Multifunctionalized biocatalytic P22 nanoreactor for combinatory treatment of ER+ breast cancer.

BACKGROUND: Tamoxifen is the standard endocrine therapy for breast cancers, which require metabolic activation by cytochrome P450 enzymes (CYP). However, the lower and variable concentrations of CYP activity at the tumor remain major bottlenecks for the efficient treatment, causing severe side-effects. Combination nanotherapy has gained much recent attention for cancer treatment as it reduces the drug-associated toxicity without affecting the therapeutic response. RESULTS: Here we show the modular design of P22 bacteriophage virus-like particles for nanoscale integration of virus-driven enzyme prodrug therapy and photodynamic therapy. These virus capsids carrying CYP activity at the core are decorated with photosensitizer and targeting moiety at the surface for effective combinatory treatment. The estradiol-functionalized nanoparticles are recognized and internalized into ER+ breast tumor cells increasing the intracellular CYP activity and showing the ability to produce reactive oxygen species (ROS) upon UV365 nm irradiation. The generated ROS in synergy with enzymatic activity drastically enhanced the tamoxifen sensitivity in vitro, strongly inhibiting tumor cells. CONCLUSIONS: This work clearly demonstrated that the targeted combinatory treatment using multifunctional biocatalytic P22 represents the effective nanotherapeutics for ER+ breast cancer.

Development of a functionalized UV-emitting nanocomposite for the treatment of cancer using indirect photodynamic therapy.

BACKGROUND: Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y2.99Pr0.01Al5O12-based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. RESULTS: A YP nanophosphor core was synthesized using the sol-gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptorFolr1, validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. CONCLUSION: Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface.

Functionalized rare earth-doped nanoparticles for breast cancer nanodiagnostic using fluorescence and CT imaging.

BACKGROUND: Breast cancer is the second leading cause of cancer death among women and represents 14% of death in women around the world. The standard diagnosis method for breast tumor is mammography, which is often related with false-negative results leading to therapeutic delays and contributing indirectly to the development of metastasis. Therefore, the development of new tools that can detect breast cancer is an urgent need to reduce mortality in women. Here, we have developed Gd2O3:Eu3+ nanoparticles functionalized with folic acid (FA), for breast cancer detection. RESULTS: Gd2O3:Eu3+ nanoparticles were synthesized by sucrose assisted combustion synthesis and functionalized with FA using EDC-NHS coupling. The FA-conjugated Gd2O3:Eu3+ nanoparticles exhibit strong red emission at 613 nm with a quantum yield of ~ 35%. In vitro cytotoxicity studies demonstrated that the nanoparticles had a negligible cytotoxic effect on normal 293T and T-47D breast cancer cells. Cellular uptake analysis showed significantly higher internalization of FA-conjugated RE nanoparticles into T-47D cells (Folr hi ) compared to MDA-MB-231 breast cancer cells (Folr lo ). In vivo confocal and CT imaging studies indicated that FA-conjugated Gd2O3:Eu3+ nanoparticles accumulated more efficiently in T-47D tumor xenograft compared to the MDA-MB-231 tumor. Moreover, we found that FA-conjugated Gd2O3:Eu3+ nanoparticles were well tolerated at high doses (300 mg/kg) in CD1 mice after an intravenous injection. Thus, FA-conjugated Gd2O3:Eu3+ nanoparticles have great potential to detect breast cancer. CONCLUSIONS: Our findings provide significant evidence that could permit the future clinical application of FA-conjugated Gd2O3:Eu3+ nanoparticles alone or in combination with the current detection methods to increase its sensitivity and precision.

Synthesis and optimization of photothermal properties of NIR emitting LiGa5O8: Cr3+ and gold nanorods as hybrid materials for theranostic applications.

The increase in incidence of degenerative diseases has fueled the development of novel materials, mostly focused on reducing adverse effects caused by current medical therapies. Theranostic materials represent an alternative to treat degenerative diseases, since they combine diagnostic properties and localized therapy within the same material. This work presents the synthesis and characterization of hybrid materials designed for theranostic purposes. The hybrid materials were composed of LiGa5O8:Cr3+ (LGO) with emission lines in the near infrared (NIR), hence providing an excellent diagnostic ability. As for the therapy part, the hybrid nanomaterials contained gold nanorods (AuR) with localized surface plasmon resonance (LSPR). Once AuR are excited, plasmonic processes are triggered at their surface resulting in increased localized temperature capable of inducing irreversible damage to the cells. A detailed characterization of the hybrid materials confirmed proper assembly of LGO and AuR. Moreover, these nanocomposites preserved their luminescent properties and LSPR. Finally, the cytotoxic potential of the hybrid material was evaluated in different cell lines by cell viability colorimetric assays to determine its possible use as theranostic agent. The success in the synthesis of hybrid materials based on LGO with emission in the NIR coupled with AuR, provides a new perspective for the design of hybrid materials with improved properties to be used in biomedical fields.

Progress on carbon dots and hydroxyapatite based biocompatible luminescent nanomaterials for cancer theranostics.

Despite the significant advancement in cancer diagnosis and therapy, a huge burden remains. Consequently, much research has been diverted on the development of multifunctional nanomaterials for improvement in conventional diagnosis and therapy. Luminescent nanomaterials offer a versatile platform for the development of such materials as their intrinsic photoluminescence (PL) property offers convergence of diagnosis as well as therapy at the same time. However, the clinical translation of nanomaterials faces various challenges, including biocompatibility and cost-effective scale up production. Thus, luminescent materials with facile synthesis approach along with intrinsic biocompatibility and anticancerous activity hold significant importance. As a result, carbon dots (CDs) and nanohydroxyapatite (nHA) have attracted much attention for the development of optical imaging probes. CDs are the newest members of the carbonaceous nanomaterials family that possess intrinsic luminescent and therapeutic properties, making them a promising candidate for cancer theranostic. Additionally, nHA is an excellent bioactive material due to its compositional similarity to the human bone matrix. The nHA crystal can efficiently host rare-earth elements to attain luminescent property, which can further be implemented for cancer theranostic applications. Herein, the development of CDs and nHA based nanomaterials as multifunctional agents for cancer has been briefly discussed. The emphasis has been given to different synthesis strategies leading to different morphologies and tunable PL spectra, followed by their diverse applications as biocompatible theranostic agents. Finally, the review has been summarized with the current challenges and future perspectives.

Camouflaged, activatable and therapeutic tandem bionanoreactors for breast cancer theranosis.

The one-pot cascade reaction of naturally occurring enzymes is exciting for highly selective complex reaction and biodegradable approaches. Tamoxifen is the main drug against breast cancer for decades and induces an anticancerous effect upon metabolic activation by cytochrome P450 (CYP450). Herein, bi-enzymatic nanoreactors (NRs) are developed as a multimodality platform for smart action against breast tumors. CYPBM3 of Bacillus magaterium (CYP) is co-confined with glucose oxidase (GOx) where GOx produces H2O2 in the presence of glucose that elicits the CYP-mediated transformation of tamoxifen. The scintillating and mesoporous LaF3:Tb as nanocarrier showed advantages like a wide range of pore size and positive surface charge for efficient loading of enzyme couple, while the smallest pores were available for substrate/product diffusion. The obtained NRs were camouflaged with human serum albumin (HSA) to overcome premature enzyme leaching and provide active stealth properties. The nanocomposite was characterized for physicochemical properties and glucose-mediated sequential catalysis. The in vitro studies demonstrated the cell internalization of NRs in both ER+ and triple-negative breast cancer cell lines and showed significant cytotoxicity. The developed NRs not only improve the outcomes of endocrine therapy in ER+ cells but also synergistically act with oxidation therapy for enhanced therapeutic effect. Importantly, inhibition of triple-negative cells was also achieved. Thus, the development of the new multimodal nanomedicine of the present work should afford new tools towards the theranosis of breast cancer with minimized adverse effects.

Dual-photosensitizer coupled nanoscintillator capable of producing type I and type II ROS for next generation photodynamic therapy.

The current photodynamic therapy (PDT) is majorly hindered by the shallow penetration depth and oxygen dependency, limiting its application to deep-seated solid hypoxic tumors. Thus, it is meaningful to develop efficient X-ray mediated PDT system capable of generating reactive oxygen species (ROS) under both the normoxic and hypoxic conditions. Herein, we report the synthesis and characterization of nanocomposite, YAG:Pr@ZnO@PpIX with an amalgamation of UV-emitting Y2.99Pr0.01Al5O12 (YAG:Pr) nanoscintillator, and zinc oxide (ZnO) and protoporphyrin IX (PpIX) as photosensitizers. YAG:Pr surface was coated with a ZnO layer (∼10 nm) by atomic layer deposition, and then PpIX was covalently conjugated via a linker to give YAG:Pr@ZnO@PpIX. The photo- and cathodoluminescence analyses gave the evidences of efficient energy transfer from YAG:Pr to ZnO at ∼320 nm, and YAG:Pr@ZnO to PpIX at Soret region (350-450 nm). The nanohybrid was able to produce both, Type I and Type II ROS upon direct and indirect photoactivation with UV365nm and UV290nm, respectively. In vitro cytotoxicity of non-activated YAG:Pr@ZnO@PpIX in mouse melanoma cells revealed low toxicity, which significantly enhanced upon photoactivation with UV365nm indicating the photokilling property of the nanohybrid. Overall, our preliminary studies successfully demonstrate the potential of YAG:Pr@ZnO@PpIX to overcome the limited penetration and oxygen-dependency of traditional PDT.

Blue light triggered generation of reactive oxygen species from silica coated Gd3Al5O12:Ce3+ nanoparticles loaded with rose Bengal.

This data article provide results of the studies conducted to develop a mesoporous silica coated Gd2.98Ce0.02Al5O12 nanoparticles loaded with a photosensitizer dye rose Bengal (RB) system (GAG@mSiO2@RB) capable of producing reactive oxygen species (ROS) upon exposure to blue light. The data reported here is related with Jain et al. (2018) [1]. It contains histogram of particle size distribution, cathodoluminescence (CL), photoluminescence spectra and there spectral overlap with the absorption spectra of RB, a graph showing the loading percentage of RB at different concentrations. Moreover, the data indicating ROS generation evaluated using 1,2-diphenylisobenzofuran (DPBF) assay and the viability of MDA-MB-231 cells upon exposure with different concentration of GAG@mSiO2 nanoparticles, upon exposure with blue light is also included in the data.

Magnetic-luminescent cerium-doped gadolinium aluminum garnet nanoparticles for simultaneous imaging and photodynamic therapy of cancer cells.

Nanoparticle (NP) and photosensitizer (PS) conjugates capable of X-ray photodynamic therapy (X-PDT) are a research focus due to their potential applications in cancer treatment. Combined with X-PDT, appropriate imaging properties of the nanocomposite will make it suitable for theranostics of deep lying tumors. In this work, we describe the development of magnetic-luminescent Gd2.98Ce0.02Al5O12 nanoparticles (GAG) coated with mesoporous silica (mSiO2) and loaded with rose bengal (RB) to yield a nanocomposite GAG@mSiO2@RB capable of X-PDT. GAG nanoparticles were synthesized using the sol-gel method. The synthesized GAG nanoparticles showed a strong visible yellow emission with a quantum yield of ∼32%. Moreover, the broad emission spectra of GAG nanoparticles centered at 585 nm showed a good overlap with the absorption of RB. Upon irradiation with X-rays (55 KV), the GAG@mSiO2@RB nanocomposite produced significantly higher singlet oxygen compared with RB alone, as confirmed by the 1,2-diphenylisobenzofuran (DPBF) assay. The developed GAG@mSiO2@RB nanocomposite significantly reduced the viability of human breast cancer (MDA-MB-231) cells upon irradiation with blue light (λ = 470 nm). The calculated LC50 of GAG@mSiO2@RB nanocomposites were 26.69, 11.2, and 6.56 µg/mL at a dose of ∼0.16, 0.33 and 0.5 J/cm2, respectively. Moreover, the nanocomposite showed paramagnetic properties with high magnetic mass susceptibility which are useful for high contrast T1 weighted magnetic resonance imaging (MRI). Together with X-PDT, the paramagnetic properties of the proposed GAG@mSiO2@RB nanocomposite system are promising for their future application in simultaneous detection and treatment of deep-lying tumors.