Nanotheranostic Probe Built on Methylene Blue Loaded Cucurbituril [8] and Gold Nanorod: Targeted Phototherapy in Combination with SERS Imaging on Breast Cancer Cells.

Recent advancements in a nanoarchitecture platform for safe and effective targeted phototherapy in a synergistic fashion is an absolute necessity in localized cancer therapy. Photothermal and photodynamic therapies (PTT and PDT) are considered as the most promising localized therapeutic intervention for cancer management as they have no long-term side effects and are minimally invasive and affordable. Herein, we have demonstrated a tailor-made nanotheranostic probe in which macrocyclic host cucurbituril [8] (CB[8]) is placed as a glue between two gold nanorods (GNRs) within ∼3 nm gaps in linear nanoassemblies with exquisitely sensitive plasmonics that exert combined phototherapy to investigate the therapeutic progression on human breast cancer cells. Photosensitizer methylene blue was positioned on CB[8] to impart the PDT effect, whereas GNR was responsible for PTT on a single laser trigger ensuring the synchronized phototherapy. Furthermore, the nanoconstruct was tagged with targeting anti-Her2 monoclonal antibody (MB-CB[8]@GNR-anti-Her2) for localized PTT and PDT on Her2 positive SKBR3 cells, subsequent cellular recognition by surface-enhanced Raman spectroscopy (SERS) platform, and further assessment of the combined intracellular phototherapy. Hence, the current strategy is definitely marked as a proof-of-concept straightforward approach that implies the perfect nature of the combined phototherapy to achieve an efficient cancer treatment.

Elucidating Gold-MnO2 Core-Shell Nanoenvelope for Real Time SERS-Guided Photothermal Therapy on Pancreatic Cancer Cells.

Pancreatic cancer represents one of the most aggressive in nature with a miserable prognosis that warrants efficient diagnostic and therapeutic interventions. Herein, a MnO2 overlaid gold nanoparticle (AuNPs) based photothermal theranostic nanoenvelope (PTTNe:MnO2@AuNPs) was fabricated to substantiate surface-enhanced Raman spectroscopy (SERS) guided real-time monitoring of photothermal therapy (PTT) in pancreatic cancer cells. A sharp enhancement of the fingerprint Raman signature of MnO2 at 569 cm-1 exhibited as a marker peak for the first time to elucidate the intracellular PTT event. In this strategic design, the leftover bare AuNPs after the degradation of the MnO2 layer from the nanoenvelope in the presence of intracellular H2O2 enabled real-time tracking of biomolecular changes of Raman spectral variations during PTT. Moreover, the surface of the as-synthesized nanoenvelope was functionalized with a pancreatic cancer cell targeting peptide sequence for cholecystokinin fashioned the PTTNe with admirable stability and biocompatibility. Finally, the precise cell death mechanism was explicitly assessed by SERS spectral analysis as a complementary technique. This targeted phototheranostic approach demonstrated in pancreatic cancer cells presented a therapeutically viable prototype for futuristic personalized cancer nanomedicine.

Elucidating a Thermoresponsive Multimodal Photo-Chemotherapeutic Nanodelivery Vehicle to Overcome the Barriers of Doxorubicin Therapy.

In an attempt to circumvent the major pitfalls associated with conventional chemotherapy including drug resistance and off-target toxicity, we have adopted a strategy to simultaneously target both mitochondrial DNA (Mt-DNA) and nuclear DNA (n-DNA) with the aid of a targeted theranostic nanodelivery vehicle (TTNDV). Herein, folic acid-anchored p-sulfo-calix[4]arene (SC4)-capped hollow gold nanoparticles (HGNPs) were meticulously loaded with antineoplastic doxorubicin (Dox) and its mitochondrion-targeted analogue, Mt-Dox, in a pretuned ratio (1:100) for sustained thermoresponsive release of cargo. This therapeutic strategy was enabled to eradicate both n-DNA and Mt-DNA leaving no space to develop drug resistance. The SC4-capped HGNPs (HGNPSC4) were experimented for the first time as a photothermal (PTT) agent with 61.6% photothermal conversion efficiency, and they generated tunable localized heat more efficiently than bare HGNPs. Moreover, the cavity of SC4 facilitated the formation of an inclusion complex with folic acid to target the folate receptor expressing cancer cells and imparted enhanced biocompatibility. The as-synthesized TTNDV was demonstrated to be an ideal substrate for surface-enhanced Raman scattering (SERS) to monitor the molecular-level therapeutic progression in cells and a spheroidal model. A significant reduction in the tumor mass with a marked survival benefit was achieved in syngraft murine models through this synergistic photo-chemotherapy. Collectively, this multifunctional nanoplatform offers a robust approach to treat cancer without any scope of generating Dox resistance and off-target toxicity.

Surface charge modulates the internalization vs. penetration of gold nanoparticles: comprehensive scrutiny on monolayer cancer cells, multicellular spheroids and solid tumors by SERS modality.

Precise control over the dynamics of nanoparticles (NPs) in a tumor microenvironment is highly warranted for the development of an efficient nanotheranostic agent. Even though inductively coupled plasma mass spectrometry can provide a quantitative assessment regarding the uptake efficiency of metal NPs, enumeration of deep tissue penetration capacity remains as a challenge. Herein, we have demonstrated an accurate tracking of the uptake efficiency and penetration phenomenon of gold nanoparticles (AuNPs: 40-50 nm) with respect to three different surface charges in monolayer (2D) cells, multicellular spheroids (3D) and in vivo tumors by surface-enhanced Raman spectroscopy (SERS). While positively charged AuNPs showed around two-fold increased internalization in monolayer cells, SERS-tag-based line scanning on multi-layered tumor spheroids illustrated almost nine-fold superior penetration capability with negatively charged AuNPs. Further, the enhanced solid tumor distribution contributed by the negatively charged AuNPs could appreciably escalate its clinical utility in cancer management.

Biogenic Cluster-Encased Gold Nanorods as a Targeted Three-in-One Theranostic Nanoenvelope for SERS-Guided Photochemotherapy against Metastatic Melanoma.

Effective treatment of malignant melanoma requires an appropriate combination of therapeutic intervention with long-term prognosis as it often survives by monotherapies. Herein, we report a novel melanoma-targeted theranostic nanoenvelope (MTTNe: ISQ@BSA-AuNC@AuNR@DAC@DR5) which has been constructed by assembling a bovine serum albumin (BSA) stabilized gold nanocluster on a gold nanorod (BSA-AuNC@AuNR), a three-in-one theranostic modality, i.e., photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy, tethered with a surface-enhanced Raman scattering (SERS) detection technique. The resultant MTTNe was coloaded with the melanoma-specific FDA approved drug dacarbazine (DAC) and a newly synthesized near-infrared (NIR) absorbing squaraine molecule ISQ that served partly as a photosensitizer and multiplex Raman reporter. Finally, a nanoenvelope was anchored with anti-DR5 monoclonal antibodies as a targeting motif for highly expressed melanoma-specific death receptors in malignant cells. Significant phototherapies of MTTNe were initiated upon an 808 nm single laser trigger which showed a synergistic effect of photothermal hyperthermia as well as singlet oxygen (1O2) driven photodynamic effect in the presence of ISQ followed by on-demand thermoresponsive drug release in the intracellular milieu. Moreover, a multiplex SERS spectral pattern of ISQ (1345 cm-1) and DAC (1269 cm-1) has been utilized for monitoring precise drug release kinetics and target-specific recognition on melanoma cells by Raman imaging. Therapeutic performance of the nanoenvelope was evaluated by in vitro cytotoxicity studies in human melanoma cells (A375) and confirmed the apoptotic phenomenon by molecular-level monitoring of intracellular SERS fingerprints. Finally, to address the biocompatibility of MTTNe, in vivo subacute toxicity was conducted on BALB/c mice. Hence, the current studies mark a footstep of a facile strategy for the treatment of melanoma by synergistic multimodal photothermal/photodynamic/chemotherapy.

Endogenous H2S-Assisted Cancer-Cell-Specific Activation of Theranostics with Emission Readout.

Realizing the importance of activation of the anticancer drug, its distribution, and for cancer management, a new theranostic probe has been developed. Endogenous H2S stimulated the theranostic molecular prodrug (TP-HS) which is activated in cancer cells; it monitors the actual time of formation of therapeutic agent SN-38 in cellular milieu through fluorescence imaging. Upon exposure to H2S in a similar physiological condition, the azide functionality converted to amine (-NH2) in TP-HS which allows self-immolative scission of the labile benzyl-carbonate moiety for release of rhodol and SN-38 in a concerted manner. Thus, an intense emission band centered at 548 nm has appeared for quantifying the active therapeutic component. The fluorescence image revealed that the TP-HS preferentially releases rhodol and SN-38 in colon cancer (HCT116 cells) and lung cancer cells (A549 cells) compared to normal human fibroblast cells (WI-38). Further, the dose-dependent antiproliferative activity of TP-HS against various cells supports that TP-HS releases SN-38 based on endogenous H2S in cancer cells followed by its apoptotic progression monitored by (a) live-dead, i.e., acridine orange-ethidium bromide double staining assay, (b) APOPercentage apoptotic assay, and (c) Annexin V-FITC staining by flow cytometry. The theranostic prodrug TP-HS showed anticancer efficacy via the desirable apoptotic pathway. It is the first demonstration of a strategic theranostic molecular prodrug system that could be delivered chemotherapeutically with validating the real-time activation of chemotherapy in the cancer cells without the support of a cancer-directing ligand.

Exploring the margins of SERS in practical domain: An emerging diagnostic modality for modern biomedical applications.

Excellent multiplexing capability, molecular specificity, high sensitivity and the potential of resolving complex molecular level biological compositions augmented the diagnostic modality of surface-enhanced Raman scattering (SERS) in biology and medicine. While maintaining all the merits of classical Raman spectroscopy, SERS provides a more sensitive and selective detection and quantification platform. Non-invasive, chemically specific and spatially resolved analysis facilitates the exploration of SERS-based nano probes in diagnostic and theranostic applications with improved clinical outcomes compared to the currently available so called state-of-art technologies. Adequate knowledge on the mechanism and properties of SERS based nano probes are inevitable in utilizing the full potential of this modality for biomedical applications. The safety and efficiency of metal nanoparticles and Raman reporters have to be critically evaluated for the successful translation of SERS in to clinics. In this context, the present review attempts to give a comprehensive overview about the selected medical, biomedical and allied applications of SERS while highlighting recent and relevant outcomes ranging from simple detection platforms to complicated clinical applications.