of multiple contrast agents. However, limited functionality, inefficient or incompatible targeting, and unknown biodistribution are significant drawbacks for such complicated nanodesigns. We report a biofriendly pentamodal imaging agent with the synergistic dual-targeting ability (passive and active) based on fluoromagnetic NaGdF4:Yb,Er upconverting nanoparticles (UCNPs). Besides the nano-enabled passive targeting, the apo-human serum transferrin protein (Tf) conjugation actively targets the transferrin receptors (TfR) over-expressed on different cancer cells. The radiolabel, 99mTc, chelates in the Tf core increase the radiolabeling efficiency (∼95%) and stability (∼100% for 24 h), enabling efficient single-photon emission computed tomography imaging. Deep-penetrating 980 nm excited UCNPs are inherently active luminescent and photothermal agents enabling fluorescence and photothermal imaging, respectively. The Gd in UCNPs produces a T1-weighted MRI signal, and the Yb helps in computed tomography (CT) as contrast agents. A pentamodal imaging agent (UCNP@Tf-99mTc) with synergistic dual-targeting ability is thus designed. In vitro studies demonstrated receptor-mediated endocytosis and minimal cytotoxicity of the UCNP@Tf-99mTc nanoformulation (>75% cell viability at 1000 ppm). The in vivo biodistribution studies in the mice model under SPECT/CT revealed its near-ideal bioavailability and renal clearance behavior. The MRI investigation on 4 T1 tumor-bearing mice brought direct evidence of passive and synergistic passive-active targeted tumor accumulation of the nanoformulation. The in vivo multimodal tumor imaging (MRI/SPECT/thermal-camera/CT) demonstrates the potency of UCNP@Tf-99mTc as a single replacement for multiple imaging agents and a perfect candidate for the ultramodern Advanced Multimodality Image Guided Operating (AMIGO) suite.

Nanodecoys: A Quintessential Candidate to Augment Theranostic Applications for a Plethora of Diseases

“…There are four general ways to fabricate a theranostic particle: (i) therapeutic agent can be encapsulated or conjugated onto imaging NPs such as SPION, UCNPs, quantum dots, etc. [ 67 , 68 , 69 ], (ii) CA can be tagged onto a therapeutic nanoparticle such as silver nanoparticles, etc. [ 70 ], (iii) both the CA and therapeutic agent can be encapsulated onto a biocompatible NPs such as polymeric NPs, nano-vesicles, MSN, etc., (iv) engineering of unique NPs with imaging and therapeutic potential is possible with PEGylation to improve biocompatibility.…”

ZnAl2O4:Er3+ Upconversion Nanophosphor for SPECT Imaging and Luminescence Modulation via Defect Engineering

“…17 Presently, an in-depth investigation of the in vivo biodistribution of radiolabeled UC nanomaterials is of utmost importance for the development of potential multimodal imaging contrast agents and clinical transfer. Recently, Akhtar et al 18 reported the use of NaGdF 4 :Yb,Er upconversion nanoparticles (UCNPs) as contrast agents for multimodal cancer imaging. The radiolabel, 99m Tc, was employed for SPECT imaging, and Yb presented the potential for CT imaging.…”

Biocompatible Upconverting Nanoprobes for Dual-Modal Imaging and Temperature Sensing

“…This has led to the emergence of many innovative strategies for nanotheranostics and new approaches for personalized medicine. Owing to their distinctive optical properties, such as the absence of blinking, low excitation rates, and high emission signal-to-noise ratio, rare-earth doped upconverting nanoparticles (UCNPs) have proven to be promising candidates for the detection, visualization, and treatment of various diseases. − Moreover, UCNPs after additional doping of the UCNPs matrix with Lu 3+ , Ho 3+ , Sm 3+ , or Gd 3+ ions could be used as multimodal contrast agents for computed tomography, , magnetic resonance imaging, , and single-photon emission computerized tomography . Recently, it was demonstrated that upconverting nanoparticles are also promising as remote thermal nanoprobes, particularly for monitoring treatment progress or inducing tissue inflammation, where direct temperature measurement is critical .…”