Nanotechnology assisted photo-and sonodynamic therapy for overcoming drug resistance

Drug resistance is considered the most important reason for the clinical failure of cancer chemotherapy.Circumventing drug resistance and improving the efficacy of anticancer agents remains a major challenge.Over the past several decades,photodynamic therapy(PDT)and sonodynamic therapy(SDT)have attracted substantial attention for their efficacy in cancer treatment,and have been combined with chemotherapy to overcome drug resistance.However,simultaneously delivering sensitizers and chemotherapy drugs to same tumor cell remains challenging,thus greatly limiting this combinational therapy.The rapid development of nanotechnology provides a new approach to solve this problem.Nano-based drug delivery systems can not only improve the targeted delivery of agents but also co-deliver multiple drug components in single nanoparticles to achieve optimal synergistic effects.In this review,we briefly summarize the mechanisms of drug resistance,discuss the advantages and disadvantages of PDT and SDT in reversing drug resistance,and describe state-of-the-art research using nano-mediated PDT and SDT to solve these refractory problems.This review also highlights the clinical translational potential for this combinational therapy.

Photosensitizer Nanoparticles Boost Photodynamic Therapy for Pancreatic Cancer Treatment

Patients with pancreatic cancer(PCa)have a poor prognosis apart from the few suitable for surgery.Photodynamic therapy(PDT)is a minimally invasive treatment modality whose efficacy and safety in treating unresectable localized PCa have been corroborated in clinic.Yet,it suffers from certain limitations during clinical exploitation,including insufficient photosensitizers(PSs)delivery,tumor-oxygenation dependency,and treatment escape of aggressive tumors.To overcome these obstacles,an increasing number of researchers are currently on a quest to develop photosensitizer nanoparticles(NPs)by the use of a variety of nanocarrier systems to improve cellular uptake and biodistribution of photosensitizers.Encapsulation of PSs with NPs endows them significantly higher accumulation within PCa tumors due to the increased solubility and stability in blood circulation.A number of approaches have been explored to produce NPs co-delivering multi-agents affording PDT-based synergistic therapies for improved response rates and durability of response after treatment.This review provides an overview of available data regarding the design,methodology,and oncological outcome of the innovative NPs-based PDT of PCa.

分析化学教学中的课程思政设计与探索

分析化学学科发展迅速,知识体系庞大繁杂,与众多学科相互交错,密切关联,课程教学难度大。在课堂教学过程中,教师应根据课程特点和教学内容,精心挖掘关于教学内容的思政教育元素,巧妙还原教学内容涉及知识点的产生和发展过程,还原科学成果、技术的认知发现过程,教育学生从学科的动态历史发展中体会到如何做学问、如何做人。本文根据分析化学教材章节内容模块,介绍了分析化学教学过程中课程思政的设计与探索,以期为分析化学课程思政教育提供有益参考。

Ultrasmall pH-responsive silicon phthalocyanine micelle for selective photodynamic therapy against tumo

Targeted photodynamic therapy(TPDT)based on the photosensitizers responsive for tumor micr oenvironment is promising because of the better anti-tumor effect and less phototoxicity against normal tissue than the traditional PDT.Nanoparticle based stimuli responsive photo-sensitizers have been widely explored for TPDT.Based on the acidic microenvironments in solid tumors,an ultrasmall pH-responsive silicon phthalocyanine nanomicelle(PSN)(smaller than 10 nm)was designed for selective PDT of tumor.PSN had high drug loading efficacy(more than 28%)and exhibited morphological transitions,enhanced fuorescence and improved singlet∞x-ygen yield under acidic environments.PSN was renal dlearable and could rapidly accumulate and be retained at tumor sites,achieving a tumor-inhibiting ffect better than phthalocyanine micelle without pH response.Tumors of mice treated with PSN for PDT were completely ablated without recurrence.Thus,we have developed a phthalocyanine-based pH responsive micelle with excellent tumor targeting ability,which is expected to realize the selective PDT of tumor.

Photodynamic eradication of intratumoral microbiota with bacteria-targeted micelles overcomes gemcitabine resistance of pancreatic cancer

Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine(Gem)into its inactive form,thus rendering chemotherapy ineffective.Herein,a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model.An antimicrobial peptide was linked with photosensitizer through a poly(ethylene glycol)chain,which can self-assemble into micelles with a diameter of∼20 nm.The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization,thereby inhibiting Gem metabolism.In a bacteria-resident pancreatic cancer animal model,the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance.This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.

Ultrasound contrast agents from microbubbles to biogenic gas vesicles

Microbubbles have been the earliest and most widely used ultrasound contrast agents by virtue of their unique features:such as non-toxicity,intravenous inject-ability,ability to cross the pulmonary capillary bed,and significant enhancement of echo signals for the duration of the examination,resulting in essential preclinical and clinical applications.The use of microbubbles functional-ized with targeting ligands to bind to specific targets in the bloodstream has further enabled ultrasound molecular imaging.Nevertheless,it is very challenging to utilize targeted microbubbles for molecular imaging of extra-vascular targets due to their size.A series of acoustic nanomaterials have been developed for breaking free from this constraint.Especially,biogenic gas vesicles,gas-filled protein nanostructures from microorganisms,were engineered as thefirst biomolecular ultrasound contrast agents,opening the door for more direct visual-ization of cellular and molecular function by ultrasound imaging.The ordered protein shell structure and unique gasfilling mechanism of biogenic gas vesicles endow them with excellent stability and attractive acoustic responses.What’s more,their genetic encodability enables them to act as acoustic reporter genes.This article reviews the upgrading progresses of ultrasound contrast agents from microbubbles to biogenic gas vesicles,and the opportu-nities and challenges for the commercial and clinical translation of the nascentfield of biomolecular ultrasound.

Nanotherapeutic approaches targeting angiogenesis and immune dysfunction in tumor microenvironment

Tumor microenvironment(TME) comprising cellular and non-cellular components is a major source of cancer hallmarks.Notably, angiogenesis responsible for normal physiological remodeling process can otherwise harness vessel abnormalities during tumorigenesis eliciting severe therapeutic inefficiency. Currently, FDA approved antiangiogenic drugs have only shown modest clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and limited knowledge in understanding TME. In order to overcome these limitations, targeting angiogenesis combined with immunosuppressive TME could offer potential therapeutic opportunities. Indeed, these therapeutic approaches can be further revisited with the advent of nanotechnology that can target the key cellular components of TME and tumor cells more precisely. Synergetic targeting without eliciting systemic toxicity achieved by integration of antiangiogenic and immunotherapy in a single nanoplatform is vital for therapeutic success. In this review, we will discuss the most promising nanotechnological advancements oriented to modulate the immunosuppressive TME in association with antiangiogenic therapy that has gained immense popularity in cancer treatment.

Prussian blue nanoparticle-loaded microbubbles for photothermally enhanced gene delivery through ultrasound-targeted microbubble destruction

By adsorbing chitosan(CS)-functionalized Prussian blue(PB) nanoparticles(CS/PB NPs) complexing DNA onto the surface of gas encapsulated microbubbles(MBs), a multifunctional gene delivery system of MBs@CS/PB/DNA was fabricated for photothermally enhanced gene transfection through ultrasound-targeted microbubble destruction. CS/PB NPs of(2.69 ± 0.49) nm could complex DNA effectively when the mass ratio was2:1. It was found that MBs@CS/PB/DNA could enhance ultrasound imaging greatly both in vitro and in vivo. In addition, MBs@CS/PB/DNA could be disrupted by applying a higher-intensity ultrasound irradiation to release CS/PB/DNA, which could effectively transform the nearinfrared(NIR) light into heat to assist the uptake of CS/PB/DNA by cells. With the aid of ultrasound irradiation and NIR light irradiation, the gene transfection efficiency was significantly enhanced to(43.08 ± 1.13) %, much higher than polyethylenimine. Moreover, MBs@CS/PB/DNA showed excellent biocompatibility, encouraging the further exploration of MBs@CS/PB/DNA to be a platform for combined ultrasound image, photothermal therapy, drug delivery, and gene therapy.

Cyanine conjugates in cancer theranostics

Cyanine is a meritorious fluorogenic core for the construction of fluorescent probes and its phototherapeutic potential has been enthusiastically explored as well.Alternatively,the covalent conjugation of cyanine with other potent therapeutic agents not only boosts its therapeutic efficacy but also broadens its therapeutic modality.Herein,we summarize miscellaneous cyanine-therapeutic agent conjugates in cancer theranostics from literature published between 2014 and 2020.The application scenarios of such theranostic cyanine conjugates covered common cancer therapeutic modalities,including chemotherapy,phototherapy and targeted therapy.Besides,cyanine conjugates that serve as nanocarriers for drug delivery are introduced as well.In an additional section,we analyze the potential of these conjugates for clinical translation.Overall,this review is aimed to stimulate research interest in exploring unattempted therapeutic agents and novel conjugation strategies and hopefully,accelerate clinical translation in this field.

Spatial control of robust transgene expression in mouse artery endothelium under ultrasound guidance

Dear Editor,Dysfunctional vascular endothelial cells(ECs)contribute to the pathophysiology of several cardiovascular diseases,such as atherosclerosis and its life-threatening complications.1 Gene therapy can be a valuable approach to modulate endothelial cell function for the prevention of atherosclerosis.However,there is still a lack of method for transgene expression in vascular endothelium.2 Herein,an effective and specific strategy was established for noninvasive spatial control of transgene expression into the target region of the mouse artery without systemic spillover using an ultrasound and microbubble(MB)guided adenoassociated viral vector(UMGAAV)(Supplementary Fig.S1).To the best of our knowledge,this is the first report on noninvasive spatial control of transgene expression in arterial endothelium in vivo.

Fibronectin-targeted dual-acting micelles for combination therapy of metastatic breast cancer

Stage IV breast cancer,which has a high risk of invasion,often develops into metastases in distant organs,especially in the lung,and this could threaten the lives of women.Thus,the development of more advanced therapeutics that can efficiently target metastatic foci is crucial.In this study,we built an dual-acting therapeutic strategy using micelles with high stability functionalized with fibronectin-targeting CREKA peptides encapsulating two slightly soluble chemotherapy agents in water,doxorubicin(D)and vinorelbine(V),which we termed C-DVM.We found that small C-DVM micelles could efficiently codeliver drugs into 4T1 cells and disrupt microtubule structures.C-DVM also exhibited a powerful ability to eradicate and inhibit invasion of 4T1 cells.Moreover,an in vivo pharmacokinetics study showed that C-DVM increased the drug circulation half-life and led to increased enrichment of drugs in lung metastatic foci after 24 h.Moreover,dual-acting C-DVM treatment led to 90%inhibition of metastatic foci development and reduced invasion of metastases.C-DVM could potentially be used as a targeted treatment for metastasis and represents a new approach with higher therapeutic efficacy than conventional chemotherapy for stage IV breast cancer that could be used in the future.

Imaging-guided gene delivery:seeing is delivering

To the editor:Gene therapy is considered a promising treatment option for several diseases,including neuromuscular disease,cardiovascular diseases,immunodeficiencies,and cancer.However,the promise of gene therapy is largely compromised by a lack of suitable gene delivery systems.[1,2]Gene delivery approaches using common gene vectors including viral and nonviral vectors typically rely on specific targeting moieties or tissue tropism of the vectors.However,not all tissues possess unique receptors suitable for targeted gene delivery.This issue can be potentially solved by introducing external physical stimuli,such as ultrasound,magnetic force,heat,and light,which can guide the transgene expression independent of the intrinsic properties of the cells of interest.31 In addition,such physical stimuli can be integrated with medical imaging,thus making imaging-guided gene delivery possible.In this scenario,physical stimuli are applied to the area of interest guided by medical imaging and can then trigger robust transgene expression in selected areas.

Current trends and key considerations in the clinical translation of targeted fluorescent probes for intraoperative navigation

The rapid development of fluorescence imaging for intraoperative navigation has spurred further development of targeted fluorescent probes in the past decade.Only a few nontargeted dyes,including indocyanine green and methylene blue,are currently applied for fluorescence guided surgery in the clinic.While no targeted fluorescent probes have been approved for the clinic,a number of them have entered clinical trials.These probes have emission wavelengths in the visible and near infrared(NIR)-I(700-900 nm)range.Among them,activatable probes and nanoprobes have generated special interest.Compared with NIR-I fluorescent probes,NIR-II(1000-1700 nm)fluorescent probes exhibit better intravital performance in terms of increased penetration depths,reduced tissue autofluorescence,and higher signalto-background ratios.However,more challenges are expected before the successful translation of NIR-II probes from bench to bedside.This review provides a brief overview of targeted fluorescent probes under clinical evaluation and recent achievements in the field of NIR-II fluorescence imaging.In addition,we outline key considerations concerning the design of fluorescent probes for clinical translation.

Antitumor immune responses induced by photodynamic and sonodynamic therapy:a narrative review

The immune system has the function of immune surveillance to resist the occurrence and development of tumors,and is essential for inhibition of tumor metastasis.Nevertheless,tumor cells can still suppress immune responses through multiple mechanisms to escape recognition and elimination.Photodynamic and sonodynamic therapy involve systemic or local use of sensitizers followed by light or ultrasound treatment of the affected area,leading to tumor cell death by various mechanisms.The capability of the immune system is essentially affected by photodynamic and sonodynamic therapy.To understand the tumor therapeutic mechanisms of photodynamic and sonodynamic therapy and to explore the use of these modalities for improvement of the antitumor immune effect,extensive preclinical and clinical studies have been carried out.Besides direct killing of tumors,photodynamic and sonodynamic therapy also cause inflammatory reactions,achieve antitumor immune responses,and potentially prevent tumor recurrence,thereby treating both primary and metastatic tumors.In this review,we summarize the antitumor immune responses induced by photodynamic and sonodynamic therapy,describe the processes of the antitumor immune responses in detail,and discuss the clinical applications of the resulting antitumor immunity.