Boron encapsulated in a liposome can be used for combinational neutron capture therapy.

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies.

Desilylation Induced by Metal Fluoride Nanocrystals Enables Cleavage Chemistry In Vivo.

Metal fluoride nanocrystals are widely used in biomedical studies owing to their unique physicochemical properties. The release of metal ions and fluorides from nanocrystals is intrinsic due to the solubility equilibrium. It used to be considered as a drawback because it is related to the decomposition and defunction of metal fluoride nanocrystals. Many strategies have been developed to stabilize the nanocrystals, and the equilibrium concentrations of fluoride are often <1 mM. Here we make good use of this minimum amount of fluoride and unveil that metal fluoride nanocrystals could effectively induce desilylation cleavage chemistry, enabling controlled release of fluorophores and drug molecules in test tubes, living cells, and tumor-bearing mice. Biocompatible PEG (polyethylene glycol)-coated CaF2 nanocrystals have been prepared to assay the efficiency of desilylation-induced controlled release of functional molecules. We apply the strategy to a prodrug activation of monomethyl auristatin E (MMAE), showing a remarkable anticancer effect, while side effects are almost negligible. In conclusion, this desilylation-induced cleavage chemistry avails the drawback on empowering metal fluoride nanocrystals with a new function of perturbing or activating for further biological applications.

External-Radiation-Induced Local Hydroxylation Enables Remote Release of Functional Molecules in Tumors.

Radiation-induced cleavage for controlled release in vivo is yet to be established. We demonstrate the use of 3,5-dihydroxybenzyl carbamate (DHBC) as a masking group that is selectively and efficiently removed by external radiation in vitro and in vivo. DHBC reacts mainly with hydroxyl radicals produced by radiation to afford hydroxylation at para/ortho positions, followed by 1,4- or 1,6-elimination to rescue the functionality of the client molecule. The reaction is rapid and can liberate functional molecules under physiological conditions. This controlled-release platform is compatible with living systems, as demonstrated by the release of a rhodol fluorophore derivative in cells and tumor xenografts. The combined benefits of the robust caging group, the good release yield, and the independence of penetration depth make DHBC derivatives attractive chemical caging moieties for use in chemical biology and prodrug activation.

Total Aqueous Synthesis of Au@Cu2-x S Core-Shell Nanoparticles for In Vitro and In Vivo SERS/PA Imaging-Guided Photothermal Cancer Therapy.

Both accurate tumor navigation and nanostructures with high photothermal (PT) conversion efficiency are important but remain challenging to achieve in current biomedical applications. This study reports an anion exchange-based facile and green approach for synthesizing Au@Cu2-x S core-shell nanoparticles (NPs) in an aqueous system. In addition to the PT effect of the suggested NPs, the surface-enhanced Raman scattering (SERS) is also significantly improved due to the tailored localized surface plasmon resonance coupling between the Au metal core and the Cu2-x S semiconductor shell. Using an epitaxial strategy, Au@Cu2 O NPs are first obtained by the in situ reduction of cupric hydroxide on a cresyl violet acetate-coated Au core; then, Au@Cu2-x S NPs are obtained via anion exchange between the S2- and Cu2 O shell. Both the Cu/S atomic ratio and the Cu2-x S shell thickness can be adjusted conveniently. Hence, the ideal integration of the plasmonic Au core and Cu2-x S shell into a single unit is conducive not only to highly efficient PT conversion but also to the construction of a SERS-based navigator. This new type of SERS-guided NP, with enhanced photoacoustic signals, is an important candidate for both accurate tumor navigation and nondestructive PT treatment guided in vivo by two modes of optical imaging.

Size-Controlled Synthesis of Drug-Loaded Zeolitic Imidazolate Framework in Aqueous Solution and Size Effect on Their Cancer Theranostics in Vivo.

Recently, metal-organic frameworks (MOFs) or coordination polymers have shown great potential for drug delivery, yet little has been done to study how particle size affects their tumor targeting and other in vivo features. This plight is probably due to two challenges: (1) the lack of a biocompatible method to precisely control the size of drug-loaded MOFs and (2) the lack of a robust and facile radiolabeling technique to trace particles in vivo. Here, we report a one-pot, rapid, and completely aqueous approach that can precisely tune the size of drug-loaded MOF at room temperature. A chelator-free 64Cu-labeled method was developed by taking the advantage of this rapid and aqueous synthesis. Cancer cells were found to take drug-loaded MOFs in a size-dependent manner. The in vivo biodistribution of drug-loaded MOF was analyzed with positron emission tomography imaging, which, as far as we know, was used for the first time to quantitatively evaluate MOF in living animals, unveiling that 60 nm MOF showed longer blood circulation and over 50% higher tumor accumulation than 130 nm MOF. Altogether, this size-controlled method helps to find the optimal size of MOF as a drug carrier and opens new possibilities to construct multifunctional delivery systems for cancer theranostics.

Tracing Boron with Fluorescence and Positron Emission Tomography Imaging of Boronated Porphyrin Nanocomplex for Imaging-Guided Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible poly(lactide- co-glycolide)-monomethoxy-poly(polyethylene-glycol) (PLGA-mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with the previously reported boronated porphyrin drugs. Fluorescence imaging and positron emission tomography (PET) imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17 ± 13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumors to liver, muscle, fat, and blood were 3.24 ± 0.22, 61.46 ± 20.26, 31.55 ± 10.30, and 33.85 ± 5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT.

Preclinical Study of a Fully Human Anti-PD-L1 Antibody as a Theranostic Agent for Cancer Immunotherapy.

Recently, inhibiting the PD-1/PD-L1 checkpoint pathway utilizing anti-PD-1 or anti-PD-L1 antibodies has achieved great clinical success in cancer treatment. However, anti-PD-1 immunotherapy cannot be applied to all cancer patients, no more than 25% showed a positive response. Immunohistochemistry (IHC) is the gold standard to determine the PD-L1 expression level in malignant lesions, but a noninvasive imaging-meditated strategy is urgently required for clinical diagnosis to cover the shortcomings of invasive techniques. MX001, which is an anti-PD-L1 antibody, was labeled with Cu-64 ( t1/2 = 12.7 h) and purified by PD-10 chromatography. Comprehensive studies including positron emission tomography (PET), ex vivo biodistribution, IHC, and immunotherapy have been performed in mice bearing MC38 (PD-L1 positive (+)) and 4T1 (PD-L1 negative (-)) xenografts. PET imaging of [18F]FDG was taken before and after therapy to monitor the therapeutic efficacy. [64Cu]Cu-NOTA-MX001 exhibited 2.3 ± 1.2, 5.6 ± 2.1, 5.6 ± 1.2, 6.1 ± 1.1, 6.1 ± 0.5, and 10.2 ± 1.7%ID/g uptake in MC38 xenografts at 0.5, 12, 24, 36, 48, and 62 h post-injection (p.i.), respectively. Meanwhile, the uptake in the liver and muscle at corresponding time points was 17.5 ± 2.2, 8.4 ± 2.4, 11.3 ± 3.2, 7.2 ± 2.1, 7.9.1 ± 3.5, and 3.8 ± 1.8%ID/g, and 1.2 ± 0.5, 1.3 ± 0.4, 1.5 ± 0.5, 0.7 ± 0.1, 0.6 ± 0.2, and 0.2 ± 0.1%ID/g, respectively. The uptake of [18F]FDG in MC38 and 4T1 xenografts at 1-h p.i. was 5.3 ± 0.4 and 6.4 ± 0.6%ID/g, while the uptake of [64Cu]Cu-NOTA-MX001 was 5.6 ± 0.3 and 1.3 ± 0.4%ID/g at 12-h p.i. IHC analysis confirmed that the MC38 tumor exhibited high PD-L1 expression, and the 4T1 tumor, liver, and muscle exhibited low PD-L1 expression. In addition, MC38 xenografts were suppressed by MX001 about 88% in the immunotherapy study. MX001 was successfully developed as a fully human anti-PD-L1 antibody with a high binding affinity in mouse, monkey, and human. The in vivo pharmacokinetics of MX001 was evaluated with PET imaging after being radiolabeled with Cu-64. The uptake of [64Cu]Cu-NOTA-MX001 was clearly correlated to the PD-L1 expression on various types of cancer. Subsequent immunotherapy studies demonstrated that MX001 could effectively suppress tumor growth with positive PD-L1 expression, but had poor antitumor efficacy on tumors which exhibited low PD-L1 expression. Together with the above results, MX001 has the potential to be further developed as an antibody theranostic agent for both PET imaging and immunotherapy of cancers in clinics.

Preclinical study of an 18F-labeled glutamine derivative for cancer imaging.

INTRODUCTION: The emerging evidence that demonstrated the extra-demand of glutamine for cancer surviving strongly called for the development of PET tracer for imaging glutamine uptake in cancer. In this work, [18F]Gln-BF3 as a natural glutamine derivative was synthesized to explore its potential application of imaging glutamine uptake for cancer diagnosis. METHODS: [18F]Gln-BF3 was prepared by deprotection of purified precursor trityl-Gln-BF3 (amide bond protected with triphenylmethyl group) using TFA and radiolabeled using 18F-19F isotope exchange protocol. PET imaging and biodistribution studies were conducted in Balb/c mice bearing 4T1 xenograft. RESULTS: Gln-BF3 was identified with HRMS ([M-H]- = 169.0765). [18F]Gln-BF3 was radiolabeled in high radiochemical yield (RCY > 25%) and characterized with Radio-HPLC-MS. Preliminary PET imaging showed the radioactivity was fast cleared from muscle tissue and excreted mainly via the renal pathway. PET study demonstrated that uptake of [18F]Gln-BF3 in 4T1 xenografts was significant. The biodistribution results of [18F]Gln-BF3 in mice bearing 4T1 xenograft indicate a tumor-to-muscle ratio of 2.58 ±â€¯0.64 (n = 4) and a 6.29 ±â€¯0.42%ID/g (n = 4) uptake in tumor at 45 min post injection. CONCLUSION: [18F]Gln-BF3 was radiolabeled in a "kit-like" manner and showed notable and tumor-selective uptake in tumor-bearing animal models, suggesting that this new strategy of radiolabeling amino acid provided a promising solution for the future development of glutamine-derived PET tracers.

Activating TiO2 Nanoparticles: Gallium-68 Serves as a High-Yield Photon Emitter for Cerenkov-Induced Photodynamic Therapy.

The classical photodynamic therapy (PDT) requires external light to activate photosensitizers for cancer treatment. However, limited tissue penetration of light has been a long-standing challenge for PDT to cure malignant tumors in deep tissues. Recently, Cerenkov radiation (CR) emitted by radiotracers such as 18F-fluorodeoxyglucose (18F-FDG) has become an alternative and promising internal light source. Nevertheless, fluorine-18 (F-18) only releases 1.3 photons per decay in average; consequently, injection dose of F-18 goes beyond 10-30 times more than usual to acquire therapeutic efficacy because of its low Cerenkov productivity. Gallium-68 (Ga-68) is a favorable CR source owing to its ready availability from generator and 30-time higher Cerenkov productivity. Herein, we report, for the first time, the use of Ga-68 as a CR source to activate dextran-modified TiO2 nanoparticles (D-TiO2 NPs) for CR-induced PDT. Compared with 18F-FDG, 68Ga-labeled bovine serum albumin (68Ga-BSA) inhibited the growth of 4T1 cells and exhibited significantly stronger DNA damage to tumor cells. In vivo studies showed that the tumor growth was almost completely inhibited when tumor-bearing mice were treated with a combination of D-TiO2 NPs and 68Ga-BSA. This study proved that Ga-68 is a more potent radionuclide for PDT than F-18 both in vitro and in vivo offered a promising strategy of using a diagnostic dose of radioactivity to achieve depth-independent cancer therapy without using any external light source.