Bioconjugate Chemistry最新文献

Near-infrared II (NIR-II) photoacoustic (PA)/photothermal imaging-guided tumor therapy holds great promise in precision medicine for cancer treatment. This work reports on the synthesis and application of an organic small molecule nanoagent that has exceptional PA and photothermal properties in the near-infrared region. BCy-TPE was constructed by linking an NIR-II absorbing cyanine dye BCy-Cl with a twisted tetraphenylethene unit. The synthesized BCy-TPE exhibited an intense absorption peak at 1032 nm. After encapsulation into water-dispersible nanoparticles (NPs), BCy-TPE NPs exhibited two absorption peaks at 880 and 1046 nm. Notably, under 1064 nm laser excitation, BCy-TPE NPs deliver a remarkable photothermal conversion efficiency of 92%, together with superior biocompatibility, photostability, and PA/photothermal imaging capability. Moreover, after intravenous administration of BCy-TPE NPs into 4T1 tumor-bearing mice and treatment with safe-intensity (1.0 W cm^-2 and 1064 nm) laser irradiation, tumor temperature increased rapidly to 52 °C within 1 min and tumors are completely ablated after a single photothermal therapy treatment. Overall, this work offers a novel strategy to develop superb NIR-II photothermal agents for PA/photothermal imaging-guided highly efficient therapy in cancer.

Near-infrared II (NIR-II) photoacoustic (PA)/photothermal imaging-guided tumor therapy holds great promise in precision medicine for cancer treatment. This work reports on the synthesis and application of an organic small molecule nanoagent that has exceptional PA and photothermal properties in the near-infrared region. BCy-TPE was constructed by linking an NIR-II absorbing cyanine dye BCy-Cl with a twisted tetraphenylethene unit. The synthesized BCy-TPE exhibited an intense absorption peak at 1032 nm. After encapsulation into water-dispersible nanoparticles (NPs), BCy-TPE NPs exhibited two absorption peaks at 880 and 1046 nm. Notably, under 1064 nm laser excitation, BCy-TPE NPs deliver a remarkable photothermal conversion efficiency of 92%, together with superior biocompatibility, photostability, and PA/photothermal imaging capability. Moreover, after intravenous administration of BCy-TPE NPs into 4T1 tumor-bearing mice and treatment with safe-intensity (1.0 W cm^–2 and 1064 nm) laser irradiation, tumor temperature increased rapidly to 52 °C within 1 min and tumors are completely ablated after a single photothermal therapy treatment. Overall, this work offers a novel strategy to develop superb NIR-II photothermal agents for PA/photothermal imaging-guided highly efficient therapy in cancer.

The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, noninvasive routes of administration are currently unviable due to the presence of the blood-nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through noninvasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-b-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide RVG29 (RVG) and loaded with near-infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural-specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague-Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 h post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased the AlexaFluor647 fluorescence after IM injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while using RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating the area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.

Successful gene therapies require the efficient delivery of the therapeutic nucleic acids in the target cells, which is a major bottleneck. Our group has demonstrated that quinine-based polymers are effective and promising carriers for delivering nucleic acids, such as plasmid DNA (pDNA). However, the inherent hydrophobicity of quinine-based polymers makes the polymer-pDNA complexes (polyplexes) colloidally unstable leading to aggregation, which is relevant in clinical scenarios as larger particles (diameter >1000 nm) tend to perform poorly when administered systemically in vivo. Herein, we overcome the hydrophobicity-induced aggregation by using two types of quinine-based polymer systems to form polyplexes via a facile blending approach. We balanced desirable properties using quinine-based copolymers (HQ-X) as the pDNA binding component along with a quinine-based diblock copolymer (PHQ), having a polyethylene glycol chain, to provide colloidal stability to the particles. Using 5 polymer pairs, 5 mixing ratios, and 3 mixing sequences, we screened 66 formulations out of which 37 resulted in nonaggregating small polyplexes (diameter <300 nm) with colloidal stability tested up to 7 days at 4 °C. Furthermore, 18 out of these 37 colloidally stable formulations showed transfection performance better than or comparable to the commercial control, jetPEI. Our results clearly indicated that while the three mixing sequences generate polyplexes of similar characteristics, the best balance of transfection efficiency, toxicity, and colloidal stability is achieved at moderate PHQ % in the mixture when colloidal stability does not compromise payload binding. Our results showcase that polymer blending, in a manner similar to lipids, is an effective and parallel approach to achieving desirable polyplex characteristics, such as particle size, colloidal stability, and performance.

The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, noninvasive routes of administration are currently unviable due to the presence of the blood–nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through noninvasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-b-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide RVG29 (RVG) and loaded with near-infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural-specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague–Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 h post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased the AlexaFluor647 fluorescence after IM injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while using RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating the area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.

Successful gene therapies require the efficient delivery of the therapeutic nucleic acids in the target cells, which is a major bottleneck. Our group has demonstrated that quinine-based polymers are effective and promising carriers for delivering nucleic acids, such as plasmid DNA (pDNA). However, the inherent hydrophobicity of quinine-based polymers makes the polymer-pDNA complexes (polyplexes) colloidally unstable leading to aggregation, which is relevant in clinical scenarios as larger particles (diameter >1000 nm) tend to perform poorly when administered systemically in vivo. Herein, we overcome the hydrophobicity-induced aggregation by using two types of quinine-based polymer systems to form polyplexes via a facile blending approach. We balanced desirable properties using quinine-based copolymers (HQ-X) as the pDNA binding component along with a quinine-based diblock copolymer (PHQ), having a polyethylene glycol chain, to provide colloidal stability to the particles. Using 5 polymer pairs, 5 mixing ratios, and 3 mixing sequences, we screened 66 formulations out of which 37 resulted in nonaggregating small polyplexes (diameter <300 nm) with colloidal stability tested up to 7 days at 4 °C. Furthermore, 18 out of these 37 colloidally stable formulations showed transfection performance better than or comparable to the commercial control, jetPEI. Our results clearly indicated that while the three mixing sequences generate polyplexes of similar characteristics, the best balance of transfection efficiency, toxicity, and colloidal stability is achieved at moderate PHQ % in the mixture when colloidal stability does not compromise payload binding. Our results showcase that polymer blending, in a manner similar to lipids, is an effective and parallel approach to achieving desirable polyplex characteristics, such as particle size, colloidal stability, and performance.

Cu(II) coordination complexes are emerging as promising anticancer agents due to their ability to induce oxidative stress through reactive oxygen species (ROS) generation. In this study, we synthesized and characterized two novel Cu(II) metallopeptide systems, 1/Cu(II) and 2/Cu(II), derived from the oligocationic bipyridyl cyclopeptides 1 and 2, and designed to enhance the transport of Cu(II) into cells and increase ROS levels. Spectroscopic and electrochemical analyses confirmed the formation of stable metallopeptide species in aqueous media. Inductively coupled plasma mass spectrometry (ICP-MS) studies demonstrated that both metallopeptides significantly increase intracellular Cu(II) accumulation in NCI/ADR-RES cancer cells, highlighting their role as efficient Cu(II) transporters. Additionally, ROS generation assays revealed that 1/Cu(II) induces a substantial increase in intracellular ROS levels, supporting the hypothesis of oxidative stress-induced cytotoxicity. Cell-viability assays further confirmed that both 1/Cu(II) and 2/Cu(II) exhibit strong anticancer activity in a number of cancer cell lines, with IC₅₀ values significantly lower than those of their free cyclopeptide counterparts or Cu(II) alone, showing an order of activity higher than that of cisplatin. Finally, molecular modeling studies provided further insights into the structural stability and coordination environment of Cu(II) within the metallopeptide complexes. These findings suggest that these Cu(II) cyclometallopeptide systems hold potential as novel metal-based therapeutic agents, leveraging Cu(II) transport and ROS increase as key strategies for cancer treatment.

Radiotherapy (RT) continues to encounter significant obstacles such as formidable resistance, potential harm to adjacent healthy cells, and restricted effectiveness against tumors, resulting in a notable recurrence rate. Therefore, combining imaging, other treatments, and suitable enzyme activity in one nanoplatform can enhance the RT effect and reduce the damage to normal tissue. In this study, integrating hafnium in Prussian blue (PB) nanoparticles (PB NPs) provided innovative hafnium-doped PB (HPB) NPs as multifunctional radiosensitizers. The HPB NPs were enveloped by the cancer cell membrane, resulting in cancer cell membrane-camouflaged HPB (CMHPB) NPs that can specifically target homologous tumors. Moreover, owing to the inherent ability of photothermal therapy (PTT), magnetic resonance imaging (MRI), and catalase (CAT)-like activity of PB NPs, CMHPB NPs effectively overcome tumor hypoxia and realize the MRI-guided combined RT and PTT. The prepared HPB NPs possessed uniform and cubic morphology with a monodisperse size of approximately 80 nm and T₁ MRI capability (r₁ = 0.9309 mM^–1 S^–1). The HPB NPs showed reliable PTT efficiency and CAT-like activity in vitro and in vivo. Guided by MRI, the CMHPB NPs can be precisely delivered to the tumor region for combined RT and PTT for targeted destruction of tumor cells, significantly inhibiting tumor growth. The innovative multifunctional CMHPB NPs can be used for MRI-guided RT and PTT, which address the key challenges of RT and provide a viable strategy for enhancing tumor treatment.