Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent.

To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r2/r1 ratio of the reported Gd macrochelates that is an important factor for T1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r1 value of 16.35 mM-1 s-1 and r2/r1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 â„ƒ or 1.8 cP at 37 â„ƒ, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.

Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1 -Weighted Magnetic Resonance Imaging and Imaging-Guided Therapy of Tumors.

Magnetic iron oxide nanoparticles (MIONs) based T2 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) are liver-specific with good biocompatibility, but have been withdrawn from the market and replaced with Eovist (Gd-EOB-DTPA) due to their inherent limitations (e.g., susceptibility to artifacts, high magnetic moment, dark signals, long processing time of T2 imaging, and long waiting time for patients after administration). Without the disadvantages of Gd-chelates and MIONs, the recently emerging exceedingly small MIONs (ES-MIONs) (<5 nm) are promising T1 CAs for MRI. However, there are rare review articles focusing on ES-MIONs for T1 -weighted MRI. Herein, the recent progress of ES-MIONs, including synthesis methods (the current basic synthesis methods and improved methods), surface modifications (artificial polymers, natural polymers, zwitterions, and functional protein), T1 -MRI visual strategies (structural remodeling, reversible self-assemblies, metal ions doped, T1 /T2 dual imaging modes, and PET/MRI strategy), and imaging-guided cancer therapy (chemotherapy, gene therapy, ferroptosis therapy, photothermal therapy, photodymatic therapy, radiotherapy, immuotherapy, sonodynamic therapy, and multimode therapy), is summarized. The detailed description of synthesis methods and applications of ES-MIONs in this review is anticipated to attract extensive interest from researchers in different fields and promote their participation in the establishment of ES-MIONs based nanoplatforms for tumor theranostics.

Intelligent Pore Switch of Hollow Mesoporous Organosilica Nanoparticles for High Contrast Magnetic Resonance Imaging and Tumor-Specific Chemotherapy.

Hollow mesoporous organosilica nanoparticles (HMONs) are widely considered as a promising drug nanocarrier, but the loaded drugs can easily leak from HMONs, resulting in the considerably decreased drug loading capacity and increased biosafety risk. This study reports the smart use of core/shell Fe3O4/Gd2O3 (FG) hybrid nanoparticles as a gatekeeper to block the pores of HMONs, which can yield an unreported large loading content (up to 20.4%) of DOX. The conjugation of RGD dimer (R2) onto the DOX-loaded HMON with FG capping (D@HMON@FG@R2) allowed for active tumor-targeted delivery. The aggregated FG in D@HMON@FG@R2 could darken the normal tissue surrounding the tumor due to the high r2 value (253.7 mM-1 s-1) and high r2/r1 ratio (19.13), and the intratumorally released FG as a result of reducibility-triggered HMON degradation could brighten the tumor because of the high r1 value (20.1 mM-1 s-1) and low r2/r1 ratio (7.01), which contributed to high contrast magnetic resonance imaging (MRI) for guiding highly efficient tumor-specific DOX release and chemotherapy.

Boron-Containing Lipids and Liposomes: New Conjugates of Cholesterol with Polyhedral Boron Hydrides.

A series of boron-containing lipids were prepared by reactions of cyclic oxonium derivatives of polyhedron boranes and metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations, on the basis of synthesized boron-containing lipids, hydrogenated soybean l-α-phosphatidylcholine and (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients, were prepared and then characterized by dynamic light scattering (DLS) that revealed the formation of particles to be smaller than 200 nm in diameter. The resulting liposomal formulations showed moderate to excellent loading and entrapment efficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuring ease of in vivo use for future application. The liposomal formulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normal epithelial cells MCF-10A and human breast cancer cells MCF-7.

Gadolinium Metallofullerene-Based Activatable Contrast Agent for Tumor Signal Amplification and Monitoring of Drug Release.

Activatable imaging probes are promising to achieve increased signal-to-noise ratio for accurate tumor diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is a noninvasive imaging technique with excellent anatomic spatial resolution and unlimited tissue penetration depth. However, most of the activatable MRI contrast agents suffer from metal ion-associated potential long-term toxicity, which may limit their bioapplications and clinical translation. Herein, an activatable MRI agent with efficient MRI performance and high safety is developed for drug (doxorubicin) loading and tumor signal amplification. The agent is based on pH-responsive polymer and gadolinium metallofullerene (GMF). This GMF-based contrast agent shows high relaxivity and low risk of gadolinium ion release. At physiological pH, both GMF and drug molecules are encapsulated into the hydrophobic core of nanoparticles formed by the pH-responsive polymer and shielded from the aqueous environment, resulting in relatively low longitudinal relativity and slow drug release. However, in acidic tumor microenvironment, the hydrophobic-to-hydrophilic conversion of the pH-responsive polymer leads to amplified MR signal and rapid drug release simultaneously. These results suggest that the prepared activatable MRI contrast agent holds great promise for tumor detection and monitoring of drug release.

Exceedingly Small Gadolinium Oxide Nanoparticles with Remarkable Relaxivities for Magnetic Resonance Imaging of Tumors.

Gd chelates have occupied most of the market of magnetic resonance imaging (MRI) contrast agents for decades. However, there have been some problems (nephrotoxicity, non-specificity, and low r1 ) that limit their applications. Herein, a wet-chemical method is proposed for facile synthesis of poly(acrylic acid) (PAA) stabilized exceedingly small gadolinium oxide nanoparticles (ES-GON-PAA) with an excellent water dispersibility and a size smaller than 2.0 nm, which is a powerful T1 -weighted MRI contrast agent for diagnosis of diseases due to its remarkable relaxivities (r1 = 70.2 ± 1.8 mM-1 s-1 , and r2 /r1 = 1.02 ± 0.03, at 1.5 T). The r1 is much higher and the r2 /r1 is lower than that of the commercial Gd chelates and reported gadolinium oxide nanoparticles (GONs). Further ES-GON-PAA is developed with conjugation of RGD2 (RGD dimer) (i.e., ES-GON-PAA@RGD2) for T1 -weighted MRI of tumors that overexpress RGD receptors (i.e., integrin αv ß3 ). The maximum signal enhancement (ΔSNR) for T1 -weighted MRI of tumors reaches up to 372 ± 56% at 2 h post-injection of ES-GON-PAA@RGD2, which is much higher than commercial Gd-chelates (<80%). Due to the high biocompatibility and high tumor accumulation, ES-GON-PAA@RGD2 with remarkable relaxivities is a promising and powerful T1 -weighted MRI contrast agent.

Synchronous Chemoradiation Nanovesicles by X-Ray Triggered Cascade of Drug Release.

The approach of concurrent-to-synchronous chemoradiation has now been advanced by well-designed nanovesicles that permit X-ray irradiation-triggered instant drug release. The nanovesicles consist of Au nanoparticles tethered with irradiation labile linoleic acid hydroperoxide (LAHP) molecules and oxidation-responsive poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) polymers, where DOX were loaded in the inner core of the vesicles (Au-LAHP-vDOX). Upon irradiation, the in situ formation of hydroxyl radicals from LAHP molecules triggers the internal oxidation of PPS from being hydrophobic to hydrophilic, leading to degradation of the vesicles and burst release of cargo drugs. In this manner, synchronous chemoradiation showed impressive anticancer efficacy both in vitro and in a subcutaneous mouse tumor model by one-dose injection and one-time irradiation.

Near-Infrared Semiconducting Polymer Brush and pH/GSH-Responsive Polyoxometalate Cluster Hybrid Platform for Enhanced Tumor-Specific Phototheranostics.

Tumor-specific phototheranostics is conducive to realizing precise cancer therapy. Herein, a novel tumor microenvironment (TME)-responsive phototheranostic paradigm based on the combination of semiconducting polymer brushes and polyoxometalate clusters (SPB@POM) is rationally designed. The acidic TME could drive the self-assembly of SPB@POM into bigger aggregates for enhanced tumor retention and accumulation, while the reducing TME could significantly enhance the NIR absorption of SPB@POM for significant improvement of photoacoustic imaging contrast and photothermal therapy efficacy. Therefore, the smart pH/glutathione (GSH)-responsive SPB@POM allows for remarkable phototheranostic enhancement under the unique TME, which has potential for precise tumor-specific phototheranostics with minimal side effects.

A strategy of "adding fuel to the flames" enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy.

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry (i.e., "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

Synthesis and Bioapplications of Ag2 S Quantum Dots with Near-Infrared Fluorescence.

Quantum dots (QDs) with near-infrared fluorescence (NIR) are an emerging class of QDs with unique capabilities owing to the deeper tissue penetrability of NIR light compared with visible light. NIR light also effectively overcomes organism autofluorescence, making NIR QDs particularly attractive in biological imaging applications for disease diagnosis. Considering latest developments, Ag2 S QDs are a rising star among NIR QDs due to their excellent NIR fluorescence properties and biocompatibility. This review presents the various methods to synthesize NIR Ag2 S QDs, and systematically discusses their applications in biosensing, bioimaging, and theranostics. Major challenges and future perspectives concerning the synthesis and bioapplications of NIR Ag2 S QDs are discussed.

Effects of Linkers on the Development of Liposomal Formulation of Cholesterol Conjugated Cobalt Bis(dicarbollides).

Boron neutron capture therapy (BNCT) remains an important treatment arm for cancer patients with locally invasive malignant tumors. This therapy needs a significant amount of boron to deposit in cancer tissues selectively, sparing other healthy organs. Most of the liposomes contain water-soluble polyhedral boron salts stay in the core of the liposomes and have low encapsulation efficiency. Thus, modifying the polyhedral boron core to make it hydrophobic and incorporating those into the lipid layer could be one of the ways to increase drug loading and encapsulation efficiency. Additionally, a systematic study about the linker-dependent effect on drug encapsulation and drug-release is lacking, particularly for the liposomal formulation of hydrophobic-drugs. To achieve these goals, liposomal formulations of a series of lipid functionalized cobalt bis(dicarbollide) compounds have been prepared, with the linkers of different hydrophobicity. Hydrophobicity of the linkers have been evaluated through logP calculation and its effect on drug encapsulation and release have been investigated. The liposomes have shown high drug loading, excellent encapsulation efficiency, stability, and non-toxic behavior. Release experiment showed minimal release of drug from liposomes in phosphate buffer, ensuring some amount of drug, associated with liposomes, can be available to tumor tissues for Boron Neutron Capture Therapy.

A pH-sensitive polymer based precise tumor targeting strategy with reduced uptake of nanoparticles by non-cancerous cells.

Drug-loaded nanoparticles can be specifically uptaken by tumor cells to realize active targeting due to the conjugated ligands or antibodies on their surface. However, some non-cancerous cells express non-specific receptors or antigens on their surface, which can react with the ligands or antibodies conjugated on the nanoparticle surface and then result in non-specific uptake of the nanoparticles by non-cancerous cells. In order to reduce the non-specific uptake of nanoparticles by non-cancerous cells, in this study, we proposed a pH-sensitive polymer based precise tumor targeting strategy and synthesized superparamagnetic iron oxide nanoparticle (SPION) encapsulated albumin nanoparticles (AN) with conjugation of folic acid (FA) and mPEG-DCA (SPION-AN-FA@mPEG), in which mPEG can shield FA, avoiding the non-specific recognition by normal cells under physiological conditions, and can be shed to expose FA in tumor microenvironments. The pH-sensitivity of mPEG-DCA was verified by HPLC characterization and 1H-NMR spectroscopy. The graft density and length of mPEG-DCA were optimized via the cellular uptake of SPION-AN-FA@mPEG measured by flow cytometry analysis. The r2 value and r2/r1 ratio of the optimized SPION-AN-FA@mPEG (i.e., SPION-AN-FA@mPEG4) are 168.6 mM-1 s-1 and 42.8, respectively, which are both much higher than that of the commercial contrast agent Resovist®. The in vitro T2-weighted MR images and in vivo MRI performance demonstrate that our SPION-AN-FA@mPEG4 nanoparticles can be used as an effective T2-weighted MRI contrast agent.

Polyphenol-based nanoplatform for MRI/PET dual-modality imaging guided effective combination chemotherapy.

Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe3+ or Mn2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe3+ or Mn2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.

A Rationally Designed Semiconducting Polymer Brush for NIR-II Imaging-Guided Light-Triggered Remote Control of CRISPR/Cas9 Genome Editing.

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) genome-editing system has shown great potential in biomedical applications. Although physical approaches, viruses, and some nonviral vectors have been employed for CRISPR/Cas9 delivery and induce some promising genome-editing efficacy, precise genome editing remains challenging and has not been reported yet. Herein, second near-infrared window (NIR-II) imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 genome-editing strategy is reported based on a rationally designed semiconducting polymer brush (SPPF). SPPF can not only be a vector to deliver CRISPR/Cas9 cassettes but also controls the endolysosomal escape and payloads release through photothermal conversion under laser irradiation. Upon laser exposure, the nanocomplex of SPPF and CRISPR/Cas9 cassettes induces effective site-specific precise genome editing both in vitro and in vivo with minimal toxicity. Besides, NIR-II imaging based on SPPF can also be applied to monitor the in vivo distribution of the genome-editing system and guide laser irradiation in real time. Thus, this study offers a typical paradigm for NIR-II imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 system for precise genome editing. This strategy may open an avenue for CRISPR/Cas9 genome-editing-based precise gene therapy in the near future.

Generic synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy.

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers.

Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy.

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

Thermosensitive polymer-conjugated albumin nanospheres as thermal targeting anti-cancer drug carrier.

Thermosensitive Poly(N-isopropylacrylamide-co-acrylamide-co-allylamine) (PNIPAM-AAm-AA)-conjugated albumin nanospheres (PAN) was developed as a new thermal targeting anti-cancer drug carrier by conjugating PNIPAM-AAm-AA on the surface of albumin nanospheres (AN). AN with diameter below 200nm and narrow size distribution was successfully prepared in the first step with desolvation technique. PNIPAM-AAm-AA with different molecular weight (M(w)) was synthesized in the second step by radical polymerization and conjugated onto the surface of AN. Anti-cancer drug adriamycin (ADR) was then entrapped into the AN and PAN during the particle preparation. Compared with AN, the release rate of ADR from PAN in trypsin solution was slower, and decreased with increasing the conjugation amounts (hairy density) or M(w) of PNIPAM-AAm-AA (hairy length). Moreover, the release of ADR from PAN above the cloud-point temperature (T(cp)) of PNIPAM-AAm-AA became faster due to shrinkage of hairy thermosensitive polymer. To testify the thermal targetability in vivo, PAN was incubated with HepG2 cells. As expected, PAN can target cancer cells above the T(cp) of PNIPAM-AAm-AA, whereas it cannot below the T(cp). These results might reflect that PAN may selectively accumulate onto solid tumors that are maintained above physiological temperature due to local hyperthermia.

Preparation and characterization of thermo-responsive albumin nanospheres.

Thermo-responsive poly(N-isopropylacrylamide-co-acrylamide)-block-polyallylamine-conjugated albumin nanospheres (PAN), new thermal targeting anti-cancer drug carrier, was developed by conjugating poly(N-isopropylacrylamide-co-acrylamide)-block-polyallylamine (PNIPAM-AAm-b-PAA) on the surface of albumin nanospheres (AN). PAN may selectively accumulate onto solid tumors that are maintained above physiological temperature due to local hyperthermia. PNIPAM-AAm-b-PAA was synthesized by radical polymerization, and AN was prepared by ultrasonic emulsification. AN with diameter below 200 nm and narrow size distribution was obtained by optimizing the preparative conditions. Rose Bengal (RB) was used as model drug for entrapment into the AN and PAN during the particle preparation. The release rate of RB from PAN compared with AN in trypsin solution was slower, and decreased with the increase of PNIPAM-AAm-b-PAA molecular weight, which suggested that the existence of a steric hydrophilic barrier on AN made digestion of AN more difficult. Moreover, the release of RB from PAN above the cloud-point temperature (T(cp)) of PNIPAM-AAm-b-PAA became faster. This was because the density of temperature-responsive polymers on AN was not so high, so that the interspace between the polymer chains increased after they shrunk due to the high temperature. As a result, the biodegradable AN was attacked more easily by trypsin. The design of PAN overcame the disadvantages of temperature-responsive polymeric micelles.

Enhanced Afterglow Performance of Persistent Luminescence Implants for Efficient Repeatable Photodynamic Therapy.

Persistent luminescence nanoparticles (PLNPs) have been used for bioimaging without autofluorescence background interference, but the poor afterglow performance impedes their further applications in cancer therapy. To overcome the Achilles' heel of PLNPs, herein we report the construction of injectable persistent luminescence implants (denoted as PL implants) as a built-in excitation source for efficient repeatable photodynamic therapy (PDT). The injectable ZGC (ZnGa1.996O4:Cr0.004) PL implants were prepared by dissolving ZGC PLNPs in poly(lactic-co-glycolic acid)/N-methylpyrrolidone oleosol, which demonstrated much stronger persistent luminescence (PersL) intensity and longer PersL lifetime than that of ZGC PLNPs both in vitro and in vivo. More importantly, the intratumorally fixed ZGC PL implants can serve as a built-in excitation source for repeatable light emitting diode (LED) and PersL-excited PDT upon and after periodic LED irradiation, which leads to the overall improvement of therapeutic effectiveness for efficient tumor growth suppression. This work represents efficient repeatable PDT based on the injectable yet periodically rechargeable ZGC PL implants.

Rational Design of Branched Nanoporous Gold Nanoshells with Enhanced Physico-Optical Properties for Optical Imaging and Cancer Therapy.

Reported procedures on the synthesis of gold nanoshells with smooth surfaces have merely demonstrated efficient control of shell thickness and particle size, yet no branch and nanoporous features on the nanoshell have been implemented to date. Herein, we demonstrate the ability to control the roughness and nanoscale porosity of gold nanoshells by using redox-active polymer poly(vinylphenol)-b-(styrene) nanoparticles as reducing agent and template. The porosity and size of the branches on this branched nanoporous gold nanoshell (BAuNSP) material can be facilely adjusted by control of the reaction speed or the reaction time between the redox-active polymer nanoparticles and gold ions (Au3+). Due to the strong reduction ability of the redox-active polymer, the yield of BAuNSP was virtually 100%. By taking advantage of the sharp branches and nanoporous features, BAuNSP exhibited greatly enhanced physico-optical properties, including photothermal effect, surface-enhanced Raman scattering (SERS), and photoacoustic (PA) signals. The photothermal conversion efficiency can reach as high as 75.5%, which is greater than most gold nanocrystals. Furthermore, the nanoporous nature of the shells allows for effective drug loading and controlled drug release. The thermoresponsive polymer coated on the BAuNSP surface serves as a gate keeper, governing the drug release behavior through photothermal heating. Positron emission tomography imaging demonstrated a high passive tumor accumulation of 64Cu-labeled BAuNSP. The strong SERS signal generated by the SERS-active BAuNSP in vivo, accompanied by enhanced PA signals in the tumor region, provide significant tumor information, including size, morphology, position, and boundaries between tumor and healthy tissues. In vivo tumor therapy experiments demonstrated a highly synergistic chemo-photothermal therapy effect of drug-loaded BAuNSPs, guided by three modes of optical imaging.