Cancer Theranostic Agents Research Articles

Two-Photon Excited FRET Dyads for Lysosome-Targeted Imaging and Photodynamic Therapy.

Two-photon excitable fluorescent dyes with integrated functions of targeted imaging and photodynamic therapy (PDT) are highly desired for the development of cancer theranostic agents. Herein, fluorescence resonance energy transfer (FRET) dyads, AceDAN-H2Por-Lyso (1a) and AceDAN-ZnPor-Lyso (1b), were developed for two-photon excited (TPE) lysosome-targeted fluorescence imaging and PDT of cancer cells. Under one-photon or two-photon excitation, the AceDAN donor can effectively transfer the excited state energy to the porphyrin acceptor via high efficient FRET, leading to the generation of deep-red fluorescence and singlet oxygen for cell imaging and PDT, respectively. 1a and 1b exhibit high photocytotoxicity and low dark cytotoxicity, in addition to strong lysosomal targeting capability in living cells. By taking the advantages of the two-photon absorption properties of the AceDAN donor and the properly distributed S1 and T1 states of the porphyrin acceptor, the AceDAN-porphyrin dyads 1a and 1b have been successfully applied to TPE-fluorescence imaging for tracking the significant morphology changes of cancer cells under two-photon laser irradiation.

Biocompatible semiconducting polymer nanoparticles as robust photoacoustic and photothermal agents revealing the effects of chemical structure on high photothermal conversion efficiency

Understanding the relationship between polymer chemical structure and its performance of photoacoustic imaging (PAI) and photothermal therapy (PTT) is important for developing ideal PAI/PTT agents. In this report, four semiconducting polymer nanoparticles (SPNs) with different donor-acceptor architectures are self-assembled for highly effective PAI-guided PTT. In particular, SPN1 with the longest π-conjugation length and the highest mass extinction coefficient which are beneficial for intramolecular charge transfer as well as light harvesting, exhibits the highest photothermal conversion efficiency up to 52.6%. Moreover, the as-prepared SPN1 possess good water-dispersibility, robust size-stability and excellent photothermal properties. Furthermore, the SPN1 not only exhibits a remarkable cancer cell-killing ability but also shows a prominent tumor inhibition capacity. Finally, the as-prepared water-dispersible SPN1 displays good biocompatibility and biosafety, making it a promising candidate for future biomedical applications. Considering the plenty of near-infrared absorbing semiconducting polymer available, our work provides fundamental insights for rational design and preparation of highly efficient SPN-based PAI/PTT agents for cancer theranostics.

Myeloid‐Derived Suppressor Cell Membrane‐Coated Magnetic Nanoparticles for Cancer Theranostics by Inducing Macrophage Polarization and Synergizing Immunogenic Cell Death

AbstractA major challenge for traditional cancer therapy, including surgical resection, chemoradiotherapy, and immunotherapy, is how to induce tumor cell death and leverage the host immune system at the same time. Here, a myeloid‐derived suppressor cell (MDSC) membrane‐coated iron oxide magnetic nanoparticle (MNP@MDSC) to overcome this conundrum for cancer therapy is developed. In this study, MNP@MDSC demonstrates its superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, and photothermal therapy (PTT)‐induced tumor killing. Compared with red blood cell membrane‐coated nanoparticles (MNPs@RBC) or naked MNPs, MNP@MDSCs are much more effective in active tumor‐targeting, a beneficial property afforded by coating MNP with membranes from naturally occurring MDSC, thus converting the MNP into “smart” agents that like to accumulate in tumors as the source MDSCs. Once targeted to the tumor microenvironment, MNPs@MDSC can act as a PTT agents for enhanced antitumor response by inducing immunogenic cell death, reprogramming the tumor infiltrating macrophages, and reducing the tumor's metabolic activity. These benefits, in combination with the excellent biocompatibility and pharmacological kinetics characteristics, make MNP@MDSC a promising, multimodal agent for cancer theranostics.

Self-Quenched Metal-Organic Particles as Dual-Mode Therapeutic Agents for Photoacoustic Imaging-Guided Second Near-Infrared Window Photochemotherapy.

The nanosized metal-organic particles (NMOPs) recently have attracted tremendous attentions in biomedical applications. However, few studies have developed metal-organic nanoparticles (NMOPs) as near-infrared (NIR) II phototherapeutic agents and as Fenton-like agents for cancer theranostics. Herein, directly using organic dye and Cu(II)-ion complexes to construct NMOPs, as dual-mode therapeutic agent for PA imaging-guided photochemotherapy in NIR II window, is reported. The NMOPs are simply an assembly of Cu(II) ion and tetrahydroxyanthraquinone (THQ) complexes [Cu(II)-THQ] n through the coordination effect, van der Waals force, and π-π interactions. After modification of polyethylene glycol (PEG-(NH2)2), the obtained Cu-THQNPs endow excellent biocompatibility and stability in physiological conditions. Because of the strong absorption at NIR II window and photoinduced electrontransfer (PET) mechanism, the Cu-THQNPs not only acted as an excellent photothermal agent with extremely high light-to-heat conversion ability (51.34%) at 1064 nm for phototherapy but also explored as the PA contrast agent for precisely tracking and guiding the therapy in vivo. Most strikingly, our Cu-THQNPs can be degraded by tumor-specific acidic-cleaving of the coordination bonds and follow by the slow release of Cu(II) into tumors, which can act as Fenton-like agents to generate •OH from H2O2 for enhancing the antitumor efficacy in vivo. With almost 100% prevention of the tumor growth for ca. 14 days and no obvious toxicity based on blood biochemical/histological analysis, this work highlights the Cu-THQNPs as an efficient NIR II therapeutic agent for precise cancer theranostics.

SERS Signal Enhancement of Methylene Blue‐embedded Agglomerated Gold Nanorod@SiO2 Core@Shell Composites

In medical science, Raman spectroscopy has received considerable attention as the next noninvasive diagnostic imaging technique. However, its clinical applications are limited by the weak signal intensities of Raman active molecules. Previously, we showed that a methylene‐blue‐loaded gold nanorod@silica (MB‐GNR@SiO2) core@shell nanostructure is promising for the development of a cancer theranostic agent due to its excellent surface‐enhanced Raman scattering (SERS) performance and synergistic cancer‐destroying efficacy. In this study, we successfully synthesized MB‐embedded agglomerated gold nanorod@SiO2 (MB‐A.GNR@SiO2) composites, in which the many interparticle junctions created by the agglomerated GNRs were able to enhance the SERS signal of the loaded MB by a factor of five compared to MB‐GNR@SiO2. This high SERS performance of the present MB‐A.GNR@SiO2 could provide us with an approach to explore a rapid and ultra‐sensitive SERS detection method for various biological molecules.

Graphene Oxide/ZnS:Mn Nanocomposite Functionalized with Folic Acid as a Nontoxic and Effective Theranostic Platform for Breast Cancer Treatment.

Nanoparticle-based cancer theranostic agents generally suffer of poor dispersability in biological media, re-agglomeration over time, and toxicity concerns. To address these challenges, we developed a nanocomposite consisting of chemically-reduced graphene oxide combined with manganese-doped zinc sulfide quantum dots and functionalized with folic acid (FA-rGO/ZnS:Mn). We studied the dispersion stability, Doxorubicin (DOX) loading and release efficiency, target specificity, internalization, and biocompatibility of FA-rGO/ZnS:Mn against folate-rich breast cancer cells, and compared to its uncoated counterpart (rGO/ZnS:Mn). The results indicate that DOX is adsorbed on the graphene surface via π–π stacking and hydrophobic interaction, with enhanced loading (~35%) and entrapment (~60%) efficiency that are associated to the chelation of DOX and surface Zn2+ ions. DOX release is favored under acidic conditions reaching a release of up to 95% after 70 h. Membrane integrity of the cells assessed by Lactate dehydrogenase (LDH) release indicate that the surface passivation caused by folic acid (FA) functionalization decreases the strong hydrophobic interaction between the cell membrane wall and the edges/corners of graphene flakes. Chemotherapeutic effect assays reveal that the cancer cell viability was reduced up to ~50% at 3 µg/mL of DOX-FA-rGO/ZnS:Mn exposure, which is more pronounced than those obtained for free DOX at the same doses. Moreover, DOX-rGO/ZnS:Mn did not show any signs of toxicity. An opposite trend was observed for cells that do not overexpress the folate receptors, indicating that FA functionalization endows rGO/ZnS:Mn with an effective ability to discriminate positive folate receptor cancerous cells, enhancing its drug loading/release efficiency as a compact drug delivery system (DDS). This study paves the way for the potential use of functionalized rGO/ZnS:Mn nanocomposite as a platform for targeted cancer treatment.

N-(2-hydroxypropyl)methacrylamide polymer conjugated pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising therapeutic strategy for cancer treatment. In this study, we synthesized a pHPMA conjugated pyropheophorbide-a (P-PyF) as a cancer theranostic agent for PDT and photodynamic diagnostics (PDD). Pyropheophorbide-a has one carboxyl group which was conjugated to pHPMA via amide bond yielding the intended product with high purity. In aqueous solutions, P-PyF showed a mean particle size of ∼200 nm as it forms micelle which exhibited fluorescence quenching and thus very little singlet oxygen (1O2) production. In contrast, upon disruption of micelle strong fluorescence and 1O2 production were observed. In vitro study clearly showed the PDT effect of P-PyF. More potent 1O2 production and PDT effect were observed during irradiation at ∼420 nm, the maximal absorbance of pyropheophorbide-a, than irradiation at longer wavelength (i.e., ∼680 nm), suggesting selection of proper absorption light is essential for successful PDT. In vivo study showed high tumor accumulation of P-PyF compared with most of normal tissues due to the enhanced permeability and retention (EPR) effect, which resulting in superior antitumor effect under irradiation using normal xenon light source of endoscope, and clear tumor imaging profiles even in the metastatic lung cancer at 28 days after administration of P-PyF. On the contrary irradiation using long wavelength (i.e., ∼680 nm), the lowest Q-Band, exhibited remarkable tumor imaging effect with little autofluorescence of background. These findings strongly suggested P-PyF may be a potential candidate-drug for PDT/PDD, particularly using two different wavelength for treatment and detection/imaging, respectively.

Synthesis and Biological Evaluations of Organoruthenium Scaffolds: A Comprehensive Update

Background: Currently ruthenium complexes are immerging as effective anticancer agents due to their less toxicity, better antiproliferative and antimetastatic activity, better stability in cellular environment and most importantly variable oxidation and co-ordination states of ruthenium allows binding this molecule with a variety of ligands. So in past few years researchers have shifted their interest towards organoruthenium complexes having good fluorescent profile that may be applicable for cancer theranostics. Nowadays, photodynamic therapy has become more acceptable because of its easy and effective approach towards killing cancer cells. Objective: Objective of this review article is to shed light on synthesis, characterization, stability and fluorescence studies of various ruthenium [Ru(II) and Ru(III)] complexes and different bioactivity studies conducted with the synthesized compounds to test their candidacy as potent chemotherapeutic agents. Methods: Various heterocyclic ligands containing N,O and S as heteroatom mainly were prepared and subjected to complexation with ruthenium-p-cymene moiety. In most cases [Ru(η6-p-cymene)(µ-Cl)Cl]2 was used as ruthenium precursor and the reactions were conducted in various alcohol medium such as methanol, ethanol or propanol. The synthesized complexes were characterized by 1H NMR and 13C NMR spectroscopy, GC-MS, ESI-MS, elemental analysis and single crystal X-ray crystallography methods. Fluorescence study and stability study were conducted accordingly using water, PBS buffer or DMSO. Stable compounds were considered for cell viability studies. To study the efficacy of the compounds in ROS generation as photosensitizers, in few cases, singlet oxygen quantum yields in presence of light were calculated. Suitable compounds were selected for in vitro & in vivo antiproliferative, anti-invasive activity studies. Result: Many newly synthesized compounds were found to have less IC50 compared to a standard drug cysplatin. Those compounds were also stable preferably in physiological conditions. Good fluorescence profile and ROS generation ability were observed for few compounds. Conclusion: Numerous ruthenium complexes were developed which can be used as cancer theranostic agents. Few molecules were synthesized as photosensitizers which were supposed to generate reactive singlet oxygen species in targeted cellular environment in presence of a particular type of light and thereby ceasing cancer cell growth.

Metallic Nanoclusters for Cancer Imaging and Therapy.

Nanoclusters are made of a few to tens of atoms with a size below 2 nm. Compared with nanoparticles, they exhibited excellent properties, such as tunable fluorescence, ease of conjugation, high quantum yield and biocompatibility, which are highly desired in the development of cancer nanotheranostics. Hence, the metallic nanoclusters have emerged as a newcomer in cancer nanomedicines. This review aims to summarize recently developed approaches to preparing metallic nanoclusters, highlight their applications in cancer theranostics, and provide a brief outlook for the future developments of nanoclusters in nanomedicine. We carried out a thorough literature search using online databases. The search was focused on a centered question. Irrelevant articles were excluded after further examination and directly relevant articles were included. The relevant articles were classified by the subjects and the information from these articles was synthesized. One hundred and forty-three articles were included in this review. About eighty articles outlined the development in the synthetic methods of nanoclusters. The synthesis approaches include chemical reduction, photoreduction and so on. The progress in the application of gold and silver nanoclusters to cancer theranostics was described in fifteen and eight articles, respectively. The rest articles were about the advancements in the use of other metal nanoclusters and nanocluster nanocomposites as cancer theranostic agents. This review summarizes the synthesis and use of metallic nanoclusters or their nanocomposites as cancer theranostic agents. It confirms their importance, advantages and potentials in serving as a new generation of cancer theranostics in clinics.

Multifunctional fluorescent titania nanoparticles: green preparation and applications as antibacterial and cancer theranostic agents

Theranostic nanoparticles have attracted considerable attention in recently revolutionized medicine. Since the last decade, there has been a growing attempt to design various theranostic nanoparticles but difficulties still exist in the fabrication of their biocompatible one. Herein, fluorescent titania nanoparticles (FTN) were fabricated using a one-step green method. This FTN had ultra-high doxorubicin hydrochloride (DOX) loading capacity (encapsulation efficiency 95.50% and loading content 38.20%) that release the loaded drug in response to acidic pH. In vitro cytotoxicity experiments on human osteosarcoma (SaOs-2) and breast cancer (MCF-7) cell lines revealed superior anticancer efficacy (lowered the IC50 concentration by 3- and 5.5-fold for SaOs-2 and MCF-7 cells, respectively) and also better imaging for intracellular tracking of DOX/FTN relative to free DOX. Furthermore, the prepared nanoparticles showed efficient antibacterial activity against both gram-negative (Escherichia coli ATCC 25922) and gram-positive (Staphylococcus aureus ATCC 25923) bacteria. In this study, we have developed novel theranostic titania nanoparticles with inherent fluorescence property for cancer imaging and therapy.

MHI-148 Cyanine Dye Conjugated Chitosan Nanomicelle with NIR Light-Trigger Release Property as Cancer Targeting Theranostic Agent.

Paclitaxel (PTX) loaded hydrophobically modified glycol chitosan (HGC) micelle is biocompatible in nature, but it requires cancer targeting ability and stimuli release property for better efficiency. To improve tumor retention and drug release characteristic of HGC-PTX nanomicelles, we conjugated cancer targeting heptamethine dye, MHI-148, which acts as an optical imaging agent, targeting moiety and also trigger on-demand drug release on application of NIR 808nm laser. The amine group of glycol chitosan modified with hydrophobic 5β-cholanic acid and the carboxyl group of MHI-148 were bonded by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide chemistry. Paclitaxel was loaded to MHI-HGC nanomicelle by an oil-in-water emulsion method, thereby forming MHI-HGC-PTX. Comparison of near infrared (NIR) dyes, MHI-148, and Flamma-774 conjugated to HGC showed higher accumulation for MHI-HGC in 4T1 tumor and 4T1 tumor spheroid. In vitro studies showed high accumulation of MHI-HGC-PTX in 4T1 and SCC7 cancer cell lines compared to NIH3T3 cell line. In vivo fluorescence imaging of the 4T1 and SCC7 tumor showed peak accumulation of MHI-HGC-PTX at day 1 and elimination from the body at day 6. MHI-HGC-PTX showed good photothermal heating ability (50.3°C), even at a low concentration of 33μg/ml in 1W/cm2 808nm laser at 1min time point. Tumor reduction studies in BALB/c nude mice with SCC7 tumor showed marked reduction in MHI-HGC-PTX in the PTT group combined with photothermal therapy compared to MHI-HGC-PTX in the group without PTT. MHI-HGC-PTX is a cancer theranostic agent with cancer targeting and optical imaging capability. Our studies also showed that it has cancer targeting property independent of tumor type and tumor reduction property by combined photothermal and chemotherapeutic effects.

Nano-sized Ultrasound Contrast Agents for Cancer Therapy and Theranostics.

Ultrasound contrast agents (UCA) represented by gas-filled microbubble, can provide simultaneous and co-localized enhancement on image contrast to help disease diagnosis by highlighting tissue borders. Nowadays, Some UCAs (e.g. Levovist®, Optison®, Definity®, and Sonovue®) are commercially available, and have been clinically utilized for enhanced ultrasonography in the US, Canada, Europe, Asia and so on. However, their large diameters (1~10 µm) mainly hinder more precise and deeper applications in the imaging of capillaryabundant organs or tissues (e.g. tumor), and undersized nanoscale UCAs also lack enough backscattering echo intensity to distinguish abnormal distribution of vessels. So novel shapes, structures and materials of nano-sized UCAs are constantly emerging for cancer ultrasonic imaging. Particularly, the cavitation effect of diagnostic ultrasound can accelerate effusion of loaded contents from UCAs, following cellular uptake. This will inevitably contribute to develop other potential applications of nano-sized UCAs towards cancer therapy and theranostics.

Shape-, size- and structure-controlled synthesis and biocompatibility of iron oxide nanoparticles for magnetic theranostics.

In the past decade, iron oxide nanoparticles (IONPs) have attracted more and more attention for their excellent physicochemical properties and promising biomedical applications. In this review, we summarize and highlight recent progress in the design, synthesis, biocompatibility evaluation and magnetic theranostic applications of IONPs, with a special focus on cancer treatment. Firstly, we provide an overview of the controlling synthesis strategies for fabricating zero-, one- and three-dimensional IONPs with different shapes, sizes and structures. Then, the in vitro and in vivo biocompatibility evaluation and biotranslocation of IONPs are discussed in relation to their chemo-physical properties including particle size, surface properties, shape and structure. Finally, we also highlight significant achievements in magnetic theranostic applications including magnetic resonance imaging (MRI), magnetic hyperthermia and targeted drug delivery. This review provides a background on the controlled synthesis, biocompatibility evaluation and applications of IONPs as cancer theranostic agents and an overview of the most up-to-date developments in this area.

A novel core-shell structured upconversion nanorod as a multimodal bioimaging and photothermal ablation agent for cancer theranostics.

A multifunctional core-shell nanocomposite based on noble metal plasmons coated with upconversion material has emerged as a promising cancer theranostics nanoplatform that integrates properties such as multimodal imaging, photothermal effects, good biocompatibility, and efficient therapy. However, a reasonable combination of plasmons and upconversion materials, as well as increased penetration depth, has always challenged the anti-cancer efficiency. Here, a unique kind of fluorescent thermal-magnetic resonance core-shell upconversion nanostructure has been designed and fabricated to simultaneously achieve photothermal therapy (PTT) and multimodal imaging. Gold nanorods (GNRs) are used as the plasmon cores and NaGdF4 with rare-earth Yb3+/Er3+ ions co-doping are used as the upconversion luminescence (UCL) shells, merging into upconversion nanorods (UCNRs) of GNRs@NaGdF4:Yb3+,Er3+. An NaGdF4 shell synthesized by a hydrothermal method can substitute for the cetyltrimethylammonium bromide (CTAB) on the surface of GNRs, which offers the benefits of reducing toxicity and increasing biocompatibility. More significantly, the red and green emission of Yb3+/Er3+ couples convert near-infrared (NIR) into visible light, appropriately overlapping with absorbance of GNRs, which improves the photothermal conversion efficiency. Meanwhile, we designed small and low-aspect-ratio GNR cores for the absorption of UCNRs in vivo. Verification with evidence from in vivo and in vitro assays shows that these core-shell UCNRs exhibit a talented potential application in multimodal bioimaging and PTT.

Ultrafast synthesis of ultrasmall polyethylenimine-protected AgBiS2 nanodots by "rookie method" for in vivo dual-modal CT/PA imaging and simultaneous photothermal therapy.

Developing a biocompatible nanotheranostic platform integrating diagnostic and therapeutic functions is a great prospect for cancer treatment. However, it is still a great challenge to synthesize nanotheranostic agents using an ultra-facile method. In the research reported here, ultrasmall polyethylenimine-protected silver bismuth sulfide (PEI-AgBiS2) nanodots were successfully synthesized using an ultra-facile and environmentally friendly strategy (1 min only at room temperature), which could be described as a "rookie method". PEI-AgBiS2 nanodots show good monodispersity and biocompatibility. For the first time, PEI-AgBiS2 nanodots were reported as a powerful and safe nanotheranostic agent for cancer treatment. PEI-AgBiS2 nanodots exhibit excellent computed tomography (CT) and photoacoustic (PA) dual-modal imaging ability, which could effectively guide photothermal cancer therapy. Furthermore, PEI-AgBiS2 nanodots exhibit a high photothermal conversion efficiency (η = 35.2%). The photothermal therapy (PTT) results demonstrated a highly efficient tumor ablation ability. More importantly, the blood biochemistry and histology analyses verify that the PEI-AgBiS2 nanodots have negligible long-term toxicity. This work highlights that PEI-AgBiS2 nanodots produced using this extremely effective method are a high-performance and safe PTT agent. These findings open a new gateway for synthesizing nanotheranostic agents by using this ultra-facile method in the future.

Disintegrable NIR Light Triggered Gold Nanorods Supported Liposomal Nanohybrids for Cancer Theranostics.

In this work, facile synthesis and application of targeted, dual therapeutic gold nanorods-liposome (GNR-Lipos) nanohybrid for imaging guided photothermal therapy and chemotherapy is investigated. The dual therapeutic GNR-Lipos nanohybrid consists of GNR supported, and doxorubicin (DOX) loaded liposome. GNRs not only serve as a photothermal agent and increase the drug release in intracellular environment of cancer cells, but also provide mechanical strength to liposomes by being decorated both inside and outside of bilayer surfaces. The designed nanohybrid shows a remarkable response for synergistic chemophotothermal therapy compared to only chemotherapy or photothermal therapy. The NIR response, efficient uptake by the cells, disintegration of GNR-Lipos nanohybrid, and synergistic therapeutic effect of photothermal and chemotherapy over breast cancer cells MDA-MB-231 are studied for the better development of a biocompatible nanomaterial based multifunctional cancer theranostic agent.

Amberlite IR-120 (H) mediated “on water” synthesis of fluorescent Ruthenium(II)-arene 8-hydroxyquinoline complexes for cancer therapy and live cell imaging

A series of Ruthenium-Quinolinol complexes (3a–d &4a–d) has been synthesized by employing a simple, efficient and environmental friendly condition. Catalytic role of Amberlite IRA-120(H) has been demonstrated. The structures of the new compounds were elucidated by the analysis of spectroscopic data. The stability of these complexes was measured by UV spectroscopy & time dependent NMR spectroscopy. These newly developed complexes were represented as potential anticancer agent against human breast carcinoma cell line (MCF-7), human Epitheloid Cervix Carcinoma (HeLa), human lung adenocarcinoma epithelial cell line (A549) and human colon cancer cell line (Caco-2). Most of the ruthenium complexes showed higher anticancer activity in MCF-7, HeLa and Caco-2 cell lines than cisplatin. A high selectivity (9–28 folds) was observed with these newly developed organoruthenium compounds in human cancer cell lines (MCF-7, HeLa and Caco-2) with respect to normal fibroblast cell line (MRC-5). Complex [(η6-hexamethylbenzene)RuCl(κ2-O,N-5-chloro-HyQ)]·Cl (4b), [(η6-hexamethylbenzene)RuCl(κ2-O,N-5,7-dibromo-HyQ)]·Cl (4c) and [(η6-hexamethylbenzene)RuCl(κ2-O,N-5-chloro-7-iodo-HyQ)]·Cl (4d) exhibited best cytotoxicity profiles in three reported human cancer cell lines (MCF-7, HeLa, Caco-2). Cellular imaging study was also performed with these newly developed organoruthenium compounds. Compound 4c might be utilized for cancer theranostic agents because of its significant quantum yield in water, high potency, selectivity and high cellular uptake in cancer cell lines.

Structure-Guided Design and Synthesis of a Mitochondria-Targeting Near-Infrared Fluorophore with Multimodal Therapeutic Activities.

An urgent challenge for imaging-guided disease-targeted multimodal therapy is to develop the appropriate multifunctional agents to meet the requirements for potential applications. Here, a rigid cyclohexenyl substitution in the middle of a polymethine linker and two asymmetrical amphipathic N-alkyl side chains to indocyanine green (ICG) (the only FDA-approved NIR contrast agent) are introduced, and a new analog, IR-DBI, is developed with simultaneous cancer-cell mitochondrial targeting, NIR imaging, and chemo-/PDT/PTT/multimodal therapeutic activities. The asymmetrical and amphipathic structural modification renders IR-DBI a close binding to albumin protein site II to form a drug-protein complex and primarily facilitates its preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. The released IR-DBI dye is further actively taken up by cancer cells through organic-anion-transporting polypeptide transporters, and the lipophilic cationic property leads to its selective accumulation in the mitochondria of cancer cells. Finally, based on the high albumin-binding affinity, IR-DBI is modified into human serum albumin (HSA) via self-assembly to produce a nanosized complex, which exhibits significant improvement in the cancer targeting and multimodal cancer treatment with better biocompatibility. This finding may present a practicable strategy to develop small-molecule-based cancer theranostic agents for simultaneous cancer diagnostics and therapeutics.

Multifunctional Small Molecule Fluorophore for Long‐Duration Tumor‐Targeted Monitoring and Dual Modal Phototherapy

In this work, a specific tumor‐targeted small molecular fluorophore for synchronous long‐duration cancer imaging, photodynamic therapy, and photothermal therapy is synthesized. This novel fluorophore exhibits specific targeting ability in certain tumors (U87MG, MDA‐MB‐231, A549, etc.) based on its inherent structure and efficiently generates local hyperthermia and reactive oxygen species simultaneously for imaging‐guided precise cancer therapy combining the photothermic and photodynamic effects under laser irradiation. Meanwhile, compared to traditional near infrared fluorophore, this novel fluorophore with significantly enhanced stability against photobleaching can prolong the time of tumor imaging and improve the phototherapy efficiency. This work presents a potential strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.

SPION loaded poly(L-lysine)/hyaluronic acid micelles as MR contrast agent and gene delivery vehicle for cancer theranostics

In this work we evaluated the ability of a SPION (Superparamagnetic iron oxide nanoparticle) loaded micelle system to safely and efficiently transfer foreign DNA into cells with the help of poly(L-lysine) (PLL) as DNA-carrier. Average particle size of PLL coated hyaluronic acid (HA) loaded SPION (PLL-HA-SPION) micelle was approximately 200 nm in size with spherical morphology. PLL-HA-SPION micelle was found to be nontoxic to the NIH3T3 (murine fibroblast cells) and the in vitro uptake was also tested in CT-26 (murine colon cancer cells) by prussian blue staining. Agarose gel retardation study showed the efficient binding of PLL-HA-SPION micelle with plasmid DNA (pLuc). The formed PLL-HA-SPION/pLuc complex could be efficiently transfected into CT-26 cell line. Finally, MR imaging was also used to check uptake property of SPION loaded in PLL-HA-SPION/DNA complex in vitro. The result showed that the PLL-HA-SPION micelle can be applied to MR imagingguided gene therapy in vivo and it is also advantageous for using this system for the magnetic hyperthermia based cancer therapy.