Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.

INTRODUCTION: Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use. AREAS COVERED: To design therapies to combat CLD, it is essential to consider the dysregulation of other tissues that contribute to its development and progression. As such, proper therapies must combat this throughout the body rather than focusing only on the liver. To detail this, literature characterizing the pathogenesis of CLD was pulled from PubMed, with a particular focus placed on the role of PDE4 in inflammation and metabolism. Then, the focus is shifted to detailing the available information on existing PDE4 inhibitors. EXPERT OPINION: This review gives a brief overview of some of the pathologies of organ systems that are distinct from the liver but contribute to disease progression. The demonstrated efficacy of PDE4 inhibitors in other human inflammatory diseases should earn them further examination for the treatment of CLD.

Gemcitabine-Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice.

Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment. Moreover, the pancreatic cancer cells that were able to bypass apoptosis after treatment of ONC201 get arrested in the G1-phase, which makes them highly sensitive to GEM. To enhance the in vivo stability of GEM, we first synthesized a disulfide bond containing stearate conjugated GEM (lipid-GEM), which makes it sensitive to the redox tumor microenvironment (TME) comprising high glutathione levels. In addition, with the help of colipids 1,2-dioleoyl-glycero-3-phosphocholine (DOPC), cholesterol, and 1,2-distearoyl-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (DSPE-PEG 2000), we were able to synthesize the lipid-GEM conjugate and ONC201 releasing liposomes. A cumulative drug release study confirmed that both ONC201 and GEM showed sustained release from the formulation. Since MUC1 is highly expressed in 70-90% PDAC, we conjugated a MUC1 binding peptide in the liposomes which showed higher cytotoxicity, apoptosis, and cellular internalization by MIA PaCa-2 cells. A biodistribution study further confirmed that the systemic delivery of the liposomes through the tail vein resulted in a higher accumulation of drugs in orthotopic PDAC tumors in NSG mice. The IHC of the excised tumor grafts further confirmed the higher apoptosis and lower metastasis and cell proliferation. Thus, our MUC1 targeting binary drug-releasing liposomal formulation showed higher drug payload, enhanced plasma stability, and accumulation of drugs in the pancreatic orthotopic tumor and thus is a promising therapeutic alternative for the treatment of PDAC.

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and "KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Recent advances in drug delivery and targeting for the treatment of pancreatic cancer.

Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies. In this review, we discuss how the complexity of various tumor microenvironment (TME) components and the oncogenic signaling pathways that they are connected to actively contribute to the development and spread of PDAC, as well as the ways that recent therapeutic approaches have been targeted to restore it. We also illustrate how many endogenous stimuli-responsive linker-based nanocarriers have recently been developed for the specific targeting of distinct oncogenes and their downstream signaling cascades as well as their ongoing clinical trials. We also discuss the present challenges, prospects, and difficulties in the development of first-line oncogene-targeting medicines for the treatment of pancreatic cancer patients.

Evaluating active leprosy case identification methods in six districts of Nepal.

BACKGROUND: Nepal has achieved and sustained the elimination of leprosy as a public health problem since 2009, but 17 districts and 3 provinces with 41% (10,907,128) of Nepal's population have yet to eliminate the disease. Pediatric cases and grade-2 disabilities (G2D) indicate recent transmission and late diagnosis, respectively, which necessitate active and early case detection. This operational research was performed to identify approaches best suited for early case detection, determine community-based leprosy epidemiology, and identify hidden leprosy cases early and respond with prompt treatment. METHODS: Active case detection was undertaken in two Nepali provinces with the greatest burden of leprosy, Madhesh Province (40% national cases) and Lumbini Province (18%) and at-risk prison populations in Madhesh, Lumbini and Bagmati provinces. Case detection was performed by (1) house-to-house visits among vulnerable populations (n = 26,469); (2) contact examination and tracing (n = 7608); in Madhesh and Lumbini Provinces and, (3) screening prison populations (n = 4428) in Madhesh, Lumbini and Bagmati Provinces of Nepal. Per case direct medical and non-medical costs for each approach were calculated. RESULTS: New case detection rates were highest for contact tracing (250), followed by house-to-house visits (102) and prison screening (45) per 100,000 population screened. However, the cost per case identified was cheapest for house-to-house visits [Nepalese rupee (NPR) 76,500/case], followed by contact tracing (NPR 90,286/case) and prison screening (NPR 298,300/case). House-to-house and contact tracing case paucibacillary/multibacillary (PB:MB) ratios were 59:41 and 68:32; female/male ratios 63:37 and 57:43; pediatric cases 11% in both approaches; and grade-2 disabilities (G2D) 11% and 5%, respectively. Developing leprosy was not significantly different among household and neighbor contacts [odds ratios (OR) = 1.4, 95% confidence interval (CI): 0.24-5.85] and for contacts of MB versus PB cases (OR = 0.7, 95% CI 0.26-2.0). Attack rates were not significantly different among household contacts of MB cases (0.32%, 95% CI 0.07-0.94%) and PB cases (0.13%, 95% CI 0.03-0.73) (χ2 = 0.07, df = 1, P = 0.9) and neighbor contacts of MB cases (0.23%, 0.1-0.46) and PB cases (0.48%, 0.19-0.98) (χ2 = 0.8, df = 1, P = 0.7). BCG vaccination with scar presence had a significant protective effect against leprosy (OR = 0.42, 0.22-0.81). CONCLUSIONS: The most effective case identification approach here is contact tracing, followed by house-to-house visits in vulnerable populations and screening in prisons, although house-to-house visits are cheaper. The findings suggest that hidden cases, recent transmission, and late diagnosis in the community exist and highlight the importance of early case detection.

Seroprevalence of SARS-CoV-2 infection in the general population of Nepal during the first and second generalized waves of the COVID-19 pandemic-2020-2021.

Few seroprevalence studies have been conducted on coronavirus disease (COVID-19) in Nepal. Here, we aimed to estimate seroprevalence and assess risk factors for infection in the general population of Nepal by conducting two rounds of sampling. The first round was in October 2020, at the peak of the first generalized wave of COVID-19, and the second round in July-August 2021, following the peak of the wave caused by the delta variant of SARS-CoV-2. We used cross-sectional probability-to-size (PPS)-based multistage cluster sampling to estimate the seroprevalence in the general population of Nepal at the national and provincial levels. We tested for anti-SARS-CoV-2 total antibody using the WANTAI SARS-CoV-2 Ab ELISA kit. In Round 1, the overall national seroprevalence was 14.4%, with provincial estimates ranging from 5.3% in Sudurpaschim to 27.3% in Madhesh Province. In Round 2, the estimated national seroprevalence was 70.7%, with the highest in the Madhesh Province (84.8%) and the lowest in the Gandaki Province (62.9%). Seroprevalence was comparable between males and females (Round 1, 15.8% vs. 12.2% and Round 2, 72.3% vs. 68.7%). The seroprevalence in the ecozones-Terai, hills, and mountains-was 76.3%, 65.3%, and 60.5% in Round 2 and 17.7%, 11.7%, and 4.6% in Round 1, respectively. In Nepal, COVID-19 vaccination was introduced in January 2021. At the peak of the first generalized wave of COVID-19, most of the population of Nepal remained unexposed to SARS-CoV-2. Towards the end of the second generalized wave in April 2021, two thirds of the population was exposed.

Natural killer cells for pancreatic cancer immunotherapy: Role of nanoparticles.

Advanced pancreatic cancer patients have a dismal prognosis despite advances in integrative therapy. The field of tumor immunology has witnessed significant advancements for cancer treatment. However, immunotherapy for pancreatic cancer is not very effective due to its highly complex tumor microenvironment (TME). Natural killer (NK) cells are lymphocytes that play an important role in the innate immune system. NK cells do not require antigen pre-sensitization, nor are they confined by the major histocompatibility complex (MHC). NK cells have the potential to eliminate cancer cells through CAR-dependent and CAR-independent pathways, demonstrating reduced levels of systemic toxicity in the process. The availability of several potential sources of NK cells is an additional benefit that contributes to meeting the therapeutic criteria. Adding nanotechnology to enhance the functions of effector NK cells is also an appealing strategy. This article primarily discusses various approaches recently been utilized to enhance the NK functions for the treatment of pancreatic cancer. In addition, new advances in boosting NK cell therapeutic efficacy by nanoparticle mediation are presented, with a focus on pancreatic cancer.

Gemcitabine elaidate and ONC201 combination therapy inhibits pancreatic cancer in a KRAS mutated syngeneic mouse model.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to access of toxicity. ONC201 targets DR5 to induce apoptosis in several types of cancers and has an excellent safety profile. ONC201 is also a dual PI3K/AKT and MEK pathways inhibitor. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable, which can be stabilized by prodrug approach. Here, we used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. We evaluated the efficacy of L_GEM and ONC201 in PanCan cells, and "KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. ONC201, in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade, to overcome chemoresistance, and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Anti-miR-96 and Hh pathway inhibitor MDB5 synergistically ameliorate alcohol-associated liver injury in mice.

Alcohol-associated liver disease (ALD) and its complications are significant health problems worldwide. Several pathways in ALD are influenced by alcohol that drives inflammation, fatty acid metabolism, and fibrosis. Although miR-96 has become a key regulator in several liver diseases, its function in ALD remains unclear. In contrast, sonic hedgehog (SHH) signaling has a well-defined role in liver disease through influencing the activation of hepatic stellate cells (HSCs) and the inducement of liver fibrosis. In this study, we investigated the expression patterns of miR-96 and Hh molecules in mouse and human liver samples. We showed that miR-96 and Shh were upregulated in ethanol-fed mice. Furthermore, alcoholic hepatitis (AH) patient specimens also showed upregulated FOXO3a, TGF-ß1, SHH, and GLI2 proteins. We then examined the effects of Hh inhibitor MDB5 and anti-miR-96 on inflammatory and extracellular matrix (ECM)-related genes. We identified FOXO3 and SMAD7 as direct target genes of miR-96. Inhibition of miR-96 decreased the expression of these genes in vitro in AML12 cells, HSC-T6 cells, and in vivo in ALD mice. Furthermore, MDB5 decreased HSCs activation and the expression of ECM-related genes, such as Gli1, Tgf-ß1, and collagen. Lipid nanoparticles (LNPs) loaded with the combination of MDB5, and anti-miR-96 ameliorated ALD in mice. Our study demonstrated that this combination therapy could serve as a new therapeutic target for ALD.

Targeting BRD4 and PI3K signaling pathways for the treatment of medulloblastoma.

Medulloblastoma (MB) is a malignant pediatric brain tumor which shows upregulation of MYC and sonic hedgehog (SHH) signaling. SHH inhibitors face acquired resistance, which is a major cause of relapse. Further, direct MYC oncogene inhibition is challenging, inhibition of MYC upstream insulin-like growth factor/ phosphatidylinositol-4,5-bisphosphate 3-kinase (IGF/PI3K) is a promising alternative. While PI3K inhibition activates resistance mechanisms, simultaneous inhibition of bromodomain-containing protein 4 (BRD4) and PI3K can overcome resistance. We synthesized a new molecule 8-(2,3-dihydrobenzo[b] [1, 4] dioxin-6-yl)-2-morpholino-4H-chromen-4-one (MDP5) that targets both BRD4 and PI3K pathways. We used X-ray crystal structures and a molecular modeling approach to confirm the interactions between MDP5 with bromo domains (BDs) from both BRD2 and BRD4, and molecular modeling for PI3K binding. MDP5 was shown to inhibit target pathways and MB cell growth in vitro and in vivo. MDP5 showed higher potency in DAOY cells (IC50 5.5 µM) compared to SF2523 (IC50 12.6 µM), and its IC50 values in HD-MB03 cells were like SF2523. Treatment of MB cells with MDP5 significantly decreased colony formation, increased apoptosis, and halted cell cycle progression. Further, MDP5 was well tolerated in NSG mice bearing either xenograft or orthotopic MB tumors at the dose of 20 mg/kg, and significantly reduced tumor growth and prolonged animal survival.

Recent advances in drug delivery and targeting to the brain.

Our body keeps separating the toxic chemicals in the blood from the brain. A significant number of drugs do not enter the central nervous system (CNS) due to the blood-brain barrier (BBB). Certain diseases, such as tumor growth and stroke, are known to increase the permeability of the BBB. However, the heterogeneity of this permeation makes it difficult and unpredictable to transport drugs to the brain. In recent years, research has been directed toward increasing drug penetration inside the brain, and nanomedicine has emerged as a promising approach. Active targeting requires one or more specific ligands on the surface of nanoparticles (NPs), which brain endothelial cells (ECs) recognize, allowing controlled drug delivery compared to conventional targeting strategies. This review highlights the mechanistic insights about different cell types contributing to the development and maintenance of the BBB and summarizes the recent advancement in brain-specific NPs for different pathological conditions. Furthermore, fundamental properties of brain-targeted NPs will be discussed, and the standard lesion features classified by neurological pathology are summarized.

Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease.

The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted ß-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber-DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid ß-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice.

pH-sensitive nanomedicine of novel tubulin polymerization inhibitor for lung metastatic melanoma.

Microtubule binding agents such as paclitaxel and vincristine have activity in metastatic melanoma. However, even responsive tumors develop resistance, highlighting the need to investigate new drug molecules. Here, we showed that a new compound, CH-2-102, developed by our group, has high anti-tumor efficacy in human and murine melanoma cells. We confirmed that CH-2-102 robustly suppresses the microtubule polymerization process by directly interacting with the colchicine binding site. Our results unveil that CH-2-102 suppresses microtubule polymerization and subsequently induces G2 phase cell arrest as one of the possible mechanisms. Notably, CH-2-102 maintains its efficacy even in the paclitaxel resistance melanoma cells due to different binding sites and a non-Pgp substrate. We developed a pH-responsive drug-polymer Schiff bases linker for high drug loading into nanoparticles (NPs). Our CH-2-102 conjugated NPs induced tumor regression more effectively than Abraxane® (Nab-paclitaxel, N-PTX), free drug, and non-sensitive NPs in B16-F10 cell-derived lung metastasis mouse model. Furthermore, our results suggest that the formulation has a high impact on the in vivo efficacy of the drug and warrants further investigation in other cancers, particularly taxane resistant. In conclusion, the microtubule polymerization inhibitor CH-2-102 conjugated pH-responsive NPs induce tumor regression in lung metastasis melanoma mice, suggesting it may be an effective strategy for treating metastatic melanoma.

Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia.

INTRODUCTION: Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection. MATERIALS AND METHODS: In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418). In the present report, we demonstrate feasibility of this approach. RESULTS: Broad eligibility criteria and co-management of patients with community oncologists allowed enrollment of 45% of all patients with AML treated at our center during the study period. The median time from enrollment to therapy initiation was two days (range 0-9). Over half of the trial patients had a score of ≥3 on hematopoietic cell transplantation comorbidity index, impairment in physical function (Short Physical Performance Battery), and Montreal Cognitive Assessment. Three fit patients received intensive chemotherapy, whereas other patients received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 3.7% (95% confidence interval [CI] 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). One-year overall survival was 66% (95% CI 60-87%). DISCUSSION: Our data demonstrate the feasibility of integrating geriatric assessment in precision oncology trials to define fitness for intensive chemotherapy. Broad eligibility criteria and academic-community collaboration can expand access to clinical trials.

Effect of magnesium stearate surface coating method on the aerosol performance and permeability of micronized fluticasone propionate.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis. Additional techniques were used to determine powder properties such as the dynamic vapor sorption (DVS), particle size distribution (PSD) by laser diffraction light scattering, and particle surface properties by scanning electron microscope (SEM). The aerodynamic performance was studied by the next-generation impactor (NGI) using drug-loaded capsules in a PlastiApi® device. Physiochemical properties such as porosity, particle size distribution, and surface area of the formulations were studied with adsorption and desorption curves fitted to several well-known models including Brunauer-Emmett-Teller (BET), Barret Joyner Halenda (BJH), and the density functional theory (DFT). The dissolution behavior of the formulations collected on the transwell inserts incorporated into stages 3, 5, and 7 of the NGI with a membrane providing an air interface was evaluated. Drug permeability of formulations was assessed by directly depositing particles on Calu-3 cells at the air-liquid interface (ALI). Drug concentration was determined by LC-MS/MS. A better MgSt mixing on micronized FP particles was achieved by mixing with a RAM with and without heating than with a tumble mixer. A significant concomitant increase in the % of emitted dose and powder aerosol performance was observed after MgSt mixing. Formulation 4 (RAM mixing at room temperature) showed the highest rate of permeability and correlation with dissolution profile. The results show that the surface enrichment of hydrophobic MgSt improved aerosolization properties and the dissolution and permeability rate of micronized FP by reducing powder agglomerations. A simple low-shear acoustic dry powder mixing method was found to be efficient and substantially improved the powder aerosolization properties and enhanced dissolution and permeability rate.

Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma.

Chemoresistance and inadequate therapeutics transport across the blood brain barrier (BBB) remain the major barriers to treating medulloblastoma (MB). Hedgehog (Hh) and IGF/PI3K pathways regulate tumor cell proliferation and resistance in MB. Current Hh inhibitors are effective initially to treat SHH-MB but acquire resistance. Herein, we showed that Hh inhibitor MDB5 and BRD4/PI3K dual inhibitor SF2523 synergistically inhibited the proliferation of DAOY and HD-MB03 cells when used in combination. Treatment of these MB cells with the combination of MDB5 and SF2523 significantly decreased colony formation and expression of MYCN, p-AKT, and cyclin D1 but significantly increased in Bax expression, compared to individual drugs. We used our previously reported copolymer mPEG-b-PCC-g-DC copolymer, which showed 8.7 ± 1.0 and 6.5 ± 0.1% loading for MDB5 and SF2523 when formulated into nanoparticles (NPs). There was sustained drug release from NPs, wherein 100% of MDB5 was released in 50 h, but only 60% of SF2523 was released in 80 h. Targeted NPs prepared by mixing 30:70 ratio of COG-133-PEG-b-PBC and mPEG-b-PCC-g-DC copolymer delivered a significantly higher drug concentration in the cerebellum at 6 and 24h after intravenous injection into orthotopic SHH-MB tumor-bearing NSG mice. Moreover, systemic administration of COG-133-NPs loaded with MDB5 and SF2523 resulted in decreased tumor burden compared to non-targeted drug-loaded NPs, without any hepatic toxicity. In conclusion, our nanomedicine of MDB5 and SF2523 offers a novel therapeutic strategy to treat chemoresistant MB.