Enhanced oral absorption of teriparatide with therapeutic potential for management of osteoporosis

Luo

et al. 2023

MedComm

Osteoporosis is a type of bone loss disease characterized by a reduction in bone mass and microarchitectural deterioration of bone tissue. With the intensification of global aging, this disease is now regarded as one of the major public health problems that often leads to unbearable pain, risk of bone fractures, and even death, causing an enormous burden at both the human and socioeconomic layers. Classic anti‐osteoporosis pharmacological options include anti‐resorptive and anabolic agents, whose ability to improve bone mineral density and resist bone fracture is being gradually confirmed. However, long‐term or high‐frequency use of these drugs may bring some side effects and adverse reactions. Therefore, an increasing number of studies are devoted to finding new pathogenesis or potential therapeutic targets of osteoporosis, and it is of great importance to comprehensively recognize osteoporosis and develop viable and efficient therapeutic approaches. In this study, we systematically reviewed literatures and clinical evidences to both mechanistically and clinically demonstrate the state‐of‐art advances in osteoporosis. This work will endow readers with the mechanistical advances and clinical knowledge of osteoporosis and furthermore present the most updated anti‐osteoporosis therapies.

Section: Anti‐osteoporosis Therapiesmentioning

confidence: 99%

Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

Luo

et al. 2023

MedComm

“…However, because of the hydrophilic and macromolecular properties of GLP-1A, penetration of the intestinal mucous and cellular layers remains difficult. To address this issue, drug delivery systems for oral peptides have been developed to improve the cellular permeability of peptides using absorption enhancers [e.g., sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), bile acids, β-cyclodextrin, and cell-penetrating peptides] and ingestible devices [e.g., self-orienting millimeter-scale applicator (SOMA), liquid-injecting SOMA, luminal unfolding microneedle injector, and magnetic-controlled microneedle robots] [ 22 – 28 ]. However, these therapeutic systems use a paracellular pathway or nonspecific passive transcellular pathway, resulting in a low peptide absorption rate and high variability in absorption.…”

Section: Introductionmentioning

confidence: 99%

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery

Kweon,

Lee,

Yang

et al. 2023

Biomater Res

Self Cite

Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment. Graphical Abstract

“…Alternatively, for enhanced intestinal permeation, the surface modification of nanocarriers with various moieties targeting intestinal membrane transporters (e.g., peptide transporter, glucose transporter, apical sodium-dependent bile acid transporter [ASBT], and sodium-dependent multivitamin transporter [SMVT]) has been introduced to facilitate drug transport (Pangeni et al., 2021 ). In our previous study, we improved the oral absorption of poorly permeable drugs by ionic complex formation with a positively charged bile acid derivative via ASBT-mediated transport (Deng & Bae, 2020 ; Li et al., 2020 ; Pangeni et al., 2020 ; Subedi et al., 2022 ). Additionally, we constructed docetaxel- and etoposide-loaded nanoemulsive systems to increase aqueous solubility and intestinal permeability by physically anchoring deoxycholic acid (DOCA) in an ionic complex with the cationic lipid, 1,2-dioleyl-3-trimethylammonium propane (DOTAP) (DOCA-DOTAP); we confirmed 249% and 1752% greater oral bioavailabilities, respectively, compared to the free drugs via ASBT-mediated endocytosis (Jha et al., 2020a ; Jha et al., 2020b )…”

Section: Introductionmentioning

confidence: 99%

Enhancement of the anticancer effect of atorvastatin-loaded nanoemulsions by improving oral absorption via multivalent intestinal transporter-targeting lipids

et al. 2022

Self Cite

Atorvastatin (ATV) has attracted considerable attention as a potential therapeutic agent for cancer because it inhibits cancer cell proliferation by suppressing the mevalonate pathway. However, because of its low oral absorption, high doses of ATV are required for chemotherapeutic applications. In this study, we constructed ATV-loaded nanoemulsions (ATV-NEs) containing multivalent intestinal transporter-targeting lipids to improve the oral bioavailability of ATV. ATV-NEs were prepared via oil-in-water emulsification for transporter-targeted delivery, and contained the following anchors: an ionic complex of deoxycholic acid (DOCA) with the cationic lipid 1,2-dioleyl-3-trimethylammonium propane (DOTAP) (DOCA-DOTAP), a biotin-conjugated lipid (Biotinyl PE), and d -alpha-tocopherol polyethylene glycol succinate (TPGS) to allow bile acid- and multivitamin transporter-mediated permeation of ATV without P-glycoprotein (P-gp)-mediated efflux. The optimized formulation (ATV-NE#6) had 1,091% higher oral bioavailability than free ATV. Finally, treatment of 4T1 cell-bearing mice with oral ATV-NE#6 (equivalent to 40 mg/kg ATV) significantly suppressed tumor growth; the maximum tumor growth reduction was 2.44-fold that of the control group. The results thus suggest that ATV-NEs allow for effective oral chemotherapy by enhancing the oral bioavailability of ATV.