Ultrahigh Penetration and Retention of Graphene Quantum Dot Mesoporous Silica Nanohybrids for Image Guided Tumor Regression

Funding: This work was supported by Department of Biotechnology, Government of India. J.C. acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). We thank the staff of animal house, NCCS, Pune for supporting us during animal studies. We also thank Mr. Sumit for the discussion and Dr. Mukesh K. Kumawat for providing GQDs.So far, near-infrared (NIR) light responsive nanostructures have been well-defined in cancer nanomedicine. However, poor penetration and retention in tumors are the limiting factors. Here, we report the ultrahigh penetration and retention of carbanosilica (graphene quantum dots, GQDs embedded mesoporous silica) in solid tumors. After NIR light exposure, quick (0.5 h) emission from the tumor area is observed that is further retained up to a week (tested up to 10 days) with a single dose administration of nanohybrids. Emissive and photothermally active GQDs and porous silica shell (about 31% drug loading) make carbanosilica a promising nanotheranostic agent exhibiting 68.75% tumor shrinking compared to without NIR light exposure (34.48%). Generated heat (∼52 °C) alters the permeability of tumor enhancing the accumulation of nanotheranostics into the tumor environment. Successive tumor imaging ensures the prolonged follow-up of image guided tumor regression due to synergistic therapeutic effect of nanohybrids.publishersversionpublishe

Content Based Watermarking Techniques using HSV and Fractal Dimension in Transform Domain

The central idea of the present paper is based on selecting the watermark information from the host image itself. For which, in this work, we select the fractal dimension as the feature of the host image. The proposed method uses three techniques namely DCT, DWT, combined DCT & DWT to embed the watermark by exploiting Fractal Dimension and Human Visual System (HVS), so that a trade-off between imperceptibility and robustness will be maintained. According to the experimentation results, in all the methods, the watermarked images could be recovered effectively. Our method is also useful to detect the tampered location in the watermarked image correctly. INTRODUCTION A digital watermarking is the process that can be used to hide a piece of information into a multimedia content, which is imperceptible to a human observer, but can be easily detected by a computer. The principle advantage is that the watermark is inseparable from the content. Content based Digital Watermarking involves three major phases: (i) Watermark Creation, (ii) Watermark Embedding, (iii) Watermark Extraction. Digital Watermarks may be a pseudo random sequence or a logo of a company or an image. Watermark embedding is done in the watermark carriers such as Discrete Cosine Transform (DCT) or Discrete Wavelet Transform (DWT), etc., of the original data resulting in watermarked data. The watermarked data can be compressed in order to reduce its size, corrupted by noise during its transmission through a noisy channel. It can be subjected to other common image processing operations such as filtering, histogram modification etc. Digital watermark technology has developed extensively during the recent few years and is widely applied to protect the copyright of a digital image. A digital watermark is the information, embedded imperceptibly and robustly in the host data which cannot be removed. By adding a watermark signal to the host data the watermark signal is unobtrusive and secure in the signal mixture. Background: A new public content-based watermarking method for image authentication using ICA and DCT for gray scale images is proposed in (Dr. Latha Parameswaran and Dr. K. Anbumani, 2008). Based upon this paper, this project has been implemented for color images. Watermarks are embedded in the mid -frequency DCT coefficients. DCT is a widely used technique for watermarking (Francisco J. Gonzalez-Serrano, Harold Y. Molina-Bulla, and Juan J. Murillo-Fuentes, May 2001). In Redundant DWT (RDWT) is used i

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice

Objective: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. Methods: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. Results: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. Conclusion: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification

RGD functionalized chitosan nanoparticle mediated targeted delivery of raloxifene selectively suppresses angiogenesis and tumor growth in breast cancer

Acidic pH is a crucial intrinsic property of the microenvironment of most solid tumors. Hence, the use of pH sensitive tumor targeting nanoparticles is an attractive approach to enhance the therapeutic efficacy of anti-cancer agents in solid tumors. Chitosan nanoparticles (CHNPs) have been widely explored in the area of cancer drug delivery; nevertheless their true potential as a pH responsive targeted drug delivery vehicle in cancer therapy has not been deciphered yet as most of the research is limited to pH dependent stability and drug release. In the present study, we investigate the direct effect of pH in synergy with RGD peptide based targeting on the therapeutic efficacy of chitosan nanoparticles (RGD-CHNPs) in breast cancer. Furthermore, for the first time we performed a comprehensive study showing the anti-tumor, anti-migratory and anti-angiogenic effect of raloxifene (Rlx) loaded CHNPs in breast cancer. We prepared stable formulations of raloxifene encapsulated CHNPs and RGD-CHNPs by the nontoxic ionic gelation method. pH dependent studies revealed that NPs possess higher stability and zeta potential along with enhanced cellular uptake at acidic pH (as present in solid tumors) compared to physiological pH. Furthermore, RGD conjugation enhanced the in vitro cellular uptake of CHNPs in αβ integrin expressing breast cancer cells and induced higher cellular apoptosis in breast cancer cells which was further augmented by lower pH. Moreover, Rlx-RGD-CHNPs significantly inhibited breast cancer cell migration and angiogenesis. In vivo studies showed that Cy5.5 conjugated RGD-CHNPs can distinctly visualize tumors and Rlx-RGD-CHNPs significantly inhibit breast tumor growth without causing any toxic effect to normal tissue as confirmed by hematology and blood biochemical studies. Therefore, RGD-CHNPs could potentially enhance the therapeutic efficacy of chemotherapeutic drugs due to the synergistic effect of pH responsiveness and tumor specific targeting in breast cancer

The Biology and Therapeutic Implications of Tumor Dormancy and Reactivation

Advancements in the early detection of cancer coupled with improved surgery, radiotherapy, and adjuvant therapy led to substantial increase in patient survival. Nevertheless, cancer metastasis is the leading cause of death in several cancer patients. The majority of these deaths are associated with metastatic relapse kinetics after a variable period of clinical remission. Most of the cancer recurrences are thought to be associated with the reactivation of dormant disseminated tumor cells (DTCs). In this review, we have summarized the cellular and molecular mechanisms related to DTCs and the role of microenvironmental niche. These mechanisms regulate the dormant state and help in the reactivation, which leads to metastatic outgrowth. Identification of novel therapeutic targets to eliminate these dormant tumor cells will be highly useful in controlling the metastatic relapse-related death with several cancers

Poly(d,l‑lactide-<i>co</i>-glycolide) Surface-Anchored Biotin-Loaded Irinotecan Nanoparticles for Active Targeting of Colon Cancer

A poly(d,l-lactide-co-glycolide) (PLGA) copolymer was synthesized using the ring-opening polymerization of d,l-lactide and glycolide monomers in the presence of zinc proline complex in bulk through the green route and was well characterized using attenuated total reflectance–Fourier transform infrared, 1H and 13C nuclear magnetic resonance, gel permeation chromatography, differential scanning calorimetry, X-ray diffraction, matrix-assisted laser desorption/ionization time-of-flight, etc. Furthermore, PLGA-conjugated biotin (PLGA-B) was synthesized using the synthesized PLGA and was employed to fabricate nanoparticles for irinotecan (Ir) delivery. These nanoparticles (PLGA-NP-Ir and PLGA-B-NP-Ir) were tested for physicochemical and biological characteristics. PLGA-B-NP-Ir exhibited a stronger cellular uptake and anticancer activity as compared to PLGA-NP-Ir in CT-26 cancer cells (log p < 0.05). The accumulation and retention of fluorescence-labeled nanoparticles were observed to be better in CT-26-inoculated solid tumors in Balb/c mice. The PLGA-B-NP-Ir-treated group inhibited tumor growth significantly more (log p < 0.001) than the untreated control, PLGA-NP-Ir, and Ir-treated groups. Furthermore, no body weight loss, hematological, and blood biochemical tests demonstrated the nanocarriers’ nontoxic nature. This work presents the use of safe PLGA and the demonstration of a proof-of-concept of biotin surface attached PLGA nanoparticle-mediated active targeted Ir administration to combat colon cancer. To treat colon cancer, PLGA-B-NP-Ir performed better due to specific active tumor targeting and greater cellular uptake due to biotin