Platinum(IV) prodrug diaminedichlorodihydroxyplatinum (ACHP) conjugated with a histone deacetylase (HDAC) inhibitor valproic acid (VA), VAAP, exhibited strong synergistic cytotoxicity, about 50–100 times more cytotoxic than ACHP or its simple mixture with VA, against various human carcinoma cell lines. VAAP could be quickly absorbed in the cell membrane and diffused into the cytosol. VAAP loaded in polyethylene glycol–polycaprolactone micelles (PEG-PCL) was taken up via endocytosis. The cytosolic VAAP was intracellular reduced to Pt(II) and released VA eliciting a HDAC inhibitory effect and subsequently induced cell cycle arrest at the S phase in 24 h and cell apoptosis in a time-dependent manner. The in vivo antitumor experiment on A549-xenograft tumor model showed that VAAP dispersed in Tween 80 or loaded in PEG-PCL nanoparticles had long blood circulation times and thereby high accumulation in tumors and exerted a significant in vivo inhibitory effect on tumor growth with low systemic toxicity. Therefore, this novel conjugate is very promising for cancer chemotherapy.Keywords: cell cycle arrest and apoptosis; histone deacetylase inhibitor; platinum(IV) prodrug; synergistic cytotoxicity; valproic acid;

Metastasis is the main reason for cancer-associated mortality, and accurate diagnostic imaging of metastases is critical for the clinical administration and tailoring personalized treatments for metastatic tumors. However, magnetic resonance imaging of metastases in the liver is impeded by its low sensitivity because the currently used contrast agents accumulate in hepatocytes and Kupffer cells instead of cancer cells. Herein, a 4th generation zwitterionized biodegradable dendritic contrast agent (DCA) with a size of ca. 9 nm and a longitudinal relaxivity of 15.7 mM−1 s−1 in terms of Gd was synthesized and used to enhance the MRI of liver metastasis. The DCA could remarkably enhance the MRI of metastasized tumors in the liver, because it could simultaneously reduce the background signal in the liver by avoiding uptake by hepatocytes and Kupffer cells through the zwitterionization and increase the signal in tumors through the enhanced permeability and retention effect. Moreover, in contrast to non-biodegradable DCA, this DCA showed minimal long-term Gd3+ retention in all organs and tissues because it could be degraded into small fragments. The significant capability of enhancing the MRI of metastases in the liver plus its excellent biodegradability made this DCA a promising CA for metastatic tumor imaging.

Photothermal therapies (PPTs) with various light-absorbing materials have shown very promising therapeutic effects against cancers. However, their application was severely limited by the lack of accurate localization of tumors and real-time monitoring of the therapeutic process. Theranostic nanoparticles with both imaging and therapeutic functions are highly desired to develop imaging-mediated PPTs. Herein, we develop a facile one-pot method to synthesize a nanoparticle with functions of an MRI contrast agent and a PTT agent through oxidization of dopamine-DTPA-Gd conjugates and PEG-dopamine conjugates. The oxidized dopamine nanoparticles (ODNP) had a high R1 up to 9.6 mM−1 s−1, 2.2 times higher than that of Omniscan, and showed significantly higher MRI contrast enhancement than Omniscan in tumor. Meanwhile, the ODNP showed strong NIR light absorption and significant antitumor efficacy both in vitro and in vivo as a PPT agent. The ODNP with excellent MRI contrasting capability and PTT efficacy plus its facile synthesis and good biocompatibility are a very promising theranostic agent for MRI-mediated PTT.

Real-time tracking for where (W), when (W), and how (H) prodrugs are delivered and activated in vivo is a great challenge for prodrug development. Disulfide linkage-based prodrugs as well as their delivery systems have been studied extensively, but the WWH question in spatial and temporal (spatiotemporal) precision remains unanswered. Herein, we present a novel prodrug of camptothecin (CPT) linked to a near-infrared (NIR) cyanine dye via a disulfide linkage (Cy-S-CPT). The cleavage of the disulfide bond in Cy-S-CPT by endogenous glutathione (GSH) can activate the anti-cancer drug CPT and induce a remarkable fluorescence shift from 825 to 650 nm, thereby providing dual fluorescent channels to real-time track the prodrug biodistribution and activation in vivo. Impressively, the dual-channel NIR fluorescence bioimaging exhibits the pervasive drug distribution, i.e., the biodistribution of the intact prodrug was traced at the 825 nm-NIR fluorescence channel, whereas the activated drug was tracked at the 650 nm red fluorescence channel. In this way, we can overcome the blind spot in the metabolism kinetics of prodrugs in a certain organ or tissue. As demonstrated, the prodrug prompts activation in all the organs, particularly in the liver after an intravenous injection, and achieves predominant accumulation and activation in tumors at 24 h post injection. Cy-S-CPT loaded in PEG–PLA nanoparticles display significantly improved therapeutic efficacy and low side effects with respect to the clinical used drug CPT-11. As a consequence, the NIR spatiotemporal bioimaging in vivo with dual fluorescence channels allows the prodrug release profile to be extracted precisely, particularly in visualizing drug-released information from complex biological systems such as mice, thereby providing a unique opportunity to take insight into the relationship between theranosis and pharmacokinetics.

•A magnetic and fluorescent dual-modal nanoprobe from a star-like polymer was synthesized.•The in vivo MRI enhanced by the probe could effectively delineate the boundary of tumor.•The probe had excellent tumor-targeting capability with the highest fluorescent intensity in tumor.The combination of magnetic resonance imaging (MRI) and fluorescent imaging with a dual-modal probe could exert the advantages of the two imaging techniques, simultaneously achieving high spatial resolution and sensitivity in tumor diagnosis. Herein, a magnetic and fluorescent dual-modal nanoprobe of ca. 8 nm was prepared through self-assembly of a star-like polymer comprising of porphyrin core, gadolinium chelate and solubilizing PEG. The probe did not show photodynamic therapy capability, but displayed strong red fluorescence with two emission peaks at 650 nm and 710 nm when excited at 585 nm, and the relaxation experiment indicated the probe had a longitudinal relaxivity (r1) of 7.1 mM−1 s−1, 1.6 times higher than that of small molecule contrast agent DTPA-Gd3+. The in vivo MRI and ex vivo fluorescent imaging experiments indicated that the probe had excellent tumor-targeting capability and could effectively delineate the boundary of tumor.A magnetic and fluorescent dual-modal nanoprobe from a star-like polymer comprising of porphyrin core, gadolinium chelate and solubilizing PEG.

The specific sizes that determine optimal nanoparticle tumor accumulation, penetration, and treatment remain inconclusive because many studies compared nanoparticles with multiple physicochemical variables (e.g., chemical structures, shapes, and other physical properties) in addition to the size. In this study, we synthesized amphiphilic block copolymers of 7-ethyl-10-hydroxylcamptothecin (SN38) prodrug and fabricated micelles with sizes ranging from 20 to 300 nm from a single copolymer. The as-prepared micelles had exactly the same chemical structures and similar physical properties except for size, which provided an ideal platform for a systematic investigation of the size effects in cancer drug delivery. We found that the micelle’s blood circulation time and tumor accumulation increased with the increase in their diameters, with optimal diameter range of 100 to 160 nm. However, the much higher tumor accumulation of the large micelles (100 nm) did not result in significantly improved therapeutic efficacy, because the large micelles had poorer tumor penetration than the small ones (30 nm). An optimal size that balances drug accumulation and penetration in tumors is critical for improving the therapeutic efficacy of nanoparticulate drugs.Keywords: 7-ethyl-10-hydroxylcamptothecin; cancer drug delivery; polymeric micelle; size effect; tumor penetration;

In vivo monitoring of the biodistribution and activation of prodrugs is urgently required. Near infrared (NIR) fluorescence-active fluorophores with excellent photostability are preferable for tracking drug release in vivo. Herein, we describe a NIR prodrug DCM-S-CPT and its polyethylene glycol–polylactic acid (PEG-PLA) loaded nanoparticles as a potent cancer therapy. We have conjugated a dicyanomethylene-4H-pyran derivative as the NIR fluorophore with camptothecin (CPT) as the anticancer drug using a disulfide linker. In vitro experiments verify that the high intracellular glutathione (GSH) concentrations in tumor cells cause cleavage of the disulfide linker, resulting in concomitantly the active drug CPT release and significant NIR fluorescence turn-on with large Stokes shift (200 nm). The NIR fluorescence of DCM-S-CPT at 665 nm with fast response to GSH can act as a direct off–on signal reporter for the GSH-activatable prodrug. Particularly, DCM-S-CPT possesses much better photostability than ICG, which is highly desirable for in situ fluorescence-tracking of cancer chemotherapy. DCM-S-CPT has been successfully utilized for in vivo and in situ tracking of drug release and cancer therapeutic efficacy in living animals by NIR fluorescence. DCM-S-CPT exhibits excellent tumor-activatable performance when intravenously injected into tumor-bearing nude mice, as well as specific cancer therapy with few side effects. DCM-S-CPT loaded in PEG-PLA nanoparticles shows even higher antitumor activity than free CPT, and is also retained longer in the plasma. The tumor-targeting ability and the specific drug release in tumors make DCM-S-CPT as a promising prodrug, providing significant advances toward deeper understanding and exploration of theranostic drug-delivery systems.

Optical near-infrared (NIR) nanomaterials provide a unique opportunity for applications in bioimaging and medical diagnosis. A kind of hydrophilic NIR fluorescent core–shell structured silica nanoparticle containing NIR cyanine chromophore, named as CyN-12@NHs, for in vivo bioimaging is developed through a facile one-pot strategy. The hydrophobic CyN-12 molecules can be successfully encapsulated into the core via the self-assembly of the amphiphilic block copolymer PS-b-PAA and subsequent shell cross-linking of silane. The as-prepared CyN-12@NHs exhibits typically spherical core–shell structure, which has a uniform size of 35 nm with a narrow size distribution, and excellent dispersity in aqueous solution. Moreover, NIR absorption (690 nm) and bright fluorescence (800 nm) of CyN-12@NHs with a large Stokes shift (110 nm) in aqueous system make it an amenable high quality bioimaging contrast agent. The core–shell nanostructure significantly enhances the chemical and photo-stability of CyN-12 via the encapsulation, which possesses a 50-times longer half-life period than free CyN-12, along with a better resistance to reactive oxygen species (ROS). Furthermore, in living cell imaging, CyN-12@NHs shows nearly no cytotoxicity and is able to outline the HepG2 cells. The in vivo imaging on a tumor-bearing mouse model indicates that CyN-12@NHs selectively accumulates in the liver after intravenous injection, and has a long retention in tumor after intra-tumor injection without decrease in fluorescence activity. Overall, the excellent photo-properties of CyN-12@NHs could meet the intricate requirements for tumor imaging, such as high sensitivity, sufficient tissue penetration, and high spatial resolution. The strategy of the silica–cyanine hybrid nanoparticles paves a desirable and efficient route to fabricate highly hydrophilic NIR fluorescent contrast agents for tumor imaging and therapy, especially with a breakthrough in photo-stability, bright fluorescence as well as large Stokes shift.

Highly sensitive and safe contrast agents (CAs) are essential for magnetic resonance imaging (MRI) to achieve accurate tumor detection and imaging. Dendrimer-based macromolecular MRI contrast agents are advantageous owing to their tumor-targeting ability, enhanced imaging contrast and enlarged imaging window. However, most of them have drawbacks of non-degradability and thereby long-term retention in body and toxicity. Herein, a tumor-targeting biodegradable dendritic CA (DCA) (FA-PEG-G2-DTPA-Gd) was prepared from a polyester dendrimer conjugated with gadolinium (Gd) chelates and PEG chains with distal folic acid. The DCA had a high longitudinal relaxivity up to 17.1 mM− 1 s− 1, 4 times higher than the clinically used CA Magnevist. The MRI contrasted by FA-PEG-G2-DTPA-Gd outlined the inoculated tumor more clearly, and had much higher contrast enhancement for a much longer time than Magnevist. More importantly, the biodegradable FA-PEG-G2-DTPA-Gd gave much less Gd retentions in all the organs or tissues than non-degradable DCAs. Thus, the high efficiency in MRI contrast enhancement and low Gd retention merit it a promising CA for contrast enhanced tumor MRI.A tumor-targeting biodegradable dendritic CA with high contrast enhancement in MRI of tumor and minimal long-term retention is prepared and evaluated in vivo.

Dendritic gadolinium chelates as magnetic resonance imaging (MRI) contrast agents (CAs) have shown great potential in blood pool and tumor imaging due to their enhanced relaxivities (R1s), prolonged blood circulation time, and homogeneous pharmaceutical properties. However, the non-biodegradability of the currently used dendrimers causes long-term retention of toxic gadolinium ions, limiting their clinical applications. Herein, we report a facile synthesis of biodegradable polyester dendrimer-based CAs. The prepared dendritic CAs have nano-sized structures with the hydrodynamic diameters ranging from 2.8 to 8.6 nm, and show high R1s up to 11.7 mM−1 s−1, approximately 2.7 times that of a clinically used small molecule CA (Magnevist). They are slowly hydrolyzed at an acidic pH, but rapidly hydrolyzed at pH 7.4, especially in the presence of esterase. The in vivo evaluation indicates they not only provide much better MRI contrast enhancement than Magnevist, but also show minimal tissue retention of Gd, which is much lower than those of non-biodegradable CAs.

A biodegradable tumor targeting nano-probe based on poly(ɛ-caprolactone)-b-poly(ethylene glycol) block copolymer (PCL-b-PEG) micelle functionalized with a magnetic resonance imaging (MRI) contrast agent diethylenetriaminepentaacetic acid-gadolinium (DTPA-Gd3+) on the shell and a near-infrared (NIR) dye in the core for magnetic resonance and optical dual-modality imaging was prepared. The longitudinal relaxivity (r1) of the PCL-b-PEGDTPA-Gd3+ micelle was 13.4 (mmol/L)−1s−1, three folds of that of DTPA-Gd3+, and higher than that of many polymeric contrast agents with similar structures. The in vivo optical imaging of a nude mouse bearing xenografted breast tumor showed that the dual-modality micelle preferentially accumulated in the tumor via the folic acid-mediated active targeting and the passive accumulation by the enhanced permeability and retention (EPR) effect. The results indicated that the dualmodality micelle is a promising nano-probe for cancer detection and diagnosis.

Metastasis is the main reason for cancer-associated mortality, and accurate diagnostic imaging of metastases is critical for the clinical administration and tailoring personalized treatments for metastatic tumors. However, magnetic resonance imaging of metastases in the liver is impeded by its low sensitivity because the currently used contrast agents accumulate in hepatocytes and Kupffer cells instead of cancer cells. Herein, a 4th generation zwitterionized biodegradable dendritic contrast agent (DCA) with a size of ca. 9 nm and a longitudinal relaxivity of 15.7 mM−1 s−1 in terms of Gd was synthesized and used to enhance the MRI of liver metastasis. The DCA could remarkably enhance the MRI of metastasized tumors in the liver, because it could simultaneously reduce the background signal in the liver by avoiding uptake by hepatocytes and Kupffer cells through the zwitterionization and increase the signal in tumors through the enhanced permeability and retention effect. Moreover, in contrast to non-biodegradable DCA, this DCA showed minimal long-term Gd3+ retention in all organs and tissues because it could be degraded into small fragments. The significant capability of enhancing the MRI of metastases in the liver plus its excellent biodegradability made this DCA a promising CA for metastatic tumor imaging.

Optical near-infrared (NIR) nanomaterials provide a unique opportunity for applications in bioimaging and medical diagnosis. A kind of hydrophilic NIR fluorescent core–shell structured silica nanoparticle containing NIR cyanine chromophore, named as CyN-12@NHs, for in vivo bioimaging is developed through a facile one-pot strategy. The hydrophobic CyN-12 molecules can be successfully encapsulated into the core via the self-assembly of the amphiphilic block copolymer PS-b-PAA and subsequent shell cross-linking of silane. The as-prepared CyN-12@NHs exhibits typically spherical core–shell structure, which has a uniform size of 35 nm with a narrow size distribution, and excellent dispersity in aqueous solution. Moreover, NIR absorption (690 nm) and bright fluorescence (800 nm) of CyN-12@NHs with a large Stokes shift (110 nm) in aqueous system make it an amenable high quality bioimaging contrast agent. The core–shell nanostructure significantly enhances the chemical and photo-stability of CyN-12 via the encapsulation, which possesses a 50-times longer half-life period than free CyN-12, along with a better resistance to reactive oxygen species (ROS). Furthermore, in living cell imaging, CyN-12@NHs shows nearly no cytotoxicity and is able to outline the HepG2 cells. The in vivo imaging on a tumor-bearing mouse model indicates that CyN-12@NHs selectively accumulates in the liver after intravenous injection, and has a long retention in tumor after intra-tumor injection without decrease in fluorescence activity. Overall, the excellent photo-properties of CyN-12@NHs could meet the intricate requirements for tumor imaging, such as high sensitivity, sufficient tissue penetration, and high spatial resolution. The strategy of the silica–cyanine hybrid nanoparticles paves a desirable and efficient route to fabricate highly hydrophilic NIR fluorescent contrast agents for tumor imaging and therapy, especially with a breakthrough in photo-stability, bright fluorescence as well as large Stokes shift.

Real-time tracking for where (W), when (W), and how (H) prodrugs are delivered and activated in vivo is a great challenge for prodrug development. Disulfide linkage-based prodrugs as well as their delivery systems have been studied extensively, but the WWH question in spatial and temporal (spatiotemporal) precision remains unanswered. Herein, we present a novel prodrug of camptothecin (CPT) linked to a near-infrared (NIR) cyanine dye via a disulfide linkage (Cy-S-CPT). The cleavage of the disulfide bond in Cy-S-CPT by endogenous glutathione (GSH) can activate the anti-cancer drug CPT and induce a remarkable fluorescence shift from 825 to 650 nm, thereby providing dual fluorescent channels to real-time track the prodrug biodistribution and activation in vivo. Impressively, the dual-channel NIR fluorescence bioimaging exhibits the pervasive drug distribution, i.e., the biodistribution of the intact prodrug was traced at the 825 nm-NIR fluorescence channel, whereas the activated drug was tracked at the 650 nm red fluorescence channel. In this way, we can overcome the blind spot in the metabolism kinetics of prodrugs in a certain organ or tissue. As demonstrated, the prodrug prompts activation in all the organs, particularly in the liver after an intravenous injection, and achieves predominant accumulation and activation in tumors at 24 h post injection. Cy-S-CPT loaded in PEG–PLA nanoparticles display significantly improved therapeutic efficacy and low side effects with respect to the clinical used drug CPT-11. As a consequence, the NIR spatiotemporal bioimaging in vivo with dual fluorescence channels allows the prodrug release profile to be extracted precisely, particularly in visualizing drug-released information from complex biological systems such as mice, thereby providing a unique opportunity to take insight into the relationship between theranosis and pharmacokinetics.