Quinolines and isoquinolines as HIV-1 inhibitors: Chemical structures, action targets, and biological activities.

Human immunodeficiency virus type 1 (HIV-1), a lentivirus that causes acquired immunodeficiency syndrome (AIDS), poses a serious threat to global public health. Since the advent of the first drug zidovudine, a number of anti-HIV agents acting on different targets have been approved to combat HIV/AIDS. Among the abundant heterocyclic families, quinoline and isoquinoline moieties are recognized as promising scaffolds for HIV inhibition. This review intends to highlight the advances in diverse chemical structures and abundant biological activity of quinolines and isoquinolines as anti-HIV agents acting on different targets, which aims to provide useful references and inspirations to design and develop novel HIV inhibitors for medicinal chemists.

Studies on the in vitro and in vivo degradation behavior of amino acid derivative-based organogels.

The in vitro degradation behavior of organogel with different gelators based on amino acid was investigated in detail. Two methods were applied in this research: weighting method and high-performance liquid chromatography with evaporative light scattering detection (HPLC-ELSD) method, which was established for the first time. Their degradation behaviors in vivo were investigated by varying the kind and concentration of gelators via subcutaneous implantation. The results showed that the stronger the gelation ability or the higher the gelator concentration, the slower the degradation rate of organogel. Moreover, the organogel prepared by oils with longer alkyl length degraded slower than that of the shorter ones, which also decreased in thermal stability and mechanical strength. The investigation on degradation process showed that the degradation rate was mainly controlled by the collapse of network structure formed by gelators. In conclusion, organogel had a tunable degradation rate through altering the gelator type, oil type and the gelator concentration. It remains a promising candidate for subcutaneous in-situ implant as drug delivery vehicle.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis.

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aß phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

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.

Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimer's disease.

Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a ß-sheet breaker acting on Aß, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aß, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aß and p-tau, confirming the promising application of nano-combination strategy in AD treatment.

Medium-chain triglyceride-stabilized docetaxel-loaded HSA nanoparticles effectively inhibited metastatic non-small cell lung cancer.

Metastatic non-small cell lung cancer (NSCLC) is refractory with a very poor prognosis. Docetaxel (DTX) injection (Taxotere®) has been approved for the treatment of locally advanced or metastatic NSCLC. However, its clinical application is restricted by severe adverse effects and non-selective tissue distribution. In this study, we successfully developed DTX-loaded human serum albumin (HSA) nanoparticles (DNPs) with modified Nab technology, by introducing medium-chain triglyceride (MCT) as a stabilizer. The optimized formulation had a particle size of approximately 130 nm and a favorable stabilization time of more than 24 h. DNPs dissociated in circulation in a concentration-dependent manner and slowly released DTX. Compared with DTX injection, DNPs were more effectively taken up by NSCLC cells, thus exerting stronger inhibitory effects on their proliferation, adhesion, migration, and invasion. In addition, DNPs showed prolonged blood retention and increased tumor accumulation relative to DTX injection. Ultimately, DNPs produced more potent inhibitory effects on primary or metastatic tumor foci than DTX injections but caused markedly lower organ toxicity and hematotoxicity. Overall, these results support that DNPs hold great potential for the treatment of metastatic NSCLC in clinical.

Modulating autophagic flux via ROS-responsive targeted micelles to restore neuronal proteostasis in Alzheimer's disease.

Compromised autophagy and defective lysosomal clearance significantly contribute to impaired neuronal proteostasis, which represents a hallmark of Alzheimer's disease (AD) and other age-related neurodegenerative disorders. Growing evidence has implicated that modulating autophagic flux, instead of inducing autophagosome formation alone, would be more reliable to rescue neuronal proteostasis. Concurrently, selectively enhancing drug concentrations in the leision areas, instead of the whole brain, will maximize therapeutic efficacy while reduing non-selective autophagy induction. Herein, we design a ROS-responsive targeted micelle system (TT-NM/Rapa) to enhance the delivery efficiency of rapamycin to neurons in AD lesions guided by the fusion peptide TPL, and facilitate its intracellular release via ROS-mediated disassembly of micelles, thereby maximizing autophagic flux modulating efficacy of rapamycin in neurons. Consequently, it promotes the efficient clearance of intracellular neurotoxic proteins, ß-amyloid and hyperphosphorylated tau proteins, and ameliorates memory defects and neuronal damage in 3 × Tg-AD transgenic mice. Our studies demonstrate a promising strategy to restore autophagic flux and improve neuronal proteostasis by rationally-engineered nano-systems for delaying the progression of AD.

Precise gene delivery systems with detachable albumin shell remodeling dysfunctional microglia by TREM2 for treatment of Alzheimer's disease.

Intervention of the over-activated microglia-aggravated neuroinflammation represents a promising therapeutic strategy for Alzheimer's disease (AD). Upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) attenuates the neuroinflammatory processes and normalizes the dysfunctional microglia. However, Trem2-gene therapy for AD by the effective non-invasive delivery systems is unexploited. Herein, we report the microglia-targeted gene delivery systems (PHSA@PF/pTREM2) composed of a core of fluorinated polyethylenimine condensing the TREM2-encoding plasmid (PF/pTREM2) and a shell of human serum albumin conjugated with both cis-aconitic anhydride and neural cell adhesion molecule-mimetic peptide P2 (PHSA). Thanks to the shedding effect of the albumin coated, PHSA@PF/pTREM2 exhibit prolonged blood circulation and low cytotoxicity. PHSA@PF/pTREM2 achieve brain accumulation as high as 2.17% injected dose per gram of brain and the microglial-targeting effect (targeting specificity of 41.9%) via the systemic administration. The nanocomplexes can be detached PHSA-shell in the acidic endo-lysosomes via the cleavage of cis-aconitic amide bond, resulting in PF/pTREM2 exposure for efficient endo-lysosomal escape and gene transfection. PHSA@PF/pTREM2 upregulate the TREM2 level and regulate microglial polarization toward M2-phenotype for remodeling the inflammatory microenvironment and enhanced Aß clearance, leading to an improvement of cognitive performance in APP/PS1 mice. This work provides a promising gene delivery platform to reverse dysfunctional microglia for AD therapy.

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 Aß 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.

'Adhesion and release' nanoparticle-mediated efficient inhibition of platelet activation disrupts endothelial barriers for enhanced drug delivery in tumors.

Activated platelets can maintain tumor vessel integrity, thereby leading to limited tumor perfusion and suboptimal antitumor efficacy of nanoparticle-based drugs. Herein, to disrupt the tumor vascular endothelial barriers by inhibiting the transformation of resting platelets to activated platelets, a TM33 peptide-modified gelatin/oleic acid nanoparticle loaded with tanshinone IIA (TNA) was constructed (TM33-GON/TNA). TM33-GON/TNA could adhere to activated platelets by specifically binding their superficial P-selectin and release TNA into the extracellular space under matrix metalloproteinase-2 (MMP-2) stimulation, leading to local high TNA exposure. Thus, platelet activation, adhesion, and aggregation, which occur in the local environment around the activated platelets, were efficiently inhibited, leading to leaky tumor endothelial junctions. Accordingly, TM33-GON/TNA treatment resulted in a 3.2-, 4.0-, and 11.2-fold increase in tumor permeation of Evans blue (macromolecule marker), small-sized Nab-PTX (~10 nm), and large-sized DOX-Lip (~100 nm), respectively, without elevating drug delivery to normal tissues. Ultimately, TM33-GON/TNA plus Nab-PTX exhibited superior antitumor efficacy with minimal side effects in a murine pancreatic cancer model. In addition, the TM33-GON/TNA-induced disrupted endothelial junctions were reversibly restored after the treatment because the number of platelets was not reduced, which implies a low risk of the undesirable systemic bleeding. Hence, TM33-GON/TNA represents a clinically translational adjuvant therapy to magnify the antitumor efficacy of existing nanomedicines in pancreatic cancer and other tumors with tight endothelial lining.

A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer's disease mice.

The presence of blood-brain barrier (BBB) and specificity of neuron targeting remain two challenges in the effective delivery of nanotherapeutics for the treatment of Alzheimers disease (AD). Traditional strategy of nanocarriers for AD treatment involves co-decoration of both BBB-penetrating ligand and neuron-targeting ligand on the surface of the nanoparticles for "dual-stage" targeted delivery. Instead, we design and optimize a fusion peptide TPL comprising a BBB-penetrating peptide TGN and a neuron binding peptide Tet1 through a four-glycine linker. Compared to the mono-ligand Tet1 or CGN which is the retro-inverso isomer of TGN with higher brain targeting than TGN, the dual-ligand fusion peptide TPL has preferable blood stability and enhanced structural flexibility, resulting in higher binding affinity to either GT1b ganglioside receptor or brain capillary endothelial bEnd.3 cells. The TPL-modified nanoparticles (TPL-NP) increased the BBB-penetration and neuron-targeting efficacy than the nanoparticles co-decorated with the two mono-ligands. Encapsulation of a neuroprotective peptide NAP, TPL-NP significantly enhance reactive oxygen species scavenging ability and effectively protect microtubule from Aß25-35-induced neurotoxicity. Meanwhile, TPL-NP inhibit okadaic acid-induced tau aggregation and neuronal apoptosis. Administration of TPL-NP in AD mice also significantly improves the cognitive performance, down-regulates the tau phosphorylation level, promotes axonal transport and attenuates microgliosis. Taken together, this work demonstrates that the rationally designed dual-ligand fusion peptides can greatly improve the delivery of drugs to the AD lesions, thereby markedly enhancing the efficacy of AD treatment.

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease.

Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for ß-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aß production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aß deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as Aß and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.

Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs.

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

CONTEXT: Orgnaogels based on amino acid derivatives have been widely used in the area of drug delivery. OBJECTIVE: 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. MATERIALS AND METHODS: The organogel was prepared by injectable soybean oil and methyl (S)-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 in vitro, as well as in vivo were evaluated in comparison with the oily solution of drugs. Finally, the local inflammation response of in situ organogel was assessed by histological analysis. RESULTS AND DISCUSSION: 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. In vivo 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. CONCLUSION: The in situ forming l-lysine-derivative-based organogel could be a promising matrix for sustained drug delivery of the drugs with low solubility.