Self-assembled drug delivery system based on low-molecular-weight bis-amide organogelator: synthesis, properties and <i>in vivo</i> evaluation

<p><i>Context</i>: Orgnaogels based on amino acid derivatives have been widely used in the area of drug delivery.</p> <p><i>Objective</i>: An organogel system based on l-lysine derivatives was designed and prepared to induce a thermal sensitive implant with higher transition temperature, better mechanical strength, and shorter gelation time.</p> <p><i>Materials and methods</i>: The organogel was prepared by injectable soybean oil and methyl (<i>S</i>)-2,5-ditetradecanamidopentanoate (MDP), which was synthesized for the first time. Candesartan cilexetil (CC) was chosen as model drug. Different formulations were designed and optimized by response surface method. Thermal, rheology properties, and gelation kinetics of the optimized formulation had been characterized. The release behaviors <i>in vitro</i>, as well as <i>in vivo</i> were evaluated in comparison with the oily solution of drugs. Finally, the local inflammation response of <i>in situ</i> organogel was assessed by histological analysis.</p> <p><i>Results and discussion</i>: Results showed that the synthesized gelator, MDP, had a good gelation ability and the organogels obtained via the self-assembly of gelators in vegetable oils exhibited great thermal and rheology properties, which guaranteed their state in body. <i>In vivo</i> pharmacokinetic demonstrated that the organogel formulation could extend the drug release and maintain a therapeutically effective plasma concentration at least 10 d. In addition, this implant showed acceptable moderate inflammation.</p> <p><i>Conclusion</i>: The <i>in situ</i> forming l-lysine-derivative-based organogel could be a promising matrix for sustained drug delivery of the drugs with low solubility.</p

Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors

Cholinergic Neuron Targeting Nanosystem Delivering Hybrid Peptide for Combinatorial Mitochondrial Therapy in Alzheimer’s Disease

Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer’s disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic therapeutic effects. Therefore, we developed a multifunctional hybrid peptide HNSS composed of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin. However, suitable peptide delivery systems with excellent loading capacity and effective at-site delivery are still absent. Herein, the nanoparticles made of citraconylation-modified poly­(ethylene glycol)-poly­(trimethylene carbonate) polymer (PEG-PTMC­(Cit)) exhibited desirable loading of HNSS peptide through electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1­(FGFR1) overexpression in both the blood–brain barrier and cholinergic neuron, an FGFR1 ligand-FGL peptide was modified on the nanosystem (FGL-NP­(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation in brain with preferred distribution into cholinergic neurons in the diseased region. The acid-sensitive property of the nanosystem facilitated lysosomal escape and intracellular drug release by charge switching, resulting in HNSS enrichment in mitochondria through directing of the SS31 part. FGL-NP­(Cit)/HNSS effectively rescued mitochondria dysfunction via the PGC-1α and STAT3 pathways, inhibited Aβ deposition and tau hyperphosphorylation, and ameliorated memory defects and cholinergic neuronal damage in 3xTg-AD mice. The work provides a potential platform for targeted cationic peptide delivery, harboring utility for peptide therapy in other neurodegenerative diseases