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International Journal of Spine Surgery Jun 2024Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and...
Allogeneic Disc Progenitor Cells Safely Increase Disc Volume and Improve Pain, Disability, and Quality of Life in Patients With Lumbar Disc Degeneration-Results of an FDA-Approved Biologic Therapy Randomized Clinical Trial.
BACKGROUND
Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and efficacy results of a US Food and Drug Administration-approved clinical trial of these cells for the treatment of symptomatic degenerative disc disease.
METHODS
Sixty patients with symptomatic single-level lumbar degenerative disc disease (mean age 37.9 years, 60% men) were enrolled in a randomized, double-blinded, placebo-controlled Phase I/Phase II study at 13 clinical sites. They were randomized to receive single intradiscal injections of either low-dose cells ( = 20), high-dose cells ( = 20), vehicle alone ( = 10), or placebo ( = 10). The primary endpoint was mean visual analog scale (VAS) pain improvement >30% at 52 weeks. Disc volume was radiologically assessed. Adverse events (AEs), regardless of whether they were related to treatment, were reported. Patients were assessed at baseline and at 4, 12, 26, 52, 78, and 104 weeks posttreatment.
RESULTS
At week 52, the high-dose group had a mean VAS percentage decrease from baseline (-62.8%, = 0.0005), achieving the endpoint of back pain improvement >30%; the mean change was also significantly greater than the minimal clinically important difference of a 20-point decrease (-42.8, = 0.001). This clinical improvement was maintained at week 104. The vehicle group had a smaller significant decrease in VAS (-52.8%, = 0.044), while the low-dose and placebo groups showed nonsignificant improvements. Only the high-dose group had a significant change in disc volume, with mean increases of 249.0 mm ( = 0.028) at 52 weeks and 402.1 mm ( = 0.028) at 104 weeks. A minority of patients (18.3%) reported AEs that were severe. Overall, 6.7% of patients experienced serious AEs, all in the vehicle ( = 1) or placebo ( = 3) groups, none treatment related.
CONCLUSIONS
High-dose allogeneic disc progenitor cells produced statistically significant, clinically meaningful improvements in back pain and disc volume at 1 year following a single intradiscal injection and were safe and well tolerated. These improvements were maintained at 2 years post-injection.
CLINICAL TRIAL REGISTRATION
NCT03347708-Study to Evaluate the Safety and Preliminary Efficacy of Injectable Disc Cell Therapy, a Treatment for Symptomatic Lumbar Intervertebral Disc Degeneration.
PubMed: 38925869
DOI: 10.14444/8609 -
International Journal of Pharmaceutics Jun 2024Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study...
Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.
PubMed: 38925238
DOI: 10.1016/j.ijpharm.2024.124387 -
Journal of Colloid and Interface Science Jun 2024Nucleic acid-based therapies are transforming medicine, but rely on an efficient delivery vehicle such as lipid nanoparticles (LNPs). Concerns exists in the nanomedicine...
Nucleic acid-based therapies are transforming medicine, but rely on an efficient delivery vehicle such as lipid nanoparticles (LNPs). Concerns exists in the nanomedicine field, that a large fraction of the LNPs in the ensemble does not contain any nucleic acid cargo and thus exert no functional effect. Nevertheless, how LNP lipid formulation, the LNP preparation method employed and nucleic acid cargo size correlates with the proportion of empty LNPs remains largely unexplored. Here we employ a well-established single particle based method to study nucleic acid loading heterogeneity in LNPs. We find that only a minor fraction of LNPs are "empty", both for LNPs loaded with siRNA, mRNA and plasmids. For clinically relevant LNPs for mRNA delivery, we never detected more than 16% empty nanoparticles in the ensemble. Thus employing standard LNP lipid-cargo combinations and preparation schemes results in LNPs with the potential to serve their biomedical function.
PubMed: 38925059
DOI: 10.1016/j.jcis.2024.06.158 -
Journal of Applied Toxicology : JAT Jun 2024Hemp extracts and consumer products containing cannabidiol (CBD) and/or other phytocannabinoids derived from hemp have entered the marketplace in recent years. CBD is an...
Examining the hepatotoxic potential of cannabidiol, cannabidiol-containing hemp extract, and cannabinol at consumer-relevant exposure concentrations in primary human hepatocytes.
Hemp extracts and consumer products containing cannabidiol (CBD) and/or other phytocannabinoids derived from hemp have entered the marketplace in recent years. CBD is an approved drug in the United States for the treatment of certain seizure disorders. While effects of CBD in the liver have been well characterized, data on the effects of other cannabinoids and hemp extracts in the liver and methods for studying these effects in vitro are limited. This study examined the hepatotoxic potential of CBD, CBD concentration-matched hemp extract, and cannabinol (CBN), at consumer-relevant concentrations determined by in silico modeling, in vitro using primary human hepatocytes. Primary human hepatocytes exposed to between 10-nM and 25-μM CBD, CBN, or hemp extract for 24 and 48 h were evaluated by measuring lactate dehydrogenase release, apoptosis, albumin secretion, urea secretion, and mitochondrial membrane potential. Cell viability was not significantly affected by CBD, CBN, or the hemp extract at any of the concentrations tested. Exposure to hemp extract induced a modest but statistically significant decrease in albumin secretion, urea secretion, and mitochondrial membrane potential at the highest concentration tested whereas CBD only induced a modest but statistically significant decrease in albumin secretion compared with vehicle control. Although this study addresses data gaps in the understanding of cannabinoid hepatoxicity in vitro, additional studies will be needed to determine how these results correlate with relevant consumer exposure and the biological effects of cannabinoids in human liver.
PubMed: 38924151
DOI: 10.1002/jat.4646 -
Membranes Jun 2024Bacterial extracellular vesicles (bEVs) secreted by Gram-negative bacteria are referred to as outer membrane vesicles (OMVs) because they originate in the outer...
Bacterial extracellular vesicles (bEVs) secreted by Gram-negative bacteria are referred to as outer membrane vesicles (OMVs) because they originate in the outer membrane. OMVs are membrane-coated vesicles 20-250 nm in size. They contain lipopolysaccharide (LPS), peptidoglycan, proteins, lipids, nucleic acids, and other substances derived from their parent bacteria and participate in the transmission of information to host cells. OMVs have broad prospects in terms of potential application in the fields of adjuvants, vaccines, and drug delivery vehicles. Currently, there remains a lack of efficient and convenient methods to isolate OMVs, which greatly limits OMV-related research. In this study, we developed a fast, convenient, and low-cost gradient filtration method to separate OMVs that can achieve industrial-scale production while maintaining the biological activity of the isolated OMVs. We compared the gradient filtration method with traditional ultracentrifugation to isolate OMVs from probiotic Nissle 1917 (EcN) bacteria. Then, we used RAW264.7 macrophages as an in vitro model to study the influence on the immune function of EcN-derived OMVs obtained through the gradient filtration method. Our results indicated that EcN-derived OMVs were efficiently isolated using our gradient filtration method. The level of OMV enrichment obtained via our gradient filtration method was about twice as efficient as that achieved through traditional ultracentrifugation. The EcN-derived OMVs enriched through the gradient filtration method were successfully taken up by RAW264.7 macrophages and induced them to secrete pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukins (ILs) 6 and 1β, as well as anti-inflammatory cytokine IL-10. Furthermore, EcN-derived OMVs induced more anti-inflammatory response (i.e., IL-10) than pro-inflammatory response (i.e., TNF-α, IL-6, and IL-1β). These results were consistent with those reported in the literature. The related literature reported that EcN-derived OMVs obtained through ultracentrifugation could induce stronger anti-inflammatory responses than pro-inflammatory responses in RAW264.7 macrophages. Our simple and novel separation method may therefore have promising prospects in terms of applications involving the study of OMVs.
PubMed: 38921502
DOI: 10.3390/membranes14060135 -
Gels (Basel, Switzerland) Jun 2024A combination of Poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC) hydrosols is proposed as an in situ thermo-gelling vehicle for the nasal drug delivery of...
A combination of Poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC) hydrosols is proposed as an in situ thermo-gelling vehicle for the nasal drug delivery of chlorhexidine-silver nanoparticles conjugates (SN-CX). Optimization of the formulation was carried out by applying varying ratios of P407 and HPMC in the presence and absence of SN-CX so that gelation would occur in the temperature range of the nasal cavity (30-34 °C). Mechanisms for the observed gelation phenomena were suggested based on viscosimetry, texture analysis, and dynamic light scattering. Tests were carried out for sprayability, washout time, in vitro drug release, ex vivo permeation, and antimicrobial activity. When applied separately, HPMC was found to lower the P407 gelation temperature (T), whereas SN-CX increased it. However, in the presence of HPMC, SN-CX interfered with the P407 micellar organization in a principally contrasting way while leading to an even further decrease in T. SN-CX-loaded nasal formulations composed of P407 16% and HPMC 0.1% demonstrated a desired gelation at 31.9 °C, good sprayability (52.95% coverage of the anterior nasal cavity), mucoadhesion for 70 min under simulated nasal clearance, expedient release and permeation, and preserved anti-infective activity against seasonal Influenza virus and beta-coronavirus, and other pathogens. Our findings suggest that the current development could be considered a potential formulation of a protective nasal spray against respiratory infections.
PubMed: 38920931
DOI: 10.3390/gels10060385 -
Gels (Basel, Switzerland) May 2024Manna, a well-known herbal drug has multiple traditional and pharmaceutical uses and the entire composition, sugar derivatives and polyphenols, gives rise to a very...
Manna, a well-known herbal drug has multiple traditional and pharmaceutical uses and the entire composition, sugar derivatives and polyphenols, gives rise to a very interesting bioactive complex with versatile therapeutic and benefic properties such as antioxidant and anti-inflammatory activities. The aim of this research was to investigate a manna extract loaded in a pectin hydrogel as a synergic vehicle to evaluate the potential use of the complex for cosmetic and dermatological applications. In particular, the study set out to disclose manna properties as a wound healing agent with antimicrobial and reparative activity on infected tissues. Moreover, considering the correlation between antioxidant activity and antiaging potential, the extract was investigated in regard to the anti-elastase activity and skin whitening potential. The total phenolic content of each extract was also determined and a safe profile by in vitro cytotoxicity studies was verified. The hydrogel complex, containing the manna extract and pectin as the gelling agent, exhibited suitable properties in terms of pH (from 5.50 to 6.80), rheological behavior and ability of preserving the antioxidant activity of the manna exudate (around 10%). All the peculiarities that make the pectin hydrogels ideal systems for skin disease, as wound dressings and for antiaging cosmetic formulations.
PubMed: 38920898
DOI: 10.3390/gels10060351 -
Neurology. Genetics Jun 2024Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy...
BACKGROUND AND OBJECTIVES
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy/dy) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy/dy) LAMA2-RD mouse model and the (Col6a1) COL6-RD mouse model demonstrated decreased apoptosis.
METHODS
A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.
RESULTS
Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.
DISCUSSION
This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence of omigapil in a dose-finding phase 1 study.
TRIAL REGISTRATION INFORMATION
Clinical Trials NCT01805024.
PubMed: 38915423
DOI: 10.1212/NXG.0000000000200148 -
Scientific Reports Jun 2024Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we...
Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.
Topics: Sorafenib; Caffeic Acids; Phenylethyl Alcohol; Carcinoma, Hepatocellular; Animals; Humans; Liver Neoplasms; Cell Line, Tumor; Mice; Xenograft Model Antitumor Assays; Antineoplastic Agents; Cell Proliferation; Mice, Nude; Mice, Inbred BALB C; Male
PubMed: 38914695
DOI: 10.1038/s41598-024-65496-1 -
Journal of Medicinal Chemistry Jun 2024Breast adenocarcinoma ranks high among the foremost lethal cancers affecting women globally, with its triple-negative subtype posing the greatest challenge due to its...
Breast adenocarcinoma ranks high among the foremost lethal cancers affecting women globally, with its triple-negative subtype posing the greatest challenge due to its aggressiveness and resistance to treatment. To enhance survivorship and patients' quality of life, exploring advanced therapeutic approaches beyond conventional chemotherapies is imperative. To address this, innovative nanoscale drug delivery systems have been developed, offering precise, localized, and stimuli-triggered release of anticancer agents. Here, we present perylenemonoimide nanoparticle-based vehicles engineered for deep-red light activation, enabling direct chlorambucil release. Synthesized via the reprecipitation technique, these nanoparticles were thoroughly characterized. Light-induced drug release was monitored via spectroscopic and reverse-phase HPLC. The efficacy of the said drug delivery system was evaluated in both two-dimensional and three-dimensional spheroidal cancer models, demonstrating significant tumor regression attributed to apoptotic cell death induced by efficient drug release within cells and spheroids. This approach holds promise for advancing targeted breast cancer therapy, enhancing treatment efficacy and minimizing adverse effects.
PubMed: 38913981
DOI: 10.1021/acs.jmedchem.4c00432