In Vivo Tumor-Targeted Dual-Modality PET/Optical Imaging with a Yolk/Shell-Structured Silica Nanosystem

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic outcomes.By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

Recent biomedical advances enabled by HaloTag technology

The knowledge of interactions among functional proteins helps researchers understand disease mechanisms and design potential strategies for treatment.As a general approach,the fluorescent and affinity tags were employed for exploring this field by labeling the Protein of Interest(POI).However,the autofluorescence and weak binding strength significantly reduce the accuracy and specificity of these tags.Conversely,HaloTag,a novel self-labeling enzyme(SLE)tag,could quickly form a covalent bond with its ligand,enabling fast and specific labeling of POI.These desirable features greatly increase the accuracy and specificity,making the HaloTag a valuable system for various applications ranging from imaging to immobilization of POI.Notably,the HaloTag technique has already been successfully employed in a series of studies with excellent efficiency.In this review,we summarize the development of HaloTag and recent advanced investigations associated with HaloTag,including in vitro imaging(e.g.,POI imaging,cellular condition monitoring,microorganism imaging,system development),in vivo imaging,biomolecule immobilization(e.g.,POI collection,protein/nuclear acid interaction and protein structure analysis),targeted degradation(e.g.,L-AdPROM),and more.We also present a systematic discussion regarding the future direction and challenges of the HaloTag technique.

Intrinsically 89Zr-Labeled Gd2O2S:Eu Nanoprobes for in vivo PET And Γ-Ray-Induced Radioluminescence Imaging

Cerenkov luminescence imaging(CLI)is a non-invasive imaging technique showing immense promise for clinical translation.However,weak signal intensity and poor tissue penetration depth are two shortcomings that limit its clinical applications.

Nanostructured polyvinylpyrrolidone-curcumin conjugates allowed for kidney-targeted treatment of cisplatin induced acute kidney injury

Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.

Scavenging of reactive oxygen and nitrogen species with nanomaterials

Reactive oxygen and nitrogen species （RONS） are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicated in the development and augmented pathogenesis of various diseases. Several antioxidants may restore the chemical balance, but their use is limited by disappointing results of clinical trials. Nanoparticles are an attractive therapeutic alternative because they can change the biodistribution profile of antioxidants, and possess intrinsic ability to scavenge RONS. Herein, we review the types of RONS, how they are implicated in several diseases, and the types of nanoparticles with inherent antioxidant capability, their mechanisms of action, and their biological applications.

Efficient renal clearance of DNA tetrahedron nanopartides enables quantitative evaluation of kidney function

DNA tetrahedro n nano structure (DTN) is one of the simplest DNA nano structures and has bee n successfully applied for biose nsin g, imagi ng, and treatment of can cer. To facilitate its biomedical applications and pote ntial clinical tran slation, fun dame ntal un derstandi ng of DTN's transportation among major organs in living organisms becomes increasingly important. Here, we describe the efficient renal clearanee of DTN in healthy mice by using positron emission tomography (PET) imaging. The kidney elimination of DTN was later applied for renal function evaluation in murine models of unilateral ureteral obstruction (UUO). We further established a mathematical program of DTN to validate its changes of transportation pattern in healthy and UUO mice. We believe the establishment of pharmacokinetic profiles and mathematical model of DTN may provide in sight for future optimization of DNA nano structures for biomedical applications.

In vitro study of enhanced photodynamic cancer cell killing effect by nanometer-thick gold nanosheets

Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.

General synthesis of silica-based yolk/shell hybrid nanomaterials and in vivo tumor vasculature targeting

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 （89Zr）-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/sheU hybrid nanopartides for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanosheUs to form the yolk/sheU-structured hybrid nanopartides. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody （specific for CD105/endoglin）, and ~Zr （a positron-emitting radioisotope）, and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1 murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor- targeted imaging and drug delivery.

Spherical nucleic acids:Organized nucleotide aggregates as versatile nanomedicine

Spherical nucleic acids(SNAs)are composed of a nanoparticle core and a layer of densely arranged oligonucleotide shells.After the first report of SNA by Mirkin and coworkers in 1996,it has created a significant interest by offering new possibilities in the field of gene and drug delivery.The controlled aggregation of oligonucleotides on the surface of organic/inorganic nanoparticles improves the delivery of genes and nucleic acid–based drugs and alters and regulates the biological profiles of the nanoparticle core within living organisms.Here in this review,we present an overview of the recent progress of SNAs that has speeded up their biomedical application and their potential transition to clinical use.We start with introducing the concept and characteristics of SNAs as drug/gene delivery systems and highlight recent efforts of bioengineering SNA by imaging and treatmenting various diseases.Finally,we discuss potential challenges and opportunities of SNAs,their ongoing clinical trials,and future translation,and how they may affect the current landscape of clinical practices.We hope that this review will update our current understanding of SNA,organized oligonucleotide aggregates,for disease diagnosis and treatment.