Lake Medlock Dr

DEVELOPMENT OF "IMAGNOSTIX": A LIQUID BIOPSY SYSTEM FOR ALZHEIMER'S DISEASE - PROJECT SUMMARY DEVELOPMENT OF AD/ADRD MAY TAKE 15 TO 20 YEARS PRIOR TO SYMPTOMS. HOWEVER, CURRENT DIAGNOSIS AND DIFFERENTIATION OF AD/ADRD FROM OTHER DEMENTIAS AND EVEN COGNITIVE DECLINE ASSOCIATED WITH AGING IS MOSTLY SYMPTOM-BASED, HEAVILY RELYING ON NEUROLOGICAL AND COGNITIVE TESTS, FOLLOWED BY CONFIRMATION WITH BIOMARKER- SPECIFIC POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AND MOST RECENTLY DETECTION OF CHANGES IN AD BIOMARKERS IN CEREBROSPINAL FLUID (CSF). DELAYED DIAGNOSIS AND LACK OF TREATMENT OPTIONS TO SLOW OR REVERSE DISEASE PROGRESSION ARE MAJOR CHALLENGES IN MANAGING AD/ADRD, LARGELY DUE TO THE LACK OF EARLY AND ACCURATE DIAGNOSTIC. DETECTING AD AT PRODROMAL OR EVEN PRE-SYMPTOMATIC STAGE TO ALLOW TIMELY INTERVENTION HAS BEEN CONSIDERED THE BEST APPROACH TO MANAGE AD/ADRD. WHILE RECENT FDA-APPROVALS OF TWO DISEASE-MODIFYING DRUGS, I.E., ADUCANUMAB (ACCELERATED APPROVAL IN 2021) AND LECANEMAB (TRADITIONAL APPROVAL IN 2023), ALONG WITH THOSE IN THE PIPELINE, SUCH AS DONANEMAB FOR EARLY SYMPTOMATIC AD PARTICIPANTS8, ARE SIGNIFICANT ADVANCES THAT BROUGHT HOPE FOR MANY AD PATIENTS AND THEIR FAMILIES. THESE TREATMENTS ARE ONLY EFFECTIVE WHEN PATIENTS CAN BE DIAGNOSED AT AN EARLY STAGE AND PRESENT THE PATHOLOGY TARGETED BY THESE NEW DRUGS. THEREFORE, THERE IS AN URGENT DEMAND FOR BIOMARKER-BASED DETECTIONS FOR EARLY DIAGNOSIS FOR AD/ADRD, STRATIFICATION OF PATIENTS FOR TREATMENT AND MONITORING TREATMENT RESPONSES AND DISEASE PROGRESSION, IN PARTICULAR, COST-EFFECTIVE, EASY-TO- ACCESS AND REPEATABLE TESTS THAT CAN BE ROUTINELY APPLIED FOR PATIENTS AND THOSE WITH AD/ADRD RISKS. THE URGENT NEED OF BLOOD SAMPLE-BASED AD DIAGNOSIS PROMOTED FDA’S RECENT BREAKTHROUGH DEVICE DESIGNATIONS FOR TWO BLOOD-BASED AD DETECTION SYSTEMS, I.E., PRECIVITYAD® (2019) AND SIMOA® (2022). BOTH DETECTIONS REQUIRE BLOOD SAMPLE PROCESSING, STORAGE AND TRANSPORTATION, BEFORE MEASUREMENT USING HIGHLY SOPHISTICATED ANALYTIC INSTRUMENTS BY HIGHLY-SKILLED AND EXPERIENCE PERSONNEL, ALL OF WHICH CAN LIMIT THEIR AVAILABILITY AND COST- EFFECTIVENESS. THIS PHASE II SBIR PROJECT AIMS TO DEVELOP A MULTIPLEXED LIQUID BIOPSY, NAMELY IMAGNOSTIX, FOR DETECTION AND QUANTIFICATION OF FOUR AD BIOMARKERS. IMAGNOSTIX IS ANTICIPATED TO BE COST-EFFECTIVE, DEPLOYABLE, EASY TO OPERATE, AND CAPABLE OF QUICK TURN-AROUND TEST, WHILE STILL OFFERING A GOOD DETECTION SENSITIVITY. IT CAN BE USED FOR ROUTINE BLOOD TESTS OF INDIVIDUALS AT RISK, MONITORING OF DISEASE PROGRESSION OR TREATMENT RESPONSES, AND IN THE FUTURE, EVEN SCREENING AD/ADRD.

MULTI-FUNCTIONAL MAGNETIC NANORODS FOR CONSTRUCTING THERANOSTIC EXTRACELLULAR VESICLES FOR TREATING MYOCARDIAL INFARCTION - PROJECT SUMMARY CARDIOVASCULAR DISEASE (CVD) REMAINS THE LEADING CAUSE OF DEATH AND A GLOBAL PUBLIC HEALTH BURDEN. MYOCARDIAL INJURY WITH INFARCTION (MI) IS A COMMON CVD THAT IS ASSOCIATED WITH HEART FAILURE AND EVEN DEATH. CELL-, ESPECIALLY STEM CELL (SC)-BASED THERAPIES HAS BEEN OF GREAT INTEREST FOR TREATING HEART DISEASES, BECAUSE 1) THE ADULT HEART HAS A LIMITED NUMBER OF SCS AND THUS LIMITED CAPACITY OF SELF-REPAIR AND REGENERATION, AND 2) CURRENT TREATMENT STRATEGIES ARE ONLY ABLE TO LIMIT THE ENSUING ADVERSE DILATATION AND IMPAIRED CONTRACTILE FUNCTION. HOWEVER, CLINICAL TRANSLATION OF SC-BASED THERAPIES REMAINS CUMBERSOME WITH VERY FEW SUCCESSES, IN A LARGE PART DUE TO THE SAFETY AND ETHICAL CONCERNS OVER UNCONTROLLABLE DIFFERENTIATION OF INJECTED CELLS IN PATIENTS. AS MOUNTING EVIDENCE REVEALS THE SC-INDUCED REPAIRING FUNCTIONS PREDOMINATELY DERIVED FROM THE PARACRINE EFFECT MEDIATED BY EXTRACELLULAR VESICLES (EVS), THERAPIES BASED ON SC-DERIVED EVS (SC-EVS) HAVE EMERGED AS A HIGHLY PROMISING APPROACH FOR CELL-FREE REGENERATIVE MEDICINE THAT DELIVERS HIGH POTENCY BUT LESS SIDE-EFFECT ASSOCIATED WITH CONVENTIONAL CELL-BASED THERAPY. A MAJOR LIMITING FACTOR TO THE EFFICACY OF EV-BASED TREATMENT IS THE EFFECTIVENESS OF EV DELIVERY TO TARGET TISSUES. INDEED, MOST ANIMAL STUDIES EMPLOYED DIRECT CARDIAC INJECTION IN ORDER TO ACHIEVE SIGNIFICANT TREATMENT EFFECTS, ALTHOUGH SYSTEMIC ADMINISTRATION IS MUCH PREFERRED IN THE CLINIC. MOREOVER, CLINICAL TRANSLATION OF NEW EV THERAPIES REQUIRES NON-INVASIVE IMAGING FOR MONITORING AND QUANTIFICATION OF EV DELIVERY AND TREATMENT RESPONSES INPATIENTS, WHICH HAVE NOT BEEN FULLY DEVELOPED YET. THE OVERALL GOAL OF THIS STTR PHASE I PROJECT TAKES AN IMPORTANT FIRST STEP TO TRANSLATE AN MRI-GUIDED, THERANOSTIC (THERAPEUTICS + DIAGNOSTICS) EV PLATFORM DEVELOPED IN THE RESEARCH LAB FOR EFFECTIVELY TREATING INJURED MYOCARDIUM IN ACUTE MI. THIS COLLABORATIVE PROJECT, BETWEEN 5M BIOMED AND KENNEDY KRIEGER INSTITUTE (KKI)/JOHNS HOPKINS UNIVERSITY (JHU), IS BUILT ON OUR INNOVATIONS IN MAGNETIC LABELING AND PURIFICATION OF THERAPEUTIC HUMAN SC-EVS, MRI-BASED EV TRACKING, AND ULTRA-MAGNETIC IRON OXIDE NANORODS (IONRS). WE WILL FOCUS ON DEVELOPING AND VALIDATING A TRANSLATABLE THERANOSTIC EV SYSTEM, USING MULTIFUNCTIONAL ULTRA-MAGNETIC IONRS THAT ARE SUITABLE FOR EFFICIENT MAGNETIC PURIFICATION/ENRICHMENT, MAGNETIC TARGETING, AND NON-INVASIVE MRI OF EVS. WE WILL COLLABORATE CLOSELY TO 1) DEVELOP AND OPTIMIZE ULTRA-MAGNETIC IONRS FOR EFFICIENT PREPARATION OF MAGEV WITH HIGH MRI CONTRAST EFFECT, AND 2) TEST AND VALIDATE THE DELIVERY AND EFFICACY OF MAGEV LABELED WITH IONRS IN IMAGING AND TREATING MI. THE BENCHMARK OF SUCCESS IS TO ACHIEVE AN OPTIMAL FORMULATION OF MAGEV, I.E., MINIMAL INTERFERENCE OF IONRS ON MAGEV FUNCTIONALITIES AND THERAPEUTIC POTENTIAL TOGETHER WITH HIGH MRI CAPABILITY AND MAGNETISM. THE SUCCESS OF PHASE I STUDY WILL LEAD TO THE PHASE II PROJECT, WHICH WILL FOCUS ON SCALE-UP MANUFACTURING OF MAGEVS TOWARDS INVESTIGATIONAL NEW DRUG (IND) APPLICATION AND LARGE-ANIMAL TESTING WHICH WILL GUIDE SUBSEQUENT FIRST-IN-HUMAN STUDIES.

SMALL INTESTINE TARGETED FAST ACTING ORAL INSULIN FORMULATION - PROJECT SUMMARY DIABETES MELLITUS IS A CLASS OF METABOLIC DISEASES CHARACTERIZED BY CHRONIC HYPERGLYCEMIA DUE TO IMPAIRED INSULIN SECRETION AND/OR INSULIN RESISTANCE. PATIENTS ARE SUBJECT TO LIFE-LONG MANAGEMENT OF THEIR DIABETIC CONDITIONS AND THE HIGH RISK OF MACRO AND MICROVASCULAR COMPLICATIONS. INSULIN THERAPY IS THE MOST EFFECTIVE MEANS OF LOWERING BLOOD GLUCOSE FOR TYPE 1 DIABETES MELLITUS (T1DM) PATIENTS WITH COMPLETE ABSENCE OF ENDOGENOUS INSULIN AND TYPE 2 DIABETES MELLITUS (T2DM) PATIENTS WITH PROGRESSIVELY DEPLETED INSULIN SECRETING PANCREATIC Β-CELLS AND INSULIN RESISTANT ORGANS AND TISSUE. IT IS ALSO USED FOR CONTROLLING SHORT-TERM HYPERGLYCEMIA IN GESTATIONAL DIABETES MELLITUS (GDM). THE CURRENT THERAPY IS SUBCUTANEOUS INJECTION OR INFUSION OF INSULIN. HOWEVER, THE POOR PATIENT ADHERENCE DUE TO INCONVENIENCE AND PSYCHOLOGICAL INSULIN RESISTANCE (PIR) TO ROUTINE INJECTION IS STILL A MAJOR HINDRANCE IN MANAGING DIABETIC PATIENTS. FURTHERMORE, LONG- TERM USE OF INSULIN INJECTION CAN CAUSE SIDE EFFECTS, INCLUDING LIPODYSTROPHY, IATROGENIC HYPERINSULINEMIA, AND HYPOGLYCEMIA. ORALLY DELIVERED INSULIN, ON THE OTHER HAND, POSSESSES ADVANTAGES IN PATIENT ADHERENCE AND THERAPEUTIC EFFECT BY MIMICKING THE PHYSIOLOGICAL PATH OF ENDOGENOUS INSULIN. HOWEVER, THE DEVELOPMENT OF ORAL INSULIN FORMULATIONS HAS NOT YET BEEN SUCCESSFUL DUE TO LOW INSULIN BIOAVAILABILITY, STEMMING FROM THE DEGRADATION IN THE HIGHLY ACIDIC AND PROTEASE-ACTIVE STOMACH AND INSUFFICIENT PERMEABILITY THROUGH THE INTESTINAL EPITHELIUM AND MUCOSA. THIS STTR PHASE I PROJECT AIMS TO DEVELOP A FAST-ACTING ORAL INSULIN FORMULATION BASED ON THE PATENTED INNOVATION OF MILK PROTEIN CASEIN COATED DRUG-CARRYING NANOPARTICLES (CASNP) TO ENCAPSULATE INSULIN AND THE INTESTINAL ABSORPTION ENHANCER, SODIUM CAPRATE (C10), FOR SMALL INTESTINE-TARGETED DELIVERY OF INSULIN BY PROTECTING INSULIN AND C10 FROM THE GASTRIC PH AND PROTEASE ACTION BUT ENABLING THE ENZYME-TRIGGERED RELEASE OF INSULIN AND C10 IN THE SMALL INTESTINE. THE LIQUID FORMULATION OF NANO-SIZED CASNP/INSLULIN/C10 ALSO FACILITATES RAPID GASTRIC EMPTYING AND INTESTINAL PERMEATION AND ABSORPTION AS EXPECTED IN A FAST-ACTING ORAL INSULIN AGENT FOR CONTROLLING THE POSTPRANDIAL BLOOD GLUCOSE LEVELS. DEVELOPED CASNP/INSULIN/C10 NANOCONSTRUCT AND ENCAPSULATED INSULIN WILL BE LABELED WITH NEAR INFRARED (NIR) FLUORESCENT DYES FOR NON-INVASIVE TRACKING OF CASNP/INSULIN/C10 DELIVERY AND THE SUBSEQUENT INSULIN RELEASE AND ABSORPTION IN THE STREPTOZOTOCIN (STZ) INDUCED DIABETIC MOUSE MODEL. WE WILL PREPARE AND OPTIMIZE THE CASNP/INSULIN/C10 FORMULATION WITH DESIRED PHYSIOCHEMICAL AND BIOLOGICAL PROPERTIES, INCLUDING INSULIN AND C10 LOADING CAPACITIES, STABILITY IN THE SIMULATED GASTRIC CONDITION AND CONTROLLED RELEASE IN THE INTESTINE-MIMICKING CONDITION (AIM 1). WE WILL DETERMINE THE BIODISTRIBUTION OF CASNP/INSULIN/C10, PLASMA AND HEPATIC INSULIN BIOAVAILABILITY AND THE SYSTEMIC CYTOTOXICITY IN STZ-INDUCED DIABETIC MICE USING NIR AND MAGNETIC RESONANCE IMAGING ALONG WITH HISTOPATHOLOGICAL ANALYSES AND VALIDATION, FOLLOWED BY EVALUATING THE EFFICACY OF CASNP/INSULIN/C10 IN CONTROLLING HYPERGLYCEMIA (AIM 2).

A NEW CLASS OF MAGNETIC NANOPARTICLES FOR GLIOMA TARGETED DRUG DELIVERY - PROJECT SUMMARY GLIOBLASTOMA IS THE MOST COMMON AND AGGRESSIVE MALIGNANT BRAIN TUMOR WITH EXTREMELY POOR PROGNOSIS. CURRENT STANDARD CARE FOR GLIOBLASTOMA TREATMENT CONSISTS OF MAXIMAL SURGICAL RESECTION FOLLOWED BY CHEMOTHERAPY AND RADIATION THERAPY. UNFORTUNATELY, IT HARDLY PRODUCES LONG-TERM CONTROL ON TUMOR PROGRESSION. DUE TO THE HIGHLY HETEROGENEOUS, INFILTRATING AND RECURRING NATURES OF GLIOBLASTOMAS, CHEMOTHERAPY PLAYS A CRUCIAL ROLE IN CLINICAL MANAGEMENT OF GLIOBLASTOMAS. HOWEVER, EXISTING CHEMOTHERAPIES IN BRAIN TUMOR TREATMENT ARE MOSTLY DISAPPOINTING, OFTEN DUE TO POOR DELIVERY OF CHEMOTHERAPY AGENTS STEMMING FROM THEIR LOW WATER SOLUBILITY AND/OR INABILITY OF CROSSING THE BLOOD BRAIN BARRIER (BBB) OR BLOOD TUMOR BARRIER (BTB). ALTHOUGH NANOMATERIAL-BASED DRUG DELIVERY SYSTEMS HAVE SHOWN ADVANTAGES BY ENHANCING THE DELIVERY EFFICIENCY AND IMPROVING THE SAFETY PROFILE OF THERAPEUTICS OVER CONVENTIONAL CHEMOTHERAPY FORMULATIONS IN TREATING MANY CANCERS, THEIR DEVELOPMENT AND APPLICATIONS IN BRAIN TUMOR TREATMENT ARE LARGELY LIMITED, BECAUSE OF DELIVERY CHALLENGES IN CURRENT NANO-DELIVERY SYSTEMS WITH SIZES OF 10-200 NM. SUPPORTED BY THE PREMISES THAT: 1) FERUMOXYTOL (FERAHEME®), AN FDA APPROVED IRON OXIDE NANOPARTICLE FOR TREATING IRON DEFICIENCY ANEMIA, CAN BE USED FOR IMAGING BRAIN TUMOR WITH MAGNETIC RESONANCE IMAGING (MRI) IN PATIENTS, AND 2) OUR SUB-5 NM ULTRAFINE IRON OXIDE NANOPARTICLE (UIONP) CAN REACH BRAIN TUMORS IN THE INTRACRANIAL GLIOMA MOUSE MODEL TO ENHANCE TUMORS IN MRI WITH T1 CONTRAST, THIS STTR PHASE I PROJECT AIMS TO DEVELOP A NEW CLASS OF DRUG-CARRYING AND GLIOBLASTOMA TARGETED IONP FOR DELIVERING HIGHLY POTENT YET WATER-INSOLUBLE CHEMOTHERAPY AGENT SN38, THE ACTIVE AND MUCH MORE POTENT FORM OF CHEMOTHERAPY AGENT IRINOTECAN (CPT-11) USED IN TREATING MANY OTHER CANCERS IN ONCOLOGY CLINIC, FOR TREATING INTRACRANIAL BRAIN TUMORS. WE WILL INCORPORATE OUR PATENTED AMPHIPHILIC POLY(ETHYLENE GLYCOL)-BLOCK-(ALLYL GLYCIDYL ETHER) (PEG-B-AGE) COATING POLYMER FOR UIONPS TO ENCAPSULATE HYDROPHOBIC SN38, WHICH HAS NOT BEEN USED FOR TREATING BRAIN TUMORS DUE TO POOR INTRACRANIAL DELIVERY. TRI-PEPTIDE RGD WITH WELL-DOCUMENTED FUNCTIONS AND SAFETY PROFILE IS SELECTED AS THE LIGAND FOR FUNCTIONALIZING UIONPS TO TARGET ΑVΒ3 INTEGRIN OVEREXPRESSED IN GLIOBLASTOMAS. IN THE PROPOSED PROJECT, WE WILL PREPARE AND OPTIMIZE THE RGD-CONJUGATED UIONP WITH SN38 LOADING (RGD-UIONP/SN38) WITH CONSISTENT PHYSIOCHEMICAL AND BIOLOGICAL PROPERTIES, INCLUDING SN38 LOADING EFFICIENCY, SURFACE CHARGE, DENSITY OF CONJUGATED THE TARGETING LIGAND, GLIOBLASTOMA CELL TARGETING, INTRACELLULAR DRUG RELEASE AND CYTOTOXICITY, AND STABILITY (AIM 1). WE WILL THEN USE AN INTRACRANIAL MOUSE MODEL TO INVESTIGATE THE BLOOD HALF-LIFE, BIODISTRIBUTION, CLEARANCE, AND TUMOR UPTAKE AND INTRA-TUMORAL DISTRIBUTION OF DEVELOPED RGD-UIONP/SN38 AS WELL AS THE STABILITY OF THIS PLATFORM IN BLOOD AND ORGANS IN AIM 2, FOLLOWED BY DETERMINING THE EFFICACY OF RGD- UIONP/SN38 IN INHIBITING THE TUMOR GROWTH BASED ON MRI IN VIVO AND HISTOPATHOLOGICAL ANALYSIS. THE RESULTS WILL LEAD TO THE FURTHER DEVELOPMENT OF THIS SYSTEM TOWARDS CLINICAL TRANSLATION IN THE PHASE II PROJECT.

HIGHLY SENSITIVE AND ROBUST BLOOD TEST PLATFORM FOR SCREENING AND EARLY DETECTION OF ALZHEIMER'S DISEASE - WITH AN EFFECTIVE TREATMENT YET TO BE DEVELOPED, EARLY DETECTION AND SURVEILLANCE OF DISEASE PROGRESSION FOR ALZHEIMER’S DISEASE (AD) AND ALZHEIMER’S DISEASE RELATED DEMENTIAS (ADRD) ARE CRITICAL FOR THE MANAGEMENT AND INTERVENTION OF AD/ADRD. THE RECENT ACCELERATED APPROVAL OF THE NEW MONOCLONAL ANTIBODY DRUG TARGETING AMYLOID-Β, ADUCANUMAB®, BY FDA, WHICH IS LIKELY MORE EFFICACIOUS WHEN TREATING PROPERLY STRATIFIED PATIENTS, HIGHLIGHTED THE URGENT CLINICAL NEED FOR EARLY AND BIOMARKER-SPECIFIC DIAGNOSIS OF AD. CURRENT CLINICAL PRACTICES WITH AD BIOMARKER TARGETED POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AND CEREBROSPINAL FLUID (CSF) SAMPLE BASED PROTEOMICS ANALYSIS ARE NOT DESIRABLE POINT-OF-CARE (POC) SOLUTIONS FOR EARLY DETECTION DUE TO THE LIMITED AVAILABILITY AND ACCESSIBILITY OF IMAGING FACILITIES OR INVASIVE LUMBAR PUNCTURE FOR CSF COLLECTION. GIVEN THE ADVANTAGES OF NON-INVASIVENESS, COST EFFECTIVENESS AND EASY ACCESS IN GENERAL CLINICAL SETTINGS, BLOOD-BASED AD BIOMARKER DETECTIONS ARE MORE APPLICABLE POC DIAGNOSTIC TOOLS FOR EARLY DIAGNOSIS OF AD/ADRD. WHILE TWO PLATFORMS, I.E., PRECIVITYADTM FOR AΒ40/AΒ42 DETECTION AND SIMOA® FOR PHOSPHO-TAU 181 (P-TAU181), WERE RECENTLY GRANTED FDA BREAKTHROUGH DEVICE DESIGNATIONS FOR CLINICAL USES, BOTH SYSTEMS REQUIRE HIGHLY SPECIALIZED HIGH-END INSTRUMENTS FOR SAMPLE TESTING, LIMITING THEIR WIDE AVAILABILITY, PARTICULARLY IN THE COMMUNITIES AND REGIONS WITH LOW OR LIMITED RESOURCES AND HEALTH DISPARITY. FURTHERMORE, PRECIVITYADTM AND SIMOA® USE ANTIBODY-COATED MAGNETIC BEADS TO CAPTURE TARGETED AD BIOMARKERS. HOWEVER, THE NON-SPECIFIC ADSORPTION OF SERUM PROTEINS ON THE SURFACE OF BEADS FORMS A PROTEIN CORONA THAT CAN BLOCK THE ANTIBODY FROM CAPTURING BIOMARKERS. IN THIS SBIR PHASE I PROJECT, WE AIM TO DEVELOP A MULTIPLEXED AD BIOMARKER DETECTION PLATFORM THAT CAN INTEGRATE TWO INNOVATIVE TECHNOLOGIES, I.E., ULTRAMAGNETIC IRON OXIDE NANORODS (IONRS) AND ANTI-BIOFOULING POLYMER COATING FOR IONRS, FOR MULTIPLEXING SIX AD BIOMARKERS IN BLOOD SAMPLES. THE IONRS PROVIDE AS STRONG MAGNETISM AS THE MAGNETIC BEADS USED IN PRECIVITYADTM AND SIMOA®, AND ALSO FUNCTION AS NANO-STIRRING-BARS TO IMPROVE SAMPLE MIXING, UNDER AN ALTERNATING ELECTROMAGNETIC FIELD, FOR MORE EFFICIENT BIOMARKER CAPTURING. THE ANTI-BIOFOULING COATING MINIMIZES NON-SPECIFIC SERUM PROTEIN ADSORPTION ON IONRS TO PRESERVE THE ANTIBODY AFFINITY FOR TARGETED BIOMARKERS IN BLOOD SAMPLES. THE PHASE I PROJECT WILL FOCUS ON (1) DEVELOPING A PROTOTYPE DEVICE ENABLING EFFICIENT BLOOD SAMPLE MIXING WITH ANTI-BIOFOULING IONRS AND MULTIPLEXED DETECTION OF SIX AD BIOMARKERS, I.E., AΒ40, AΒ42, TOTAL-TAU (T-TAU), P-TAU181, AMYLOID PRECURSOR PROTEIN (APP669-711), AND NEUROFILAMENT LIGHT PROTEIN (NFL), AND (2) TESTING THE DEVELOPED SYSTEM AND EVALUATE ITS PERFORMANCE USING THE PATIENT SAMPLES, FOLLOWED BY COMPARING AND CORRELATING THE RESULTS WITH CLINICAL DIAGNOSIS AND IMAGING FINDINGS OF THE SAME PATIENTS. IF SUCCESSFUL, THE DEVICE, TO BE FURTHER ASSESSED BY LARGE-SCALE TESTS IN PHASE II, WILL PROVIDE A ROBUST AND COST-EFFECTIVE POC DETECTION FOR SCREENING AND DETECTING AD IN INDIVIDUALS AT RISK AS WELL AS SURVEILLING THE PROGRESSION AND TREATMENT RESPONSE FOR PATIENTS.

HIGHLY SENSITIVE AND ROBUST BLOOD TEST PLATFORM FOR SCREENING AND EARLY DETECTION OF ALZHEIMER'S DISEASE - WITH AN EFFECTIVE TREATMENT YET TO BE DEVELOPED, EARLY DETECTION AND SURVEILLANCE OF DISEASE PROGRESSION FOR ALZHEIMER’S DISEASE (AD) AND ALZHEIMER’S DISEASE RELATED DEMENTIAS (ADRD) ARE CRITICAL FOR THE MANAGEMENT AND INTERVENTION OF AD/ADRD. THE RECENT ACCELERATED APPROVAL OF THE NEW MONOCLONAL ANTIBODY DRUG TARGETING AMYLOID-Β, ADUCANUMAB®, BY FDA, WHICH IS LIKELY MORE EFFICACIOUS WHEN TREATING PROPERLY STRATIFIED PATIENTS, HIGHLIGHTED THE URGENT CLINICAL NEED FOR EARLY AND BIOMARKER-SPECIFIC DIAGNOSIS OF AD. CURRENT CLINICAL PRACTICES WITH AD BIOMARKER TARGETED POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AND CEREBROSPINAL FLUID (CSF) SAMPLE BASED PROTEOMICS ANALYSIS ARE NOT DESIRABLE POINT-OF-CARE (POC) SOLUTIONS FOR EARLY DETECTION DUE TO THE LIMITED AVAILABILITY AND ACCESSIBILITY OF IMAGING FACILITIES OR INVASIVE LUMBAR PUNCTURE FOR CSF COLLECTION. GIVEN THE ADVANTAGES OF NON-INVASIVENESS, COST EFFECTIVENESS AND EASY ACCESS IN GENERAL CLINICAL SETTINGS, BLOOD-BASED AD BIOMARKER DETECTIONS ARE MORE APPLICABLE POC DIAGNOSTIC TOOLS FOR EARLY DIAGNOSIS OF AD/ADRD. WHILE TWO PLATFORMS, I.E., PRECIVITYADTM FOR AΒ40/AΒ42 DETECTION AND SIMOA® FOR PHOSPHO-TAU 181 (P-TAU181), WERE RECENTLY GRANTED FDA BREAKTHROUGH DEVICE DESIGNATIONS FOR CLINICAL USES, BOTH SYSTEMS REQUIRE HIGHLY SPECIALIZED HIGH-END INSTRUMENTS FOR SAMPLE TESTING, LIMITING THEIR WIDE AVAILABILITY, PARTICULARLY IN THE COMMUNITIES AND REGIONS WITH LOW OR LIMITED RESOURCES AND HEALTH DISPARITY. FURTHERMORE, PRECIVITYADTM AND SIMOA® USE ANTIBODY-COATED MAGNETIC BEADS TO CAPTURE TARGETED AD BIOMARKERS. HOWEVER, THE NON-SPECIFIC ADSORPTION OF SERUM PROTEINS ON THE SURFACE OF BEADS FORMS A PROTEIN CORONA THAT CAN BLOCK THE ANTIBODY FROM CAPTURING BIOMARKERS. IN THIS SBIR PHASE I PROJECT, WE AIM TO DEVELOP A MULTIPLEXED AD BIOMARKER DETECTION PLATFORM THAT CAN INTEGRATE TWO INNOVATIVE TECHNOLOGIES, I.E., ULTRAMAGNETIC IRON OXIDE NANORODS (IONRS) AND ANTI-BIOFOULING POLYMER COATING FOR IONRS, FOR MULTIPLEXING SIX AD BIOMARKERS IN BLOOD SAMPLES. THE IONRS PROVIDE AS STRONG MAGNETISM AS THE MAGNETIC BEADS USED IN PRECIVITYADTM AND SIMOA®, AND ALSO FUNCTION AS NANO-STIRRING-BARS TO IMPROVE SAMPLE MIXING, UNDER AN ALTERNATING ELECTROMAGNETIC FIELD, FOR MORE EFFICIENT BIOMARKER CAPTURING. THE ANTI-BIOFOULING COATING MINIMIZES NON-SPECIFIC SERUM PROTEIN ADSORPTION ON IONRS TO PRESERVE THE ANTIBODY AFFINITY FOR TARGETED BIOMARKERS IN BLOOD SAMPLES. THE PHASE I PROJECT WILL FOCUS ON (1) DEVELOPING A PROTOTYPE DEVICE ENABLING EFFICIENT BLOOD SAMPLE MIXING WITH ANTI-BIOFOULING IONRS AND MULTIPLEXED DETECTION OF SIX AD BIOMARKERS, I.E., AΒ40, AΒ42, TOTAL-TAU (T-TAU), P-TAU181, AMYLOID PRECURSOR PROTEIN (APP669-711), AND NEUROFILAMENT LIGHT PROTEIN (NFL), AND (2) TESTING THE DEVELOPED SYSTEM AND EVALUATE ITS PERFORMANCE USING THE PATIENT SAMPLES, FOLLOWED BY COMPARING AND CORRELATING THE RESULTS WITH CLINICAL DIAGNOSIS AND IMAGING FINDINGS OF THE SAME PATIENTS. IF SUCCESSFUL, THE DEVICE, TO BE FURTHER ASSESSED BY LARGE-SCALE TESTS IN PHASE II, WILL PROVIDE A ROBUST AND COST-EFFECTIVE POC DETECTION FOR SCREENING AND DETECTING AD IN INDIVIDUALS AT RISK AS WELL AS SURVEILLING THE PROGRESSION AND TREATMENT RESPONSE FOR PATIENTS.

SMALL INTESTINE TARGETED FAST ACTING ORAL INSULIN FORMULATION - PROJECT SUMMARY DIABETES MELLITUS IS A CLASS OF METABOLIC DISEASES CHARACTERIZED BY CHRONIC HYPERGLYCEMIA DUE TO IMPAIRED INSULIN SECRETION AND/OR INSULIN RESISTANCE. PATIENTS ARE SUBJECT TO LIFE-LONG MANAGEMENT OF THEIR DIABETIC CONDITIONS AND THE HIGH RISK OF MACRO AND MICROVASCULAR COMPLICATIONS. INSULIN THERAPY IS THE MOST EFFECTIVE MEANS OF LOWERING BLOOD GLUCOSE FOR TYPE 1 DIABETES MELLITUS (T1DM) PATIENTS WITH COMPLETE ABSENCE OF ENDOGENOUS INSULIN AND TYPE 2 DIABETES MELLITUS (T2DM) PATIENTS WITH PROGRESSIVELY DEPLETED INSULIN SECRETING PANCREATIC Β-CELLS AND INSULIN RESISTANT ORGANS AND TISSUE. IT IS ALSO USED FOR CONTROLLING SHORT-TERM HYPERGLYCEMIA IN GESTATIONAL DIABETES MELLITUS (GDM). THE CURRENT THERAPY IS SUBCUTANEOUS INJECTION OR INFUSION OF INSULIN. HOWEVER, THE POOR PATIENT ADHERENCE DUE TO INCONVENIENCE AND PSYCHOLOGICAL INSULIN RESISTANCE (PIR) TO ROUTINE INJECTION IS STILL A MAJOR HINDRANCE IN MANAGING DIABETIC PATIENTS. FURTHERMORE, LONG- TERM USE OF INSULIN INJECTION CAN CAUSE SIDE EFFECTS, INCLUDING LIPODYSTROPHY, IATROGENIC HYPERINSULINEMIA, AND HYPOGLYCEMIA. ORALLY DELIVERED INSULIN, ON THE OTHER HAND, POSSESSES ADVANTAGES IN PATIENT ADHERENCE AND THERAPEUTIC EFFECT BY MIMICKING THE PHYSIOLOGICAL PATH OF ENDOGENOUS INSULIN. HOWEVER, THE DEVELOPMENT OF ORAL INSULIN FORMULATIONS HAS NOT YET BEEN SUCCESSFUL DUE TO LOW INSULIN BIOAVAILABILITY, STEMMING FROM THE DEGRADATION IN THE HIGHLY ACIDIC AND PROTEASE-ACTIVE STOMACH AND INSUFFICIENT PERMEABILITY THROUGH THE INTESTINAL EPITHELIUM AND MUCOSA. THIS STTR PHASE I PROJECT AIMS TO DEVELOP A FAST-ACTING ORAL INSULIN FORMULATION BASED ON THE PATENTED INNOVATION OF MILK PROTEIN CASEIN COATED DRUG-CARRYING NANOPARTICLES (CASNP) TO ENCAPSULATE INSULIN AND THE INTESTINAL ABSORPTION ENHANCER, SODIUM CAPRATE (C10), FOR SMALL INTESTINE-TARGETED DELIVERY OF INSULIN BY PROTECTING INSULIN AND C10 FROM THE GASTRIC PH AND PROTEASE ACTION BUT ENABLING THE ENZYME-TRIGGERED RELEASE OF INSULIN AND C10 IN THE SMALL INTESTINE. THE LIQUID FORMULATION OF NANO-SIZED CASNP/INSLULIN/C10 ALSO FACILITATES RAPID GASTRIC EMPTYING AND INTESTINAL PERMEATION AND ABSORPTION AS EXPECTED IN A FAST-ACTING ORAL INSULIN AGENT FOR CONTROLLING THE POSTPRANDIAL BLOOD GLUCOSE LEVELS. DEVELOPED CASNP/INSULIN/C10 NANOCONSTRUCT AND ENCAPSULATED INSULIN WILL BE LABELED WITH NEAR INFRARED (NIR) FLUORESCENT DYES FOR NON-INVASIVE TRACKING OF CASNP/INSULIN/C10 DELIVERY AND THE SUBSEQUENT INSULIN RELEASE AND ABSORPTION IN THE STREPTOZOTOCIN (STZ) INDUCED DIABETIC MOUSE MODEL. WE WILL PREPARE AND OPTIMIZE THE CASNP/INSULIN/C10 FORMULATION WITH DESIRED PHYSIOCHEMICAL AND BIOLOGICAL PROPERTIES, INCLUDING INSULIN AND C10 LOADING CAPACITIES, STABILITY IN THE SIMULATED GASTRIC CONDITION AND CONTROLLED RELEASE IN THE INTESTINE-MIMICKING CONDITION (AIM 1). WE WILL DETERMINE THE BIODISTRIBUTION OF CASNP/INSULIN/C10, PLASMA AND HEPATIC INSULIN BIOAVAILABILITY AND THE SYSTEMIC CYTOTOXICITY IN STZ-INDUCED DIABETIC MICE USING NIR AND MAGNETIC RESONANCE IMAGING ALONG WITH HISTOPATHOLOGICAL ANALYSES AND VALIDATION, FOLLOWED BY EVALUATING THE EFFICACY OF CASNP/INSULIN/C10 IN CONTROLLING HYPERGLYCEMIA (AIM 2).