Suma Prabhu

Bio: Suma Prabhu is an academic researcher from Manipal University. The author has contributed to research in topics: Drug delivery & Targeted drug delivery. The author has an hindex of 4, co-authored 5 publications receiving 66 citations.

A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin.

Abstract: The development of effective therapeutic strategies for glioblastoma faces challenges such as modulating the blood brain barrier (BBB) for drug influx and selectively targeting tumor cells. Nanocarrier drug delivery strategies are functionalized to enhance vascular permeability. We engineered superparamagnetic iron oxide nanoparticle (SPION) based polymeric nanocomposites (84.37 ± 12.37 nm / 101.56 ± 7.42 nm) embedding temozolomide (TMZ) targeted against glioblastoma by tagging an antibody against nestin, a stem cell marker, and transferrin / polysorbate-80 to permeate the BBB. The targeting and therapeutic efficacy of the nanocomposite resulted in enhanced permeability across the BBB in an orthotopic glioblastoma xenograft model. Sustained release of TMZ from the nanocomposite contributed to enhanced tumor cell death while sparing normal brain cells as evidenced through micro SPECT/CT analysis. The functionalized nanocomposites showed significant reductions in tumor volume compared to pure TMZ, as substantiated by reduced proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67. We report here a novel targeted TMZ delivery strategy using a potent homing moiety, nestin, tagged to a polymeric nanocomposite to target glioblastoma. In addition to tumor targeting, this study constitutes a broad horizon for enhanced therapeutic efficacy with further scope for capitalizing on the magnetic properties of SPION for targeted killing of cancer cells while sparing normal tissues.

PEGylation of superparamagnetic iron oxide nanoparticle for drug delivery applications with decreased toxicity: an in vivo study

Abstract: Superparamagnetic iron oxide nanoparticles (SPIONs) are evolving as a mainstay across various applications in the field of Science and Technology. SPIONs have enticed attention on the grounds of their unique physicochemical properties as well as potential applications in magnetic hyperthermia, immunoassays, as a contrast agent in magnetic resonance imaging and targeted drug delivery among others. Toward this goal, we synthesized SPIONs by chemical co-precipitation and PEGylated it. PEGylated SPIONs (PS) were studied for its detailed in vivo toxicity profile, in view of further surface engineering for its clinical applications. The intravenous LD50(14) of the PS was ascertained as 508.16 ± 41.52 mg/kg b wt. Histopathology of the vital organs of the animals injected with acute toxic doses showed pathological changes in spleen, lung, liver, and kidney. Accumulation of SPION was found in the aforementioned organs as confirmed by Prussian blue staining. Further, 1/10th dose of LD50(14) of PS and the Bare SPION (BS) was used to analyze a detailed toxicity profile, including genotoxicity (micronuclei formation and chromosomal aberration assays), organ-specific toxicity (a detailed serum biochemical analysis), and also determination of oxidative stress. The results of toxicity profile indicated no significant toxicity due to systemic exposure of PS. Atomic absorption spectroscopy (AAS) analysis confirmed the accumulation of SPION majorly in lungs, liver spleen, and kidneys. The present study thus indicated an optimal dose of PS which could be used for surface modification for targeted drug delivery applications with least toxicity.

Multifunctional lipidic nanocarriers for effective therapy of glioblastoma: recent advances in stimuli-responsive, receptor and subcellular targeted approaches

Abstract: Glioblastoma, or glioblastoma multiforme (GBM), remains a fatal cancer type despite the remarkable progress in understanding the genesis and propagation of the tumor. Current treatment modalities, comprising mainly of surgery followed by adjuvant chemoradiation, are insufficient for improving patients' survival owing to existing hurdles, including the blood–brain barrier (BBB). In contemporary practice, the prospect of long-term survival or cure continues to be a challenge for patients suffering from GBM. This review provides an insight into the drug delivery strategies and the significant efforts made in lipid-based nanoplatform research to circumvent the challenges in optimal drug delivery in GBM. Owing to the unique properties of lipid-based nanoplatforms and advancements in clinical translation, this article describes the application of various stimuli-responsive lipid nanocarriers and tumor subcellular organelle-targeted therapy to give an idea about the strategies that can be applied to enhance site-specific drug delivery for GBM. Furthermore, active targeting of drugs via surface-modified lipid-based nanostructures and recent findings in alternative therapeutic platforms such as gene therapy, immunotherapy, and multimodal therapy have also been overviewed. Lipid-based nanoparticles stand out among the other nanocarriers explored for GBM drug delivery, as they support both passive and active drug targeting by crossing/bypassing the BBB at the same time minimizing toxicity and projects better pharmacological parameters. Although these nanocarriers could be a plausible choice for treating GBM, in-depth research is essential to advance neuro-oncology research and enhance outcomes in patients with brain tumors.

Systemic Toxicity and Teratogenicity of Copper Oxide Nanoparticles and Copper Sulfate.

Abstract: Acceleration in development of metallic nanoparticles for their utility in medical and technological applications due to their unique physicochemical properties has concurrently raised a matter of concern due to their potential toxicity. Of the enormous metallic nanostructures, copper oxide nanoparticles (CuONPs) having optical and electrochemical properties are scrutinized for theranostic applications. Therefore, their safety profile is of a major concern in optimizing a safe dose for its clinical utility. Considering the potency of CuONPs in epitomizing toxicity, we report a dose and time dependent acute, systemic and transgenerational toxicity profile of CuONPs in comparison to the bulk copper as copper sulfate (CuSO4). Acute toxic dose (LD50(14)) of CuONPs (400 mg/kg · b · wt) was found to be three fold higher that of CuSO4(100 mg/kg · b · wt). Comparative steady state evaluation showed that CuONPs (≥5 mg/kg · b · wt.) induce greater dose and time dependent oxidative stress by increase in protein carbonylation and decreased glutathione levels in comparison to the bulk CuSO4. Furthermore, CuONPs were found to disrupt blood brain barrier (BBB) and sneak in to the brain which was quantified by atomic absorption spectroscopy (AAS) and also coax toxicity in liver, kidney and spleen, ascertained by histopathological findings (at ≥5 mg/kg · b · wt.). Considering transgenerational toxicity, CuONPs in comparison to CuSO4 severely affected sperm count and morphology in male animals, though not much teratological effects were observed, except certain extent of embryo resorption. The present study highlights a complete toxicity profile of CuONPs, giving forethought for considering them for clinical applications.

Iron Oxide Nanoparticles for Biomedical Applications: A Perspective on Synthesis, Drugs, Antimicrobial Activity, and Toxicity.

Abstract: Medical applications and biotechnological advances, including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, have strongly benefited from employing iron oxide nanoparticles (IONPs) due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a biocompatible coating. Ongoing research efforts focus on reducing drug concentration, toxicity, and other side effects, while increasing efficacy of IONPs-based treatments. This review highlights the methods of synthesis and presents the most recent reports in the literature regarding advances in drug delivery using IONPs-based systems, as well as their antimicrobial activity against different microorganisms. Furthermore, the toxicity of IONPs alone and constituting nanosystems is also addressed.

Superparamagnetic Iron Oxide Nanoparticles—Current and Prospective Medical Applications

Abstract: The recent, fast development of nanotechnology is reflected in the medical sciences. Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are an excellent example. Thanks to their superparamagnetic properties, SPIONs have found application in Magnetic Resonance Imaging (MRI) and magnetic hyperthermia. Unlike bulk iron, SPIONs do not have remnant magnetization in the absence of the external magnetic field; therefore, a precise remote control over their action is possible. This makes them also useful as a component of the advanced drug delivery systems. Due to their easy synthesis, biocompatibility, multifunctionality, and possibility of further surface modification with various chemical agents, SPIONs could support many fields of medicine. SPIONs have also some disadvantages, such as their high uptake by macrophages. Nevertheless, based on the ongoing studies, they seem to be very promising in oncological therapy (especially in the brain, breast, prostate, and pancreatic tumors). The main goal of our paper is, therefore, to present the basic properties of SPIONs, to discuss their current role in medicine, and to review their applications in order to inspire future developments of new, improved SPION systems.

The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

Abstract: Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules-TGF-β and SDF1-play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.

HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers

Abstract: Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their nontransformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications.