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Thirteen red-shifted pentamethine dimethyl and diethylamino tetrahydroxanthylium derivatives have been successfully synthesized

Aim: To characterize the pharmacokinetics of deferoxamine-conjugated nanoparticles (DFO-NPs), a novel nanochelator for removing excess iron. Materials & methods: The pharmacokinetics of DFO-NPs were evaluated in Sprague–Dawley rats at three doses (3.3, 10 and 30 μmol/kg) after intravenous and subcutaneous administration. Results: DFO-NPs exhibited a biphasic concentration-time profile after intravenous administration with a short terminal half-life (2.0–3.2 h), dose-dependent clearance (0.111–0.179 l/h/kg), minimal tissue distribution and exclusive renal excretion with a possible saturable reabsorption mechanism. DFO-NPs after subcutaneous administration exhibited absorption-rate-limited kinetics with a prolonged half-life (5.7–10.1 h) and favorable bioavailability (47–107%). Conclusion: DFO-NPs exhibit nonlinear pharmacokinetics with increasing dose, and subcutaneous administration substantially improves drug exposure, thereby making it a clinically viable administration route for iron chelation.

Phototheranostics stem from the recent advances in nanomedicines and bioimaging to diagnose and treat human diseases. Since tumors' diversity, heterogeneity, and instability limit the clinical application of traditional diagnostics and therapeutics, phototheranostics, which combine light-induced therapeutic and diagnostic modalities in a single platform, have been widely investigated. Numerous efforts have been made to develop phototheranostics for efficient light-induced antitumor therapeutics with minimal side effects. Herein, we review the fundamentals of phototheranostic nanomedicines with their biomedical applications. Furthermore, the progress of near-infrared fluorescence imaging and cancer treatments, including photodynamic therapy and photothermal therapy, along with chemotherapy, immunotherapy, and gene therapy, are summarized. This review also discusses the opportunities and challenges associated with the clinical translation of phototheranostics in pan-cancer research. Phototheranostics can pave the way for future research, improve the quality of life, and prolong cancer patients' survival times.

Background: Due to the deep tissue penetration and reduced scattering, NIR-II fluorescence imaging is advantageous over conventional visible and NIR-I fluorescence imaging for the detection of bone growth, metabolism, metastasis, and other bone-related diseases. Methods: Here, we designed bone-targeted heptamethine cyanine fluorophores by substituting the meso-carbon with a sulfur atom, resulting in a bathochromic shift and increased fluorescence intensity, which together enables NIR-II tail imaging. Results: The newly synthesized S-substituted heptamethine fluorophores demonstrated a high affinity for hydroxyapatite and calcium phosphate, which improved bone-specific targeting with signal-background ratios >3.5. Particularly, P800SO3-PEG showed minimum nonspecific uptake, and most unbound molecules were excreted into the urinary bladder. Histological analyses demonstrated that P800SO3-PEG remained stable in the bone for over two weeks and was incorporated into bone matrices. Interestingly, the flexible thiol ethylene glycol linker on P800SO3-PEG induced a promising photothermal effect, making this bone-targeted agent a potential theranostic imaging agent.Conclusions: P800SO3-PEG shows a high affinity for bone tissues, minimum nonspecific uptake in the major organs, and photothermal effect upon laser irradiation, making it promising as a targeted NIR theranostic agent for bone diseases.

Despite wide investigation on molecular imaging contrast agents, there are still strong unmet medical needs to enhance their signal-to background ratio, brightness, photostability, and biocompatibility with multimodal imaging capability. Here, we assessed the feasibility of fluorescent nanodiamonds (FNDs) as carbon based photostable and biocompatible materials for molecular imaging applications. Because FNDs have negatively charged nitrogen vacancy (NV) centers, they can emit bright red light. FNDs were conjugated to hyaluronate (HA) for target-specific molecular imaging. HA is a biocompatible, biodegradable, and linear polysaccharide with abundant HA receptors in the liver, enabling liver targeted molecular imaging. In vitro cell viability tests revealed the biocompatibility of HA–FND conjugates and the competitive cellular uptake test confirmed their target-specific intracellular delivery to HepG2 cells with HA receptors. In addition, in vivo fluorescence lifetime (FLT) assessment revealed the imaging capability of FNDs and HA–FND conjugates. After that, we could confirm the statistically significant liver-targeted delivery of HA–FND conjugates by in vivo imaging system (IVIS) analysis and ex vivo biodistribution tests in various organs. The renal clearance test and histological analysis corroborated the in vivo biocompatibility and safety of HA–FND conjugates. All these results demonstrated the feasibility of HA–FND conjugates for further molecular imaging applications., Fluorescent nanodiamond conjugated with hyaluronate is developed as a carbon based photostable and biocompatible material for liver-targeted molecular imaging applications.

Enormous efforts have been made to integrate various therapeutic interventions into multifunctional nanoplatforms, resulting in the advance of nanomedicine. Image-guided drug delivery plays a pivotal role in this field by providing specific targeting as well as image navigation for disease prognosis.

Surface-enhanced Raman scattering (SERS) enables rapid detection of single molecules with high specificity. However, quantitative and sensitive SERS analysis has been a challenge due to the lack of reliable SERS-active materials. In this study, we developed a quantitative SERS-based immunoassay using enzyme-guided Ag growth on Raman labeling compound (RLC)-immobilized gold nanoparticle (Au NP)-assembled silica NPs (SiO2@Au-RLC@Ag). The enzyme amplified Ag+ reduction as well as Ag growth on the RLC-immobilized Au NP-assembled silica NPs (SiO2@Au-RLC), which resulted in a significant increase in SERS signal. In the presence of target antigens such as immunoglobulinG (IgG) or prostate-specific antigen (PSA), Ab1-Antigen-Ab2 immune complex with alkaline phosphatase triggered an enzyme- catalyzed reaction to convert 2-phospho-L-ascorbic acid (2-phospho-L-AA) to ascorbic acid (AA). As produced AA reduced Ag+ to Ag, forming an Ag hot spot on the surface of SiO2@Au-RLC, which enhanced the SERS signal of SiO2@Au-RLC@Ag in a solution with a target antigen concentration. The plasmonic immunoassay for IgG detection showed a high linearity of SERS intensity in the range of 0.6 to 9.0 ng/mL with a detection limit (LOD) of 0.09 ng/mL, while an LOD of 0.006 ng/mL was obtained for PSA. The results indicate that the sensitivity of our novel SERS-based immunoassay is higher than that of conventional enzyme-based colorimetric immunoassays.

The second near-infrared window (NIR-II) beyond 1000 nm has attracted attention for optical contrast imaging in small animals. We sought to assess whether commercially available NIR-II dyes could be easily formulated for this purpose. 13 hydrophobic NIR-II dyes were purchased and screened by formulating them in simple solubilizing agents with established use in humans: propylene glycol, Cremaphor EL, Kolliphor HS15 (HS15), Tween 80, and cyclodextrin. Based on the absorption at 1064 nm (matching the Nd:YAG laser output commonly used in photoacoustic imaging), three of the dyes were further assessed at varying dye and surfactant concentrations. Of these, benzo indole butyl diphenylaminocyclopentene heptamethine (BIBDAH) tetrafluoroborate in HS15 generally showed the most favorable NIR-II character. 1 mg mL−1 BIBDAH in 25% HS15 exhibited a single absorption peak at 1030 nm with a calculated intensity greater than 100, which was relatively stable for weeks in storage. Following intravenous administration to mice, determination of BIBDAH pharmacokinetics was possible by absorption measurements of sampled plasma, revealing a circulating half-life of about one hour. Most of the dye was taken up by the liver. BIBDAH was used in vitro and in vivo as a photoacoustic contrast imaging agent and its accumulation could be detected in subcutaneous tumors in mice. BIBDAH was used for fluorescence imaging of blood vessels in mice, including in the brain (through intact skull), and dye clearance from blood to the liver was visualized. Taken together, this study confirms that accessible, strongly-absorbing dye can readily be formulated for injection by simply dissolving them in biocompatible surfactants and used for high-contrast preclinical optical imaging in the second NIR window.

The strategy of structure-inherent tumor targeting (SITT) with cyanine-based fluorophores is receiving more attention because no chemical conjugation of targeting moieties is required. However, the targeting mechanism behind SITT has not yet been well explained. Here, it is demonstrated that heptamethine-cyanine-based fluorophores possess not only targetability of tumor microenvironments without the need for additional targeting ligands but also second near-infrared spectral window (NIR-II) imaging capabilities, i.e., minimum scattering and ultralow autofluorescence. The new SITT mechanism suggests that bone-marrow-derived and/or tissue-resident/tumor-associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. Among the tested, SH1 provides ubiquitous tumor targetability and a high tumor-to-background ratio (TBR) ranging from 9.5 to 47 in pancreatic, breast, and lung cancer mouse models upon a single bolus intravenous injection. Furthermore, SH1 can be used to detect small cancerous tissues smaller than 2 mm in diameter in orthotopic lung cancer models. Thus, SH1 could be a promising cancer-targeting agent and have a bright future for intraoperative optical imaging and image-guided cancer surgery.

Owing to the prevalence of rotator cuff (RC) injuries and suboptimal healing outcome, rapid and functional regeneration of the tendon-bone interface (TBI) after RC repair continues to be a major clinical challenge. Given the essential role of the RC in shoulder movement, the engineering of biomimetic multi-tissue constructs presents an opportunity for complex TBI reconstruction after RC repair. Here, we propose a gradient cell-laden multi-tissue construct combined with compositional gradient TBI-specific bioinks via 3D cell-printing technology.

Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety., The build-up of iron in the body can have serious consequences; current treatment therapies suffer from adverse side effects and toxicity. Here, the authors developed renal clearable nanochelators with improved pharmacodynamics and demonstrated their efficacy and safety in iron overload animal models.

Background A new approach targeting aeroallergen sensing in the early events of mucosal immunity could have greater benefit. The CSF1-CSF1R pathway has a critical role in trafficking allergens to regional lymph nodes through activating dendritic cells. Intervention in this pathway could prevent allergen sensitization and subsequent Th2 allergic inflammation. Objective To examine the therapeutic effectiveness of CSF1 and CSF1R inhibition for blocking the dendritic cell function of sensing aeroallergens. Methods We adopted a model of chronic asthma induced by a panel of three naturally occurring allergens and novel delivery system of CSF1R inhibitor encapsulated nanoprobe. Results Selective depletion of CSF1 in airway epithelial cells abolished the production of allergen-reactive IgE, resulting in prevention of new asthma development as well as reversal of established allergic lung inflammation. CDPL-GW nanoprobe containing GW2580, a selective CSF1R inhibitor, showed favorable pharmacokinetics for inhalational treatment and intranasal insufflation delivery of CDPL-GW nanoprobe ameliorated asthma pathologies including allergen-specific serum IgE production, allergic lung and airway inflammation and airway hyper-responsiveness (AHR) with minimal pulmonary adverse reaction. Conclusion The inhibition of the CSF1-CSF1R signaling pathway effectively suppresses sensitization to aeroallergens and consequent allergic lung inflammation in a murine model of chronic asthma. CSF1R inhibition is a promising new target for the treatment of allergic asthma.

Morphology control of the surface of a nanostructure is a key issue in modulating its surface plasmon resonance and scattering properties. Here, we studied the effect of alkylamines on morphology control during the one-step fabrication of silver nanoshells (NSs) for highly enhanced Raman scattering. Various types of alkylamines were used to study the effects of chain length, existence of hydroxyl groups, and degree of alkyl chains on the surface morphology of silver NSs. The alkylamines influenced the silver ion reduction and the growth of silver domains, resulting in distinctive morphology changes. The optical properties of the silver NSs of different surface morphologies were characterized by surface-enhanced Raman spectra. Especially, when long alkylamines were used, intense and uniform surface-enhanced Raman scattering signals were obtained at the visible and near-infrared (NIR) region, and their enhancement factor was ∼107. To detect cancer biomarkers in vivo, as a feasibility test, silver NSs were modified to highly NIR-active nanoprobes and successfully applied to detect colon cancer without causing nonspecific interactions. Our one-step fabrication method of silver NSs is simple and can overcome various hurdles of morphology control and can be extended to other metal nanostructures of controlled surface morphologies or shape.

Near infrared (NIR) dyes are useful for in vivo optical imaging. Liposomes have been used extensively for delivery of diverse cargos, including hydrophilic cargos which are passively loaded in the aqueous core. However, most currently available NIR dyes are only slightly soluble in water, making passive entrapment in liposomes challenging for achieving high optical contrast. Methods: We modified a commercially-available NIR dye (IR-820) via one-step Suzuki coupling with dicarboxyphenylboronic acid, generating a disulfonated heptamethine; dicarboxyphenyl cyanine (DCP-Cy). DCP-Cy was loaded in liposomes and used for optical imaging. Results: Owing to increased charge in mildly basic aqueous solution, DCP-Cy had substantially higher water solubility than indocyanine green (by an order of magnitude), resulting in higher NIR absorption. Unexpectedly, DCP-Cy tended to form J-aggregates with pronounced spectral red-shifting to 934 nm (from 789 nm in monomeric form). J-aggregate formation was dependent on salt and DCP-Cy concentration. Dissolved at 20 mg/mL, DCP-Cy J-aggregates could be entrapped in liposomes. Full width at half maximum absorption of the liposome-entrapped dye was just 25 nm. The entrapped DCP-Cy was readily detectable by fluorescence and photoacoustic NIR imaging. Upon intravenous administration to mice, liposomal DCP-Cy circulated substantially longer than the free dye. Accumulation was largely in the spleen, which was visualized with fluorescence and photoacoustic imaging. Conclusions: DCP-Cy is simple to synthesize and exhibits high aqueous solubility and red-shifted absorption from J-aggregate formation. Liposomal dye entrapment is possible, which facilitates in vivo photoacoustic and fluorescence imaging around 930 nm.

Near-infrared (NIR) fluorescence imaging has advanced medical imaging and image-guided interventions during the past three decades. Despite tremendous advances in imaging devices, surprisingly only a few dyes are currently available in the clinic. Previous fluorophores, ZW800-1A and ZW800-1C, significantly improved the poor performance of the FDA-approved indocyanine green. However, ZW800-1A is not stable in serum and ZW800-1C induces severe stacking in aqueous media. To solve such dilemmas, ZW800-PEG was designed by introducing a flexible yet stable thiol PEG linker. ZW800-PEG shows high solubility in both aqueous and organic solvents, thus improving renal clearance with minimal binding to serum proteins during systemic circulation. The sulfide group on the meso position of the heptamethine core improves serum stability and physicochemical properties including the maximum emission wavelength shift to 800 nm, enabling the use of ZW800-PEG for image-guided interventions and augmenting photothermal therapy.

Fluorescence imaging of cancers using continuous wave (CW) detection of receptor targeted probes offer poor sensitivity and specificity due to background autofluorescence and non-specific probe accumulation. Here we show that fluorescence lifetime (FLT) imaging can significantly improve tumor contrast using epidermal growth factor receptor (EGFR) and programed death ligand 1 (PD-L1) targeted probes in a preclinical model of human breast cancer. Our results suggest that these probes have significantly longer FLTs in tumors than in normal tissue and the FLT enhancement is receptor dependent. We also show potential for simultaneous quantification of EGFR and PD-L1 using in vivo FLT multiplexing.

We present a template-assisted method for synthesizing nanogap shell structures for biomolecular detections based on surface-enhanced Raman scattering. The interior nanogap-containing a silver shell structure, referred to as a silver nanogap shell (Ag NGS), was fabricated on silver nanoparticles (Ag NPs)-coated silica, by adsorbing small aromatic thiol molecules on the Ag NPs. The Ag NGSs showed a high enhancement factor and good signal uniformity, using 785-nm excitation. We performed in vitro immunoassays using a prostate-specific antigen as a model cancer biomarker with a detection limit of 2 pg/mL. To demonstrate the versatility of Ag NGS nanoprobes, extracellular duplex surface-enhanced Raman scattering (SERS) imaging was also performed to evaluate the co-expression of cancer biomarkers, human epidermal growth factor-2 (HER2) and epidermal growth factor receptor (EGFR), in a non-small cell lung cancer cell line (H522). Developing highly sensitive Ag NGS nanoprobes that enable multiplex biomolecular detection and imaging can open up new possibilities for point-of-care diagnostics and provide appropriate treatment options and prognosis.

共同研究チームは、近赤外線レーザーを照射することで卵巣がん細胞を手術中に可視化する新しい蛍光色素を開発しました。卵巣がん治療において手術で病巣を完全に切除することは、治療成績を向上させるための最も重要な因子です。近年、がんや組織をはっきりと標識することができる蛍光ガイド手術は、腫瘍の局在を明らかにすることで取り残しを減らし、外科的な腫瘍切除成績を向上させる技術として注目を集めています。今回本研究グループは、近赤外領域に蛍光を持つスクアライン色素の化学構造や電荷に修飾を加えることで、高輝度で安定した卵巣がん指向性のある蛍光色素OCTL14の開発に成功しました。OCTL14を卵巣がん腹膜播種マウスモデルに投与したところ、投与24時間後まで1ミリ以下の微小な腫瘍組織を検出し、その蛍光ガイド下での手術では肉眼だけに比べて多数の腫瘍の除去が可能でした。OCTL14は低分子蛍光色素分子であり、比較的簡単、安価に大量合成も可能であり広い臨床応用にも適しています。この蛍光物質が将来的に認可され、手術に応用されると、産婦人科医による卵巣がんの手術成績を向上させ、女性患者の予後を改善する画期的な新技術となることが期待されます。, The residual tumor after surgery is the most significant prognostic factor of patients with epithelial ovarian cancer. Near-infrared (NIR) fluorescence-guided surgery is actively utilized for tumor localization and complete resection during surgery. However, ......

While iron is a nutrient metal, iron overload can result in multiple organ failures. Iron chelators, such as deferoxamine, are commonly used to ameliorate iron overload conditions. However, their uses are limited due to poor pharmacokinetics and adverse effects. Many novel chelator formulations have been developed to overcome these drawbacks. In this review, we have discussed various nanochelators, including linear and branched polymers, dendrimers, polyrotaxane, micelles, nanogels, polymeric nanoparticles and liposomes. Although these research efforts have mainly been focused on nanochelators with longer half-lives, prolonged residence of polymers in the body could raise potential safety issues. We also discussed recent advances in nanochelation technologies, including mechanism-based, long-acting nanochelators.

There remains a paucity of methodological tools to determine the biodistribution of vaccine antigens. In response to this, we established a near-infrared (NIR) imaging method using a NIR fluorophore, ZW800-1C, conjugated with different sizes of vaccine antigens that allows for real-time monitoring of the fate of delivered vaccines in vivo. The fluorescent signal observed using the system after a model vaccine injection in mice recapitulated the size-dependent transport of the vaccine into the secondary lymphoid tissue. This methodology can be broadly applied for optimization of formulations and safety evaluation of clinical vaccines.

Noble metal structures with interior sub-nanometer gaps are highly promising as ultra-sensitive surface-enhanced Raman scattering (SERS) nanoprobes for generating uniform and reproducible hot spots in nanogaps. However, existing methods for synthesizing interior nanogap structures are challenged by difficulties in controlling the positions of Raman label compounds in the nanogaps and in functionalizing the tethering molecules. Herein, we present a template-assisted method for synthesizing nanogap shell structures for biomolecular detections. The interior nanogap-containing silver shell structure, referred to as a silver nanogap shell (Ag NGS), was fabricated on silver nanoparticles (Ag NPs)-coated silica, by adsorbing small aromatic thiol molecules on the Ag NPs. The Ag NGSs showed a high enhancement factor and good signal uniformity, using 785-nm excitation. We performed in vitro immunoassays using a prostate-specific antigen as a model cancer biomarker with a detection limit of 2 pg/mL. To demonstrate the versatility of Ag NGS nanoprobes, extracellular duplex SERS imaging was also performed to evaluate the co-expression of cancer biomarkers, HER2 and EGFR, in a non-small cell lung cancer cell line (H522). Developing highly sensitive Ag NGS nanoprobes enabling multiplex biomolecular detection and imaging can open up new possibilities for point-of-care diagnostics and provide appropriate treatment options and prognosis.

A nanoslit-concentration-chip (NC-chip) integrated microbead assay system was fabricated to overcome the assay limits of the conventional microbead-based protein assay. The proposed assay system was composed of a microbead-trapping-chip (MT-chip) and a NC-chip as a protein-capturing device and a quantitative and sensitive protein detection device, respectively. Microbeads trapped in the MT-chip formed a three-dimensional microbead packed column leading to efficient protein capturing. The NC-chip was used to trap and concentrate nanoparticle (NP) probes that were specifically captured in the microbead bed of the MT-chip. Furthermore, the nanoslit-patterned membrane of the NC-chip enabled both signal enhancement and quantification of the amount of the trapped NPs. The NC-chip integrated microbead assay system was successfully applied to a protein assay. The sensitivity and reliability of streptavidin detection by HPQ motif containing peptide ligands were compared to those of other reported assay systems. This novel protein assay system could be applied to various microbead-based bioassays, and integration of the NC-chip could further improve their sensitivity and reliability.

The fabrication of hollow metal nanostructures on a silica core template has been widely studied by taking advantage of the chemical stabilities of silica cores. When the size of the silica core reduces, however, this benefit is no longer effective because there are the synthetic difficulties which often cause dispersion instability, and therefore finally the aggregations of nanoparticles (NPs) are often caused during introduction of metallic nanostructures. This study reports the successful fabrication of silver nanoshells (AgNSs; 119, 152, 165, 186, and 207 nm) on amorphous silica nanoparticles (Si NPs) of different core sizes (59, 82, 103, 124, and 148 nm) by overcoming the increased instabilities during fabrication with reduced core sizes. Improvements related to fabrication were made by changing the reducing agents, controlling the amount of the dispersing agent and the concentration of Si NPs. All the AgNSs showed broad extinction from the visible to the near-infrared (NIR) region regardless of particle sizes, and their size-dependent surface properties were analyzed by introducing a concept of roughness factor, with AgNS of 152 nm exhibiting the highest degree of roughness. High SERS enhancements of AgNSs of all sizes were observed at three laser excitation wavelengths (532, 660, and 785 nm), and these enhancements correlated positively with the surface roughness. Therefore, our results provide a clear understanding of size-dependent SERS activity for AgNS, facilitating proper selection of AgNS with an appropriate size depending on the purpose of the investigation.

Prostate-specific membrane antigen (PSMA) can serve as a molecular cell surface target for the detection and treatment of prostate cancer. Near-infrared (NIR) fluorescence imaging enables highly sensitive, rapid, and non-radioactive imaging of PSMA, though specific targeting still remains a challenge because no optimized contrast agents exist.

Background: Tumor-associated macrophages (TAMs) are one of the most abundant immune cell types in solid tumors and implicated in tumor progression. Toll-like receptor 4 (TLR4) is expressed in TAMs and plays a key role in immune surveillance and tumor progression. Therefore, molecular imaging of TLR4 has potential not only for detection of TAM-enriched progressing tumors, but also evaluation of TLR4 expression in tumor microenvironment. Methods: Here, we report that near-infrared (NIR) fluorescence imaging can provide a real-time imaging of a syngeneic model of murine hepatocellular carcinoma using targeted strategy against TLR4. We conjugated a zwitterionic NIR fluorophore ZW800-1C with minimal nonspecific tissue interactions to anti-TLR4 antibody and observed its targetability. The bioconjugates showed high affinity to murine macrophages in cell culture and in vivo . Results: Interestingly, we observed predominant NIR signals in the tumor site, which persisted for more than 48 h after single intravenous administration of the bioconjugate. Conclusions: This result suggests that TLR4 targeting combined with NIR fluorescence imaging is a useful tool for cancer imaging. This imaging strategy could be used to detect cancerous tissue with the increased TAM content and evaluate the status of TLR4 signaling in solid tumors, ultimately impacting on the diagnostic and prognostic imaging of human cancers.

Nanomaterials have revolutionized cancer imaging, diagnosis, and treatment. Multifunctional nanoparticles in particular have been designed for targeted cancer therapy by modulating their physicochemical properties to be delivered to the target and activated by internal and/or external stimuli. This review will focus on the fundamental “chemical” design considerations of stimuli-responsive nanosystems to achieve favorable tumor targeting beyond biological barriers and, furthermore, enhance targeted cancer therapy. In addition, we will summarize innovative smart nanosystems responsive to external stimuli (e.g., light, magnetic field, ultrasound, and electric field) and internal stimuli in the tumor microenvironment (e.g., pH, enzyme, redox potential, and oxidative stress).