Flexible Photothermal Assemblies with Tunable Gold Patterns for Improved Imaging‐Guided Synergistic Therapy

Self‐assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic‐co‐glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion‐confined and polymer‐directed self‐assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid‐modified R‐PLGA‐Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real‐time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT‐enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging‐guided synergistic therapy.     

Gadolinium‐Conjugated Gold Nanoshells for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy

Multimodal imaging offers the potential to improve diagnosis and enhance the specificity of photothermal cancer therapy. Toward this goal, gadolinium‐conjugated gold nanoshells are engineered and it is demonstrated that they enhance contrast for magnetic resonance imaging, X‐ray, optical coherence tomography, reflectance confocal microscopy, and two‐photon luminescence. Additionally, these particles effectively convert near‐infrared light to heat, which can be used to ablate cancer cells. Ultimately, these studies demonstrate the potential of gadolinium‐nanoshells for image‐guided photothermal ablation.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

Tumor pH‐Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy

Tumor‐microenvironment‐responsive theranostics have great potential for precision diagnosis and effective treatment of cancer. Polyaniline (PANI) is the first reported pH‐responsive organic photothermal agent and is widely used as a theranostic agent. However, tumor pH‐responsive PANI‐based theranostic agents are not explored, mainly because the conversion from the emeraldine base (EB) to emeraldine salt (ES) state of PANI requires pH < 4, which is lower than tumor acidic microenvironment. Herein, a tumor pH‐responsive PANI‐based theranostic agent is designed and prepared for amplified photoacoustic imaging guided augmented photothermal therapy (PTT), through intermolecular acid–base reactions between carboxyl groups of bovine serum albumin (BSA) and imine moieties of PANI. The albumin/PANI assemblies (BSA–PANI) can convert from the EB to ES state at pH < 7, accompanied by the absorbance redshift from visible to near‐infrared region. Both in vitro and in vivo results demonstrate that tumor acidic microenvironment can trigger both the photoacoustic imaging (PAI) signal amplification and the PTT efficacy enhancement of BSA–PANI assemblies. This work not only highlights that BSA–PANI assemblies overcome the limitation of low‐pH protonation, but also provides a facile assembly strategy for a tumor pH‐responsive PANI‐based nanoplatform for cancer theranostics.     

Plant Polyphenol‐Assisted Green Synthesis of Hollow CoPt Alloy Nanoparticles for Dual‐Modality Imaging Guided Photothermal Therapy

Theranostic nanomedicines that integrate diagnostic and therapeutic moieties into a single nanoscale platform are playing an increasingly important role in fighting cancer. Here, a facile and green synthetic strategy for hollow CoPt alloy nanoparticles (HCPA‐NPs) using plant polyphenols as assisted agents is reported for the first time. This novel strategy enables size‐controlled synthesis of HCPA‐NPs through the control of the molecular sizes of polyphenols. It is also a versatile strategy for synthesizing other hollow alloy nanoparticles with various metal compositions due to the diverse metal‐chelating ability of the polyphenols. Further studies show that HCPA‐NPs have good biocompatibility and can be successfully implemented for magnetic resonance and photoacoustic dual‐modal imaging guided photothermal therapy. This work brings new insights for the green synthesis of hollow nanoparticles and extends these biocompatible nanoparticles for theranostic applications.     

Second Near-Infrared Plasmonic Nanomaterials for Photoacoustic Imaging and Photothermal Therapy

Photoacoustic imaging (PAI) and imaging-guided photothermal therapy (PTT) in the second near-infrared window (NIR-II, 1000–1700 nm) have received increasing attention owing to their advantages of greater penetration depth and higher signal-to-noise ratio. Plasmonic nanomaterials with tunable optical properties and strong light absorption provide an alternative to dye molecules, showing great prospects for phototheranostic applications. In this review, the research progress in principally modulating the optical properties of plasmonic nanomaterials, especially affecting parameters such as size, morphology, and surface chemical modification, is introduced. The commonly used plasmonic nanomaterials in the NIR-II window, including noble metals, semiconductors, and heterostructures, are then summarized. In addition, the biomedical applications of these NIR-II plasmonic nanomaterials for PAI and PTT in phototheranostics are highlighted. Finally, the perspectives and challenges for advancing plasmonic nanomaterials for practical use and clinical translation are discussed.     

Functionalized Graphene@Gold Nanostar/Lipid for Pancreatic Cancer Gene and Photothermal Synergistic Therapy under Photoacoustic/Photothermal Imaging Dual‐Modal Guidance

Nanomaterial‐based pancreatic cancer treatment has received widespread attention and rapid development in the past few years. The major challenges include the poor combination of diagnosis and therapy, the difficulty in targeting therapy from the root and the unsatisfactory antitumor efficiency, which is accompanied by a great risk of relapse and metastasis. In this work, a positively charged lipid bilayer membrane is coated on reduced graphene oxide@gold nanostar (rGO@AuNS) for photoacoustic/photothermal dual‐modal imaging‐guided gene/photothermal synergistic therapy of pancreatic cancer. In addition, the cross‐linking of folic acid on the surface of rGO@AuNS‐lipid can specifically bind after recognizing folic acid receptors on the surface of cancer cells, and greatly improve the targeting ability of the nanomaterial and the performance of imaging diagnosis by receptor‐mediated endocytosis. Moreover, the photothermal and gene (targeting G12V mutant K‐Ras gene) synergistic therapy shows outstanding anticancer efficacy for pancreatic cancer tumor bearing mice, and it is noteworthy that the treatment groups have anti‐liver metastasis of pancreatic cancer.     

Ultrasmall Cu2‐xS Nanodots for Highly Efficient Photoacoustic Imaging‐Guided Photothermal Therapy

Monodisperse, ultrasmall (<5 nm) Cu_2?xS nanodots (u‐Cu_2?xS NDs) with significantly strong near‐infrared absorption and conversion are successfully demonstrated for effective deep‐tissue photoacoustic imaging‐guided photothermal therapy both in vitro and in vivo. Owing to ultrasmall nanoparticle size and high water dispersibility as well as long stability, such nanodots possess a prolonged circulation in blood and good passive accumulation within tumors through the enhanced permeability and retention effect. These u‐Cu_2?xS NDs have negligible side effects to both blood and normal tissues according to in vivo toxicity evaluations for up to 3 months, showing excellent hemo/histocompatibility. Furthermore, these u‐Cu_2?xS NDs can be thoroughly cleared through feces and urine within 5 days, showing high biosafety for further potential clinical translation. This novel photoacoustic imaging‐guided photothermal therapy based on u‐Cu_2?xS NDs composed of a single component shows great prospects as a multifunctional nanoplatform with integration and multifunction for cancer diagnosis and therapy.     

Dual‐Modal NIR‐Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid‐β Species In Vivo

Senile plaques, the extracellular deposit of amyloid‐β (Aβ) peptides, are one of the neuropathological hallmarks found in Alzheimer's disease (AD) brain. The current method of brain imaging of amyloid plaques based on positron emission tomography (PET) is expensive and invasive with low spatial resolution. Thus, the development of sensitive and nonradiative amyloid‐β (Aβ)‐specific contrast agents is highly important and beneficial to achieve early AD detection, monitor the disease progression, and evaluate the effectiveness of potential AD drugs. Here a neuroprotective dual‐modal nanoprobe developed by integrating highly Aβ‐specific and turn‐on fluorescence cyanine sensors with superparamagnetic iron oxide nanoparticles as an effective near‐infrared imaging (NIRI)/magnetic resonance imaging (MRI) contrast agent for imaging of Aβ species in vivo is reported. This Aβ‐specific probe is found not only nontoxic and noninvasive, but also highly blood brain barrier permeable. It also shows a potent neuroprotective effect against Aβ‐induced toxicities. This nanoprobe is successfully applied for in vivo fluorescence imaging with high sensitivity and selectivity to Aβ species, and MRI with high spatial resolution in an APP/PS1 transgenic mice model. Its potential as a powerful in vivo dual‐modal imaging tool for early detection and diagnosis of AD in humans is affirmed.     

Gold Nanoshelled Liquid Perfluorocarbon Nanocapsules for Combined Dual Modal Ultrasound/CT Imaging and Photothermal Therapy of Cancer

The integration of multimodal contrast‐enhanced diagnostic imaging and therapeutic capabilities could utilize imaging guided therapy to plan the treatment strategy based on the diagnostic results and to guide/monitor the therapeutic procedures. Herein, gold nanoshelled perfluorooctylbromide (PFOB) nanocapsules with PEGylation (PGsP NCs) are constructed by oil‐in‐water emulsion method to form polymeric PFOB nanocapsules, followed by the formation of PEGylated gold nanoshell on the surface. PGsP NCs could not only provide excellent contrast enhancement for dual modal ultrasound and CT imaging in vitro and in vivo, but also serve as efficient photoabsorbers for photothermal ablation of tumors on xenografted nude mouse model. To our best knowledge, this is the first report of gold nanoshell serving as both CT contrast agents and photoabsorbers for photothermal therapy. The novel multifunctional nanomedicine would be of great value to offer more comprehensive diagnostic information to guide more accurate and effective cancer therapy.     

Surface Plasmon Resonance–Enhanced Photoacoustic Imaging and Photothermal Therapy of Endogenous H2S‐Triggered Au@Cu2O

Smart theranostics agents triggered by endogenous H₂S with combined activated photoacoustic imaging and photothermal therapy can improve the diagnosis and treatment of colon cancer. However, the low theranostic performance of the current smart theranostics agents after the triggering step has limited their further application. In this work, the theranostic performance of endogenous H₂S‐triggered Au@Cu₂O for the diagnosis and treatment of colon cancer, which is generated from the localized surface plasmon resonance coupling effect between a noble metal (Au) and a semiconductor (Cu₂O), is investigated. Compared with Cu₂O, the prepared H₂S‐triggered Au@Cu₂O shows a significantly stronger absorption at the near‐infrared region, such as a ≈2.1 times change at 808 nm, giving a photothermal conversion efficiency increase of ≈1.2 times. More importantly, Au@Cu₂O still exhibits good photoacoustic imaging contrast and photothermal properties for treatment of colon cancer in vivo even at very low injection doses. This work not only investigates an endogenous H₂S‐triggered Au@Cu₂O theranostic agent with enhanced theranostic performance for colon cancer but also provides a novel strategy for designing high‐performance theranostic agents.     

Polyphenol‐Inspired Facile Construction of Smart Assemblies for ATP‐ and pH‐Responsive Tumor MR/Optical Imaging and Photothermal Therapy

Smart assemblies have attracted increased interest in various areas, especially in developing novel stimuli‐responsive theranostics. Herein, commercially available, natural tannic acid (TA) and iron oxide nanoparticles (Fe₃O₄ NPs) are utilized as models to construct smart magnetic assemblies based on polyphenol‐inspired NPs–phenolic self‐assembly between NPs and TA. Interestingly, the magnetic assemblies can be specially disassembled by adenosine triphosphate, which shows a stronger affinity to Fe₃O₄ NPs than that of TA and partly replaces the surface coordinated TA. The disassembly can further be facilitated by the acidic environment hence causing the remarkable change of the transverse relaxivity and potent “turn‐on” of fluorescence (FL) signals. Therefore, the assemblies for specific and sensitive tumor magnetic resonance and FL dual‐modal imaging and photothermal therapy after intravenous injection of the assemblies are successfully employed. This work not only provides understandings on the self‐assembly between NPs and polyphenols, but also will open new insights for facilely constructing versatile assemblies and extending their biomedical applications.     

A Smart Responsive Dual Aptamers‐Targeted Bubble‐Generating Nanosystem for Cancer Triplex Therapy and Ultrasound Imaging

The absence of targeted, single treatment methods produces low therapeutic value for treating cancers. To increase the accumulation of drugs in tumors and improve the treatment effectiveness, near‐infrared 808 nm photothermal responsive dual aptamers‐targeted docetaxel (DTX)‐containing nanoparticles is proposed. In this system, DTX and NH₄HCO₃ are loaded in thermosensitive liposomes. The surface of liposomes is coated with gold nanoshells and connected with sulfydryl (SH? ) modified AS1411 and S2.2 aptamers. The nanosystem has good biocompatibility and uniform size (diameter about 200 nm). The drug is rapidly released, reaching a maximum amount (84%) at 4 h under 808 nm laser irradiation. The experiments conducted in vitro and in vivo demonstrate the nanosystem can synergistically inhibit tumor growth by combination of chemotherapy, photothermal therapy, and biological therapy. Dual ligand functionalization significantly increases cellular uptake on breast cancer cell line (MCF‐7) cells and achieves ultrasound imaging (USI) at tumor site. The results indicate that this drug delivery system is a promising theranostic agent involving light‐thermal response at tumor sites, dual ligand targeted triplex therapy, and USI.