Phytocompounds and lipid-based drug delivery system for neurodegenerative diseases

Across the annals of time,organic molecules sourced from nature have found innumerable uses within the realms of healthcare,pharmaceuticals,and the study of living organisms.This abundant source of natural compounds has exhibited immense promise in the cure of diverse ailments,mainly neurodegenerative diseases owing to their minimum toxic and adverse effects.However,different challenges exist with phytocompounds from plants such as poor permeation,poor solubility(water/lipid),unsteadiness under extremely acidic pH conditions,and lack of targeting specificity.Furthermore,as a result of the existence of blood-brain barrier membrane and inconvenient pharmacokinetics characteristics of phytocompounds,their passage into the brain is constrained.In order to address this issue and augment the transportation of medications into the brain at a therapeutically effective level,it is imperative to formulate an innovative and pragmatic strategy.Many papers have shown that nanoformulations containing phytocompounds(resveratrol,quercetin,ferulic acid,curcumin,berberine,etc.)effectively improved many neurodegenerative diseases such as Parkinson’s,Alzheimer’s and Huntington’s diseases.This study provides an overview of phytocompounds that are used in nanosized lipid drug delivery systems.These systems are categorized according to lipid types and preparation techniques used in the formulation.Some studies regarding these systems and phytocompounds are also summarized.

Characterization of lipid-based nanomedicines at the single-particle level

Lipid-based nanomedicines(LBNMs),including liposomes,lipid nanoparticles(LNPs)and extracellular vesicles(EVs),are recognized as one of the most clinically acceptable nano-formulations.However,the bench-to-bedside translation efficiency is far from satisfactory,mainly due to the lack of in-depth understanding of their physical and biochemical attributes at the single-particle level.In this review,we first give a brief introduction of LBNMs,highlighting some milestones and related scientific and clinical achievements in the past several decades,as well as the grand challenges in the characterization of LBNMs.Next,we present an overview of each category of LB-NMs as well as the core properties that largely dictate their biological characteristics and clinical performance,such as size distribution,particle concentration,morphology,drug encapsulation and surface properties.Then,the recent applications of several analytical techniques including electron microscopy,atomic force microscopy,fluorescence microscopy,Raman microscopy,nanoparticle tracking analysis,tunable resistive pulse sensing and flow cytometry on the single-particle characterization of LBNMs are thoroughly discussed.Particularly,the com-parative advantages of the newly developed nano-flow cytometry that enables quantitative analysis of both the physical and biochemical characteristics of LBNMs smaller than 40 nm with high throughput and statistical ro-bustness are emphasized.The overall aim of this review article is to illustrate the importance,challenges and achievements associated with single-particle characterization of LBNMs.

Lipid-based nanoparticles for cancer immunotherapy

As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.

Bioavailability of 10-hydroxycamptothecin-phospholipid complex loaded by solid dispersion and lipid-based formulations

Previous study has shown that 10-hydroxycamptothecin（HCPT） has well-established pharmacological effects in vitro.However,its in vivo bioavailability is very poor due to various problems,which severely restricts its clinical applications.In the present study,phospholipid complex（PC） technology was employed to improve the solubility and bioavailability of HCPT.XRD data confirmed the formation of HCPT-PC.However,our previously prepared HCPT-PC is too sticky,which may result in the slow dissolution rate and negative effects on its absorption.Therefore,we prepared HCPT-PC-solid dispersion（HCPT-PC-SD）and lipid-based formulations of HCPT-PC through simple preparation process.The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology,which reached 91.73%in 45 min.Pharmacokinetic study revealed that the AUC_（0-t） of HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC.Moreover,we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC.In addition,we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD.In particular,lipid-base formulations could be prepared just by a simple method,suggesting its feasibility of industrialization.

Oral lipid-based drug delivery systems–an overview

The formulation of drugs is carried out with the principle objective of enhancing their bioavailability.Poorly water soluble drugs are challenging for the formulation scientists with regard to solubility and bioavailability.Lipid-based drug delivery systems(LBDDS)are one of the emerging technologies designed to address such challenges.Encapsulating or solubilizing the drug in lipid excipients can lead to increased solubilization and absorption,resulting in enhanced bioavailability.Recent advances in these formulation technologies have led to the successful commercialization of lipidbased formulations.This review provides a comprehensive summary and characterization of lipid-based formulations,especially for oral delivery,from both physicochemical and biopharmaceutical perspectives.This review also focuses on the processing techniques necessary to obtain solid lipid-based formulations for oral delivery,along with a brief discussion of lipid excipients and their characterization.

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations(LBFs)have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs.However,construction of in vitro and in vivo correlations(IVIVCs)for LBFs is quite challenging,owing to a complex in vivo processing of these formulations.In this paper,we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption;based on the concept of IVIVCs,the current status of in vitro models to establish IVIVCs for LBFs is reviewed,while future perspectives in this field are discussed.In vitro tests,which facilitate the understanding and prediction of the in vivo performance of solid dosage forms,frequently fail to mimic the in vivo processing of LBFs,leading to inconsistent results.In vitro digestion models,which more closely simulate gastrointestinal physiology,are a more promising option.Despite some successes in IVIVC modeling,the accuracy and consistency of these models are yet to be validated,particularly for human data.A reliable IVIVC model can not only reduce the risk,time,and cost of formulation development but can also contribute to the formulation design and optimization,thus promoting the clinical translation of LBFs.

Loading of tacrolimus containing lipid based drug delivery systems into mesoporous silica for extended release

Many studies had been focused on designing tacrolimus sustained release preparations based on solid dispersion technique, but no one had tried to employ mesoporous silica as the carrier material to realize this goal. The purpose of this study was to develop a novel, simple and environmental friendly drug loading method with mesoporous silica to obtain tacrolimus sustained-release preparation. Tacrolimus was firstly dissolved in the molten mixed lipid composed of Compritol 888 ATO and Gelucire 50/13 to prepare a drug loaded lipid-based drug delivery systems(LBDDS), then the liquid LBDDS was adsorbed by mesoporous silica to transfer the liquid into solid powder, ie. the tacrolimus sustained release silica-lipid hybrid(SLH). The SLH was characterized by SEM, CLSM, XRPD and DSC, and the in vitro drug release was tested using a paddle method. SEM and CLSM observation showed that the LBDDS was efficiently distributed throughout the pores of the silica. The results of DSC and XRPD illustrated that the lipid existed inside the silica at amorphous state. The drug-loaded SLH showed good flowability, compressibility, compactibilty and two-phase in vitro drug release process within 24 hours, which did not change obviously even after storage at 40 °C for 10 d.The present study provided a novel and simple method to prepare tacrolimus sustained release powder, which provided a feasible solution to solidify the liquid LBDDS of not only extended drug release behavior, but also improved stability and micromeritic properties.

Enhanced intestinal lymphatic absorption of saquinavir through supersaturated self-microemulsifying drug delivery systems

The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated selfmicroemulsifying drug delivery system(S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS.Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper selfmicroemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS.Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.

Flavonoids Loaded in Nanocarriers: An Opportunity to Increase Oral Bioavailability and Bioefficacy

Flavonoids are among the biggest group of polyphenols, widely distributed in plant-based foods. A plethora of evidence supports the health benefits and value of flavonoids can play in the physiological function treatment and in the prevention of disease particularly in the prevention of degenerative conditions including cancers, cardiovascular and neurodegenerative diseases. Hence, flavonoids represent the active constituents of many dietary supplements and herbal remedies, as well as there is an increasing interest in this class of polyphenols as functional ingredients of beverages, food grains and dairy products. Conversely, various studies have also shown that flavonoids have some drawbacks after oral administration such as stability, bioavailability and bioefficacy. This article reviews the current status of novel nanodelivery systems including nanospheres, nanocaspsules, micro- and nanoemulsions, micelles, solid lipid nanoparticles and nanostructured lipid capsules, successfully developed for overcoming the delivery challenges of flavonoids.

Small interfering RNAs based therapies for intracerebral hemorrhage: challenges and progress in drug delivery systems

Intracerebral hemorrhage(ICH)is a subtype of stroke associated with higher rates of mortality.Currently,no effective drug treatment is available for ICH.The molecular pathways following ICH are complicated and diverse.Nucleic acid therapeutics such as gene knockdown by small interfering RNAs(siRNAs)have been developed in recent years to modulate ICH’s destructive pathways and mitigate its outcomes.However,siRNAs delivery to the central nervous system is challenging and faces many roadblocks.Existing barriers to systemic delivery of siRNA limit the use of naked siRNA;therefore,siRNA-vectors developed to protect and deliver these therapies into the specific-target areas of the brain,or cell types seem quite promising.Efficient delivery of siRNA via nanoparticles emerged as a viable and effective alternative therapeutic tool for central nervous system-related diseases.This review discusses the obstacles to siRNA delivery,including the advantages and disadvantages of viral and nonviral vectors.Additionally,we provide a comprehensive overview of recent progress in nanotherapeutics areas,primarily focusing on the delivery system of siRNA for ICH treatment.

Gelatin methacryloyl granular scaffolds for localized mRNA delivery

Messenger RNA(mRNA)therapy is the intracellular delivery of mRNA to produce desired therapeutic proteins.Developing strategies for local mRNA delivery is still required where direct intra-articular injections are inappropriate for targeting a specific tissue.The mRNA delivery efficiency depends on protecting nucleic acids against nuclease-mediated degradation and safe site-specific intracellular delivery.Herein,novel mRNA-releasing matrices based on RGD-moiety-rich gelatin methacryloyl(GelMA)microporous annealed particle(MAP)scaffolds are reported.GelMA concentration in aerogel-based microgels(μgels)produced through a microfluidic process,MAP stiffnesses,and microporosity are crucial parameters for cell adhesion,spreading,and proliferation.After being loaded with mRNA complexes,MAP scaffolds composed of 10%GelMAμgels display excellent cell viability with increasing cell infiltration,adhesion,proliferation,and gene transfer.The intracellular delivery is achieved by the sustained release of mRNA complexes from MAP scaffolds and cell adhesion on mRNA-releasing scaffolds.These findings highlight that hybrid systems can achieve efficient protein expression by delivering mRNA complexes,making them promising mRNA-releasing biomaterials for tissue engineering.