Saurabh Sharma

All Publications

• Deciphering pericyte-induced temozolomide resistance in glioblastoma with a 3D microphysiological system mimicking the biomechanical properties of brain tissue. Acta biomaterialia Maity, S., Jewell, C., Yilgor, C., Kawakita, S., Sharma, S., Gomez, A., Mecwan, M., Falcone, N., Ermis, M., Monirizad, M., Kouchehbaghi, N. H., Zehtabi, F., Khorsandi, D., Dokmeci, M. R., Moniz-Garcia, D., Quiñones-Hinojosa, A., Khademhosseini, A., Jucaud, V. 2025

  Abstract

  Glioblastoma (GBM) is a highly aggressive malignancy with a poor prognosis and frequent resistance to temozolomide (TMZ), the standard-of-care chemotherapy. The complex mechanisms underlying GBM chemoresistance, particularly the role of pericytes, remain poorly understood due to the lack of physiologically relevant in vitro models replicating the complex tumor microenvironment (TME). Here, we present a biomimetic 3D GBM microphysiological system that replicates the biomechanical properties of brain tissue (G'∼800Pa, G"∼100Pa) and enables the study of pericyte-mediated TMZ resistance. GBM spheroids (U87, LN229, PDM140) were cultured alone or co-cultured with pericytes in a composite hydrogel for 14 days and remained viable and proliferative. In response to TMZ, PDM140 was the most sensitive (IC50=73μM), followed by LN229 (IC50=278μM) and U87 (IC50=446μM). Co-culture with pericytes significantly increased GBM spheroid viability by 22.7% (PDM140), 32.5% (LN229), and 22.1% (U87), confirming pericyte-induced TMZ resistance. Notably, pericytes exhibited a 160-fold upregulation of C-C motif chemokine ligand 5 (CCL5) upon TMZ treatment, implicating the CCL5-mediated pathway in chemoresistance. This innovative brain-mimicking 3D GBM model provides a physiologically relevant platform for studying tumor-pericyte interactions and testing therapeutic strategies targeting CCL5-mediated resistance mechanisms in GBM. STATEMENT OF SIGNIFICANCE: We developed a multicellular 3D glioblastoma microphysiological system mimicking the physicochemical properties of brain tissues and pericyte-mediated temozolomide resistance that can be used to screen for standard-of-care chemotherapy. This advanced hydrogel-based platform demonstrated the critical role of the glioblastoma tumor microenvironment in modulating chemotherapy sensitivity, particularly the pericyte-induced CCL5-CCR5 paracrine axis that can lead to the identification of therapeutic targets within the CCL5-CCR5 pathway toward more effective treatments disrupting these resistance mechanisms. Overall, the proposed 3D glioblastoma microphysiological system can transform drug screening and personalized treatment for GBM by offering ethical and cost-effective alternatives to animal testing and more effective drug screening and discovery efforts, ultimately improving GBM patient outcomes.

  View details for DOI 10.1016/j.actbio.2025.05.038

  View details for PubMedID 40383349

• Antibody-Free Immunopeptide Nano-Conjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme. bioRxiv : the preprint server for biology Sharma, S., Lee, D., Maity, S., Singh, P., Chadokiya, J., Mohaghegh, N., Hassani, A., Kim, H., Gangarade, A., Ljubimova, J. Y., Kirane, A., Holler, E. 2025

  Abstract

  Glioblastoma Multiforme (GBM) represents a significant clinical challenge amongst central nervous system (CNS) tumors, with a dismal mean survival rate of less than 8 months, a statistic that has remained largely unchanged for decades (National Brain Society, 2022). The specialized intricate anatomical features of the brain, notably the blood-brain barrier (BBB), pose significant challenges to effective therapeutic interventions, limiting the potential reach of modern advancements in immunotherapy to impact these types of tumors. This study introduces an innovative, actively targeted immunotherapeutic nanoconjugate (P12/AP-2/NCs) designed to serve as an immunotherapeutic agent capable of traversing the BBB via LRP-1 receptor-mediated transcytosis. P12/AP-2/NCs exert its immune-modulating effects by inhibiting the PD-1/PD-L1 axis through a small-size PD-L1/PD-L2 antagonist peptide Aurigene NP-12 (P12). P12/AP-2/NCs are synthesized from completely biodegradable, functionalized high molecular weight β-poly(L-malic acid) (PMLA) polymer, conjugated with P12 and Angiopep-2 (AP2) to yield P12/AP-2/NCs. Evaluating nanoconjugates for BBB permeability and 3-D tumor model efficacy using an in vitro BBB-Transwell spheroid based model demonstrating successful crossing of the BBB and internalization in brain 3D tumor environments. In addition, the nanoconjugate mediated T cell's cytotoxicity on 3D tumor region death in a U87 GBM 3-D spheroid model. AP2/P12/NCs is selectively inhibited in PD1/PDL1 interaction on T cells and tumor site, increasing inflammatory cytokine secretion and T cell proliferation. In an in-vivo murine brain environment, rhodamine fluorophore-labeled AP2/P12/NCs displayed significantly increased accumulation in the brain during 2-6 h time intervals post-injection with a prolonged bioavailability over unconjugated peptides. AP2/P12/NCs demonstrated a safety profile at both low and high doses based on major organ histopathology evaluations. Our findings introduce a novel, programmable nanoconjugate platform capable of penetrating the BBB for directed delivery of small peptides and significant immune environment modulation without utilizing antibodies, offering promise for treating challenging brain diseases like glioblastoma multiforme and beyond.

  View details for DOI 10.1101/2025.03.07.641755

  View details for PubMedID 40161747

  View details for PubMedCentralID PMC11952356

• Smart biomaterials in healthcare: Breakthroughs in tissue engineering, immunomodulation, patient-specific therapies, and biosensor applications APPLIED PHYSICS REVIEWS Raheem, A., Mandal, K., Biswas, S., Ahari, A., Najafabadi, A., Farhadi, N., Zehtabi, F., Gangrade, A., Mecwan, M., Maity, S., Sharma, S., Arputharaj, J., Khan, P., Udduttula, A., Kouchehbaghi, N., Khorsandi, D., Vasita, R., Haghniaz, R., Herculano, R., John, J. V., Kim, H., Dokmeci, M., Popat, K. C., Zhu, Y., Manivasagam, G. 2025; 12 (1)

  View details for DOI 10.1063/5.0238817

  View details for Web of Science ID 001447584700002

• Recent Developments in Glioblastoma-On-A-Chip for Advanced Drug Screening Applications. Small (Weinheim an der Bergstrasse, Germany) Maity, S., Bhuyan, T., Jewell, C., Kawakita, S., Sharma, S., Nguyen, H. T., Hassani Najafabadi, A., Ermis, M., Falcone, N., Chen, J., Mandal, K., Khorsandi, D., Yilgor, C., Choroomi, A., Torres, E., Mecwan, M., John, J. V., Akbari, M., Wang, Z., Moniz-Garcia, D., Quinones-Hinojosa, A., Jucaud, V., Dokmeci, M. R., Khademhosseini, A. 2024: e2405511

  Abstract

  Glioblastoma (GBM) is an aggressive form of cancer, comprising 80% of malignant brain tumors. However, there are no effective treatments for GBM due to its heterogeneity and the presence of the blood-brain barrier (BBB), which restricts the delivery of therapeutics to the brain. Despite in vitro models contributing to the understanding of GBM, conventional 2D models oversimplify the complex tumor microenvironment. Organ-on-a-chip (OoC) models have emerged as promising platforms that recapitulate human tissue physiology, enabling disease modeling, drug screening, and personalized medicine. There is a sudden increase in GBM-on-a-chip models that can significantly advance the knowledge of GBM etiology and revolutionize drug development by reducing animal testing and enhancing translation to the clinic. In this review, an overview of GBM-on-a-chip models and their applications is reported for drug screening and discussed current challenges and potential future directions for GBM-on-a-chip models.

  View details for DOI 10.1002/smll.202405511

  View details for PubMedID 39535474

• Single cell analysis of melanoma reveals a prognostic myeloid cell signature associated with survival and response to immunotherapy in advanced melanoma Ahmad, M., Heo, L., Nair, R., Sharma, S., Kirane, A. AMER ASSOC IMMUNOLOGISTS. 2024

  View details for DOI 10.4049/jimmunol.212.supp.0273.5921

  View details for Web of Science ID 001374618700037

• Clinical and Translational Opportunities of Nanocarriers Containing RNAi for the Management of Triple-Negative Breast Cancer ADVANCED THERAPEUTICS Sharma, S., Pradhan, R., Lee, D., Sharma, M., Nasab, S., Hejmady, S., Chander, S., Mohaghegh, N., Maity, S., Khan, S., Khademhosseini, A., Kirane, A. 2024

  View details for DOI 10.1002/adtp.202300388

  View details for Web of Science ID 001190306300001

• Toward the Development of Functional Biomarker Assays: Analysis of Neoadjuvant Intralesional Oncolytic Virus Response in High-Risk Stage II Melanoma Kirane, A., Lee, D., Ahmad, M., Sharma, S., Serasanambati, M., Lowe, M., Applebee, C., Safrygina, E., Swetter, S., Reddy, S., Warner, A., Funchain, P., Wang, J., Levy, R., Larijani, B., Maverakis, E. SPRINGER. 2024: S33-S34

  View details for Web of Science ID 001185577500066

• Advancing precision cancer immunotherapy drug development, administration, and response prediction with AI-enabled Raman spectroscopy. Frontiers in immunology Chadokiya, J., Chang, K., Sharma, S., Hu, J., Lill, J. R., Dionne, J., Kirane, A. 2024; 15: 1520860

  Abstract

  Molecular characterization of tumors is essential to identify predictive biomarkers that inform treatment decisions and improve precision immunotherapy development and administration. However, challenges such as the heterogeneity of tumors and patient responses, limited efficacy of current biomarkers, and the predominant reliance on single-omics data, have hindered advances in accurately predicting treatment outcomes. Standard therapy generally applies a "one size fits all" approach, which not only provides ineffective or limited responses, but also an increased risk of off-target toxicities and acceleration of resistance mechanisms or adverse effects. As the development of emerging multi- and spatial-omics platforms continues to evolve, an effective tumor assessment platform providing utility in a clinical setting should i) enable high-throughput and robust screening in a variety of biological matrices, ii) provide in-depth information resolved with single to subcellular precision, and iii) improve accessibility in economical point-of-care settings. In this perspective, we explore the application of label-free Raman spectroscopy as a tumor profiling tool for precision immunotherapy. We examine how Raman spectroscopy's non-invasive, label-free approach can deepen our understanding of intricate inter- and intra-cellular interactions within the tumor-immune microenvironment. Furthermore, we discuss the analytical advances in Raman spectroscopy, highlighting its evolution to be utilized as a single "Raman-omics" approach. Lastly, we highlight the translational potential of Raman for its integration in clinical practice for safe and precise patient-centric immunotherapy.

  View details for DOI 10.3389/fimmu.2024.1520860

  View details for PubMedID 39850874

  View details for PubMedCentralID PMC11753970

• Phenylthiazolidin-4-one piperazine Conjugates: Design, Synthesis, anticancer and antimicrobial studies RESULTS IN CHEMISTRY Singh, D., Patel, R., Aggarwal, A., Das, A., Sharma, S., Behera, B., Panigrahy, R., Kirane, A. R., Kharkwal, H., Kumar, P., Bokolia, N., Sankaranarayanan, M., Chander, S. 2024; 7

  View details for DOI 10.1016/j.rechem.2023.101237

  View details for Web of Science ID 001135230300001

• Design, Synthesis, Anticancer and Antimicrobial Studies of 2-Phenylthiazolidin-4-one Glycinamide Conjugates CHEMISTRYSELECT Singh, D., Aggarwal, A., Patel, R., Das, A., Sharma, S., Behera, B., Panigrahy, R., Maity, S., Kirane, A. R., Kharkwal, H., Sankaranarayanan, M., Wadhwa, P., Khan, A., Alshehri, J. M., Chander, S. 2023; 8 (42)

  View details for DOI 10.1002/slct.202301806

  View details for Web of Science ID 001096924100001

• Apatite-coated Ag/AgBr/TiO2 nanocomposites: Insights into the antimicrobial mechanism in the dark and under visible-light irradiation APPLIED SURFACE SCIENCE Mohaghegh, N., Endo-Kimura, M., Wang, K., Wei, Z., Najafabadi, A., Zehtabi, F., Kouchehbaghi, N., Sharma, S., Markowska-Szczupak, A., Kowalska, E. 2023; 617

  View details for DOI 10.1016/j.apsusc.2023.156574

  View details for Web of Science ID 000930642800001

• Influence of Nanocarrier Type on the Drug Delivery Aspects of Docetaxel: Empirical Evidences JOURNAL OF PHARMACEUTICAL INNOVATION Alshahrani, S. M., Thotakura, N., Sharma, S., Quadir, S., Chaurawal, N., Sharma, S., Chitkara, D., Raza, K. 2023; 18 (2): 641-652

  View details for DOI 10.1007/s12247-022-09677-3

  View details for Web of Science ID 000839575600001

• Recent Advancements Towards the Use of Vitamin D Isoforms and the Development of Their Synthetic Analogues as New Therapeutics. Biomedicines Patel, R., Kharkwal, H., Saha, M., Sankaranarayanan, M., Sharma, S., Chander, S. 2025; 13 (4)

  Abstract

  Vitamin D and its metabolites are essential in various physiological processes, including muscle strength, metabolism, antifibrotic activity, and immune regulation. Researchers are focusing on developing vitamin D derivatives with optimized receptor selectivity and reduced systemic toxicity, enhancing their therapeutic efficacy against cancer, autoimmune disorders, and inflammatory diseases. Several analogues, such as alfacalcidol, paricalcitol, and falecalcitriol, are used for managing CKD-related bone disorders, while eldecalcitol is effective for osteoporosis, and calcipotriol against psoriasis. Recent studies have explored their impact on metabolic pathways, parathyroid hormone secretion, asthma, and liver fibrosis, revealing their broad clinical potential. Despite enormous efforts in the past decades, translations of vitamin D-drugs are disproportionately limited, mainly due to toxicity due to calcemic effects and undesirable metabolic profile. This review discusses structural modifications in vitamin D3, their influence on VDR binding, transcriptional activity, and calcium homeostasis, along with their role in targeting pathways like EGFR, KRAS, and Hedgehog in cancers. Advanced analytical techniques such as LC/ESI-MS/MS facilitate precise detection of vitamin D metabolites, further improving pharmacokinetic profiling. Future research may enable the clinical approval of novel vitamin D-based therapeutics with minimal disruption to calcium-phosphorus balance.

  View details for DOI 10.3390/biomedicines13041002

  View details for PubMedID 40299638

• The Utilisation of Mushroom Leftovers, Oats, and Lactose-Free Milk Powder for the Development of Geriatric Formulation. Foods (Basel, Switzerland) Paul, S., Kaushik, R., Upadhyay, S., Akhtar, A., Chawla, P., Kumar, N., Sharma, S., Rani, P. 2024; 13 (11)

  Abstract

  This study aims to focus on developing a food supplement for the geriatric population using disposal mushrooms, oats, and lactose-free milk powder. Lactose intolerance is most common in older adults, raising the demand for lactose-free foods. One of the major global challenges currently faced by humankind is food waste (FW). Most of the food that is produced for human consumption has not been utilized completely (1/3rd-1/2 unutilized), resulting in agricultural food waste. Mushrooms are highly valuable in terms of their nutritional value and medicinal properties; however, a significant percentage of mushroom leftovers are produced during mushroom production that do not meet retailers' standards (deformation of caps/stalks) and are left unattended. Oats are rich in dietary fibre beta-glucan (55% water soluble; 45% water insoluble). Lactose-free milk powder, oats, and dried mushroom leftover powder were blended in different ratios. It was observed that increasing the amount of mushroom leftover powder increases the protein content while diluting calories. The product with 15% mushroom powder and 30% oat powder showed the highest sensory scores and the lowest microbial count. The GCMS and FTIR analyses confirmed the presence of ergosterol and other functional groups. The results of the XRD analysis showed that the product with 15% mushroom powder and 30% oat powder had a less crystalline structure than the product with 5% mushroom powder and 40% oat powder and the product with 10% mushroom powder and 35% oat powder, resulting in more solubility. The ICP-OES analysis showed significant concentrations of calcium, potassium, magnesium, sodium, and zinc. The coliform count was nil for the products, and the bacterial count was below the limited range (3 × 102 cfu/g). The product with 15% mushroom powder and 30% oat powder showed the best results, so this developed product is recommended for older adults.

  View details for DOI 10.3390/foods13111738

  View details for PubMedID 38890965

  View details for PubMedCentralID PMC11171652