Biology subjects

Madabushi, S. S.

Publications and source records attributed to Madabushi, S. S..

5 recordsLinked to original sources

bioRxiv2025

Quantitative MRI Reveals Bone Marrow Regeneration Following Targeted Marrow Irradiation and Transplantation in a Sickle Cell Disease Model

Sickle cell disease (SCD) is associated with chronic bone marrow stress, altered hematopoiesis, and reduced adiposity. Whether marrow-selective conditioning followed by transplantation normalizes these abnormalities remains unclear. We investigated bone marrow remodeling in Townes mice by comparing SCD control (SCD-Con) with mice that received total marrow irradiation (TMI) followed by bone marrow transplantation (SCD-TMI-BMT). Multiparametric micro-MRI at 7 T quantified proton density water fraction (PDWF), proton density fat fraction (PDFF), and R2*(1/T2*), and micro-CT assessed trabecular structure in the femur. SCD-Con marrow showed higher water content (elevated PDWF), reduced adiposity (lower PDFF), and imaging features consistent with erythroid hyperplasia and elevated iron burden (shorter T2* with reciprocal increase in R2*). In contrast, SCD-TMI-BMT mice demonstrated smaller R2*, reduced PDWF, and partial restoration of adiposity, accompanied by reciprocal shifts in R2*, consistent with decreased cellular iron and marrow remodeling. Micro-CT revealed an improved trabecular architecture after BMT compared to SCD control. MRI imaging biomarkers aligned with histologic evidence of reduced cellularity and larger adipocyte voids. In conclusion, a TMI-BMT SCD model promotes partial normalization of the marrow microenvironment. Multiparametric MRI with micro-CT provides a practical, non-invasive framework for monitoring marrow remodeling and skeletal health after curative therapy.

bioengineering↗

bioRxiv2025

Development of Proton Density Fat Fraction Micro-MRI for Non-Invasive Quantitative Assessment of Bone Marrow Changes with Age and Radiation in Mouse Models

Background/ObjectivesBone marrow (BM) adipocytes are critical in progressing solid tumor metastases and hematological malignancies across pediatric to aging populations. Single-point biopsies remain the gold standard for monitoring BM diseases, including hematologic malignancies, but are limited in capturing the full complexity of loco-regional and global BM microenvironments. Non-invasive imaging techniques like Magnetic Resonance Imaging (MRI), could offer valuable alternatives for real-time evaluation of BM diseases in both preclinical translational and clinical studies. MethodsWe developed a preclinical proton density fat fraction (PDFF) MRI technique for quantitative BM composition assessment, focusing on fat fraction (FF) within mouse femurs. We validated this method using aging mice and young mice subjected to 10 Gy X-ray irradiation, compared with young unirradiated mice as controls. Water-fat phantoms (0% to 100% fat content) were used to optimize the imaging sequence, and immunohistochemical (IHC) staining with H&E validates equivalent adipose content in the femur BM regions. ResultsSignificant differences in FF were observed across age groups (p = 0.001 for histology and p = 0.0002 for PDFF) and between irradiated and control mice (p = 0.005 for histology and p = 0.002 for PDFF). A strong correlation (R2 [~] 0.84) between FF values from PDFF and histology validates the accuracy of the technique. ConclusionsThese findings demonstrate the potential of PDFF MRI as a non-invasive real-time imaging biomarker for quantifying BM fat fraction in preclinical mice model studies, particularly in evaluating the effects of aging, disease progression, and irradiation therapy in pediatric and translational oncology research.

biophysics↗

bioRxiv2021

Longitudinal preclinical imaging characterization of drug delivery potential after radiotherapy in the healthy and leukemic bone marrow vascular microenvironment

ObjectivesRadiotherapy improves blood perfusion and cellular chemotherapy uptake in mice with acute lymphoblastic leukemia (ALL). However, its ability to influence drug delivery and permeation through the bone marrow vasculature (BMV) is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton (L-QMPM) imaging and used it to characterize drug delivery potential and the BMV before and after radiotherapy in mice bearing leukemia. MethodsWe developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after radiotherapy. Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements including tissue wash-in slope (WIStissue) to measure drug delivery potential. We performed L-QMPM imaging using 2 Gy and 10 Gy total body irradiation (TBI) on C57/B6 (WT) mice, mice bearing ALL, and acute myeloid leukemia (AML). ResultsImplants had no effects on calvarium dose, and parameters for WT untreated mice were stable during imaging. We observed increased angiogenesis, decreased single-vessel blood flow, and decreased WIStissue with the onset of AML and ALL. 2Gy and 10Gy TBI increased WIStissue 2 days after radiotherapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Significant increases in WIStissue were observed 2 days after 2Gy TBI compared to 5 days. Morphological and functional alterations in the BMV were sustained for a significantly longer time period after 10Gy TBI (5 days post-treatment) compared to 2Gy TBI (2 days post-treatment). ConclusionL-QMPM provides stable functional assessments of the BMV. TBI increases the drug delivery potential of the leukemic BMV 2-5 days post-treatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant 2Gy and 10Gy TBI condition the BMV for increased drug delivery.

cancer biology↗

bioRxiv2019

AML ImmunoPET: 64Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model

PurposeAcute myeloid leukemia (AML) is a highly aggressive form of leukemia that results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific non-invasive imaging method to assess disease in the whole body, including in extramedullary organs, representing an unmet clinical need. About 85-90% of human myeloid leukemia cells express CD33 (an accepted biomarker for AML) cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.\n\nExperimental DesignIn this study, we evaluated if 64Cu-DOTA-anti-CD33 murine monoclonal antibody (mAb) can be used for ImmunoPET-CT imaging of AML in preclinical model. For translational purpose, a humanized anti-CD33 antibody was produced, and after confirming its anti-CD33 PET-CT imaging ability we further explored its therapeutic potential.\n\nResults64Cu-DOTA-anti-CD33 based PET-CT imaging detected CD33+ AML in mice with high sensitivity (95.65%) and specificity (100%). In the entire skeletal system, CD33+ PET activity was significantly high in the bones of AML bearing mice over non-leukemic control mice; femur (p<0.00001), tibia (p=0.0001), humerus (p=0.0014), and lumber spine (p<0.00001). Interestingly, the imaging showed CD33+ PET activity prevelant in epiphysis/diaphysis of the bones, indicating spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (p=0.02) and 225Ac-anti-CD33-RIT (p<0.00001), significantly reduced disease burden over that of respective controls.\n\nConclusionWe have successfully developed a novel anti-CD33 immunoPET-CT based non-invasive imaging tool for diagnosis of AML and its spatial distribution, which indicates a preferential skeletal niche.\n\nTranslational RelevanceAcute myeloid leukemia (AML) exhibits extensive heterogeneity in therapeutic response, even in patients sharing similar characteristics, indicating the inadequacy of currently used biopsy-based prognostic tools. There is a critical need for non-invasive quantitative imaging modality specific to AML, which is able to assess this disease in the whole body, including in extramedullary organs and to longitudinally monitor treatment response. CD33, an accepted AML biomarker is expressed on more than 85-90% of blast cells and Mylotarg (anti-CD33-ADC) is FDA approved immunotherapy for AML. In this preclinical study using anti-human CD33 mAb (64Cu-DOTA-anti-CD33), a CD33 PET-CT imaging modality was developed that detected AML with high sensitivity and specificity. The approach also indicated spatial heterogeneity in leukemic disease, dependent on disease burden, which warrants caution in analyzing results from single point bone marrow biopsies. Therefore, this imaging modality can be used to non-invasively detect AML in humans and also monitor treatment response, an unmet clinical need.

cancer biology↗

bioRxiv2019

Development of Kinetic Modeling to Assess Multi-functional Vascular Response to Low Dose Radiation in Leukemia

Vascular permeability, tissue transfer rate (Ktrans), fractional extracellular tissue space ({nu}ec) and blood perfusion are crucial parameters to assess bone marrow vasculature (BMV) function. However, quantitative measurements of these parameters in a mouse model are difficult because of limited resolution of standard macroscopic imaging modalities. Using intravital multiphoton microscopy (MPM), live imaging of dextran transfer from BMV to calvarium tissue of mice bearing acute lymphoblastic leukemia (ALL) was performed to obtain BMV parameters. Mice bearing ALL had increased BMV permeability, altered Ktrans, increased {nu}ec, decreased blood perfusion, and increased BMV permeability resulting in reduced drug uptake. Targeted 2 Gy radiation therapy (RT) to mice bearing ALL increased local BMV perfusion and ALL chemotherapy uptake (P<0.0001 and P=0.0036, respectively), suggesting RT prior to chemotherapy treatment may increase treatment efficacy. Developed MPM techniques allow for a quantitative assessment of BMV functional parameters not previously performed with microscopic or macroscopic imaging.

cancer biology↗