Lipid Polymer Research Articles

Core Shell Lipid-Polymer Hybrid Nanoparticles for Oral Bioavailability Enhancement of Ibrutinib via Lymphatic Uptake.

The purpose of thisresearch was to develop ibrutinib (IBR)-loaded lipid-polymer hybrid nanoparticles (IBR-LPHNPs) to improve oral absorption by intestinal lymphatic uptake. IBR-LPHNPs were fabricated by nanoprecipitation method using poly(lactic-co-glycolic acid), lipoid S 100, and DSPE-MPEG 2000. The IBR-LPHNPs showed particle size of 85.27±3.82 nm, entrapment efficiency of 97.70±3.85%, and zeta potential of -24.9±3.08 mV respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry study revealed compatibility between IBR and excipients. X-ray diffraction study showed the conversion of IBR into amorphous form. High-resolution transmission electron microscopic image displayed spherical-shaped, discrete layered polymeric core and lipid shell structure. The drug release from IBR-LPHNPs exhibited prolong release profile up to 48 h and was best fitted to Korsmeyer-Peppas model. Higher fluorescence intensity at the end of 2 h in the intestinal tissue confirmed the uptake of LPHNPs by Peyer's patches. The oral bioavailability of IBR was improved 22.52-fold with LPHNPs as compared to free IBR. The intestinal lymphatic uptake study in rats pretreated with cycloheximide confirmed the intestinal lymphatic uptake of IBR-LPHNPs. All the results conclusively showed that LPHNPs could be a promising approach to improve oral bioavailability of IBR.

Recent advances in nanomedicine preparative methods and their therapeutic potential for colorectal cancer: a critical review.

Colorectal cancer (CRC) is a prevalent malignancy that affects a large percentage of the global population. The conventional treatments for CRC have a number of limitations. Nanoparticles have emerged as a promising cancer treatment method due to their ability to directly target cancer cells and regulate drug release, thereby enhancing therapeutic efficacy and minimizing side effects. This compilationexamines the use of nanoparticles as drug delivery systems for CRC treatment. Different nanomaterials can be used to administer anticancer drugs, including polymeric nanoparticles, gold nanoparticles, liposomes, and solid lipid nanoparticles. In addition, we discuss recent developments in nanoparticle preparation techniques, such as solvent evaporation, salting-out, ion gelation, and nanoprecipitation. These methods have demonstrated high efficacy in penetrating epithelial cells, a prerequisite for effective drug delivery. This article focuses on the various targeting mechanisms utilized by CRC-targeted nanoparticles and their recent advancements in this field. In addition, the review offers descriptive information regarding numerous nano-preparative procedures for colorectal cancer treatments. We also discuss the outlook for innovative therapeutic techniques in the management of CRC, including the potential application of nanoparticles for targeted drug delivery. The review concludes with a discussion of current nanotechnology patents and clinical studies used to target and diagnose CRC. The results of this investigation suggest that nanoparticles have great potential as a method of drug delivery for the treatment of colorectal cancer.

CD44-Targeted Lipid Polymer Hybrid Nanoparticles Enhance Anti-Breast Cancer Effect of Cordyceps militaris Extracts.

This study aimed to improve the anticancer effect of Cordyceps militaris herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, cholesterol- and vitamin E-grafted PGA polymers (PGA-CH and PGA-VE, respectively) were fabricated, with and without maleimide-ended polyethylene glycol. Subsequently, CME, which contained an active cordycepin equaling 9.89% of its weight, was encapsulated in the LPNPs. The results revealed that the synthesized polymers could be used to prepare CME-loaded LPNPs. The LPNP formulations containing Mal-PEG were decorated with cysteine-grafted HYA via thiol-maleimide reactions. The HYA-decorated PGA-based LPNPs substantially enhanced the anticancer effect of CME against MDA-MB-231 and MCF-7 breast cancer cells by enhancing cellular uptake through CD44 receptor-mediated endocytosis. This study demonstrated the successful targeted delivery of CME to the CD44 receptors of tumor cells by HYA-conjugated PGA-based LPNPs and the new application of synthesized PGA-CH- and PGA-VE-based polymers in LPNP preparation. The developed LPNPs showed promising potential for the targeted delivery of herbal extracts for cancer treatment and clear potential for translation in in vivo experiments.

In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy

Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid-polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.

Polymer-lipid hybrid nanoparticles of exemestane for improved oral bioavailability and anti-tumor efficacy: An extensive preclinical investigation

Exemestane (EXE), an irreversible aromatase inhibitor, is primarily used as a first-line therapy for estrogen receptor-positive breast cancer patients. However, complex physicochemical characteristics of EXE limit its oral bioavailability (<10%) and anti-breast cancer efficacy. The present study aimed to develop a novel nanocarrier system to improve the oral bioavailability and anti-breast cancer efficacy of EXE. In this perspective, EXE-loaded TPGS-based polymer lipid hybrid nanoparticles (EXE-TPGS-PLHNPs) were prepared by the nanoprecipitation method and evaluated for their potential in improving oral bioavailability, safety, and therapeutic efficacy in the animal model. EXE-TPGS-PLHNPs showed significantly higher intestinal permeation in comparison to EXE-PLHNPs (without TPGS) and free EXE. After oral administration, EXE-TPGS-PLHNPs and EXE-PLHNPs revealed 3.58 and 4.69 times higher oral bioavailability in Wistar rats compared to the conventional EXE suspension. The results of the acute toxicity experiment suggested that the developed nanocarrier was safe for oral administration. Furthermore, EXE-TPGS-PLHNPs and EXE-PLHNPs represented much better anti-breast cancer activity in Balb/c mice bearing MCF-7 tumor xenograft with tumor inhibition rate of 72.72% and 61.94% respectively in comparison with the conventional EXE suspension (30.79%) after 21 days of oral chemotherapy. In addition, insignificant changes in the histopathological examination of vital organs and hematological analysis further confirm the safety of the developed PLHNPs. Therefore, the findings of the present investigation advocated that the encapsulation of EXE in PLHNPs can be a promising approach for oral chemotherapy of breast cancer.

NIR-II Light Accelerated Prodrug Reduction of Pt(IV)-Incorporating Pseudo Semiconducting Polymers for Robust Degradation and Maximized Photothermal/Chemo-Immunotherapy.

Selective activation of Pt(IV) prodrugs within tumors is particularly attractive because of their low damage to normal tissues. However, current common activation via chemical/photoreduction of Pt(IV) prodrugs into Pt(II) counterparts is limited by undesirable spatial-temporal control over this reduction process and the ineffective tissue penetration depth of undesirable light. Here, a pseudo-conjugated-polymer is designed via Stille polymerization, resulting in PSP-Pt with a Pt(IV) prodrug of oxaliplatin (Oxa(IV)) in the polymer main chain that can be activated by NIR-II light. PSP-Pt can co-assemble with a commercially available lipid polymer, namely mPEG2k -DSPE, into NPPSP-Pt . Under 1064nm light irradiation, NPPSP-Pt can be photoactivated to accelerate the Pt(IV) reduction to release oxaliplatin, thereby killing the cancer cells by photothermal effect and chemo-immunotherapy inside a mouse model with CT26 colon cancer. This work reports the application of NIR-II light for accelerating Pt(IV) reduction for cancer tumor therapy.

Development of siRNA and Budesonide Dual‐Loaded Hybrid Lipid–Polymer Nanoparticles by Microfluidics Technology as a Platform for Dual Drug Delivery to Macrophages: An In Vitro Mechanistic Study

AbstractMacrophages play a key role in the development of many diseases, like tissue injury, cancer, and autoimmune diseases. So far, single‐drug loaded nanoparticles are developed to target macrophages. Nevertheless, macrophage dysregulation can induce multiple conditions, i.e., inflammation and fibrosis. Therefore, the simultaneous codelivery of a small molecule drug and a small interfering RNA (siRNA) for gene silencing may be beneficial to modulate macrophage dysfunction. Herein, hybrid lipid–polymer nanoparticles (LPNs) coloaded with both budesonide and enhanced green fluorescence protein siRNA (eGFP‐siRNA) as model anti‐inflammatory small molecule drug and siRNA, respectively, are developed by an optimized microfluidics method. Specifically, a poly(lactic‐co‐glycolic acid) core is coated by a lipid shell, and LPNs with size homogeneity and colloidal stability are obtained. Both payloads are loaded efficiently, and a controlled release is achieved. Additionally, LPNs are nontoxic in murine RAW 264.7 cells and human THP‐1 cells and are efficiently taken up by these cells. Finally, the transfection efficiency of dual‐loaded LPNs is high at low LPNs doses, thus proving the suitability of this nanosystem for gene silencing. Overall, the optimized LPNs are a suitable nanoplatform for the dual drug delivery to macrophages for the treatment of complex conditions requiring dual therapeutic approaches.

Hydrocortisone-Loaded Lipid-Polymer Hybrid Nanoparticles for Controlled Topical Delivery: Formulation Design Optimization and In Vitro and In Vivo Appraisal.

The barrier functionalities of the skin offer a major but not insuperable hindrance for fabrication of skin delivery effective systems. This work aimed to develop an optimized lipid polymer hybrid nanoparticle and assess the skin delivery effectiveness of hydrocortisone (9.872 ± 0.361 × 10-3 cm2/h) of a drug through the skin from an optimized formulation when compared with a drug solution. Meanwhile, histological examination after topical application of the optimized formulation showed a safe increase in epidermal thickness. In vivo, the optimized formulation showed promising anti-inflammatory activity in a croton oil-induced ear rosacea model. As an excellent anti-inflammatory agent, these findings propose that the use of lipomers could be a promising strategy to improve the topical effectiveness of hydrocortisone acetate (HCA) against inflammatory diseases. Collectively, these results support our view that lipid polymer hybrid nanoparticles can proficiently deliver hydrocortisone to the skin in treating skin inflammatory conditions.

Investigating the effectiveness of Difluprednate-Loaded core-shell lipid-polymeric hybrid nanoparticles for ocular delivery

Uveitis is a sight-threatening disease that causes inflammation in the uvea; difluprednate (DFB) is the first approved drug molecule for postoperative pain, inflammation, and endogenous uveitis. Complex ocular physiology and structure make it difficult to deliver drugs to the eye. Increased permeation and retention in the layer of the eye are required to improve the bioavailability of ocular drugs. In the current research investigation, DFB-loaded lipid polymer hybrid nanoparticles (LPHNPs) were designed and fabricated to enhance the corneal permeation and sustained release of DFB. A well-established two-step approach was used to fabricate the DFB-LPHNPs, comprising of Poly-Lactic-co-Glycolic Acid (PLGA) core that entrapped the DFB and DFB loaded PLGA NPs covered by lipid shell. The manufacturing parameters were optimized for the preparation of DFB-LPHNPs; the optimal DFB-LPHNPs showed a mean particle size of 117.3 ± 2.9 nm, suitable for ocular administration and high entrapment efficiency of 92.45 ± 2.17 % with neutral pH (7.18 ± 0.02) and isotonic Osmolality (301 ± 3 mOsm/kg). Microscopic examination confirms the core–shell morphological structure of DFB-LPHNPs. The prepared DFB-LPHNPs were extensively characterized using spectroscopic techniques and physicochemical characterization, which confirms the entrapment of the drug and the formation of the DFB-LPHNPs. The confocal laser scanning microscopy studies revealed that Rhodamine B-loaded LPHNPs were penetrated into stromal layers of the cornea in ex-vivo conditions. The DFB-LPHNPs showed a sustained release pattern in simulated tear fluid and 4- folds enhanced permeation of DFB as compared to pure DFB solution. The ex-vivo histopathological studies revealed that DFB-LPHNPs didn't cause any damage or no alteration in the cellular structure of the cornea. Additionally, the results of the HET-CAM assay confirmed that the DFB-LPHNPs were not toxic for ophthalmic administration.

味覚センサの辛味測定のためのグルコース酸化酵素標識抗体を用いた前処理法の基礎検討

A polyclonal antibody against the analog of piperine, which is a typical pungent taste substance, was produced, and its binding ability to piperine was evaluated using a surface plasmon resonance sensor. The antibody was labeled with glucose oxidase (GOx), and the hydrogen ions produced by the enzymatic reaction were measured at a lipid polymer membrane electrode for sourness in a taste sensor. The results showed that piperine could be detected by that polyclonal antibody; the response of the sourness sensor increased in dependence on the GOx-labeled antibody concentration when the GOx of GOx-labeled antibody was reacted with glucose. Thus, it was shown that uncharged pungent compounds can be converted into hydrogen ions. Pungent taste can be measured by the taste sensor using GOx-labeled antibodies, and GOx-labeled antibodies can be used as a pretreatment.

Targeting cellular gaps using Janus nanoparticles containing cationic polymers and surfactant lipids.

Since nanoparticles are taken up into cells by endocytosis, phagocytosis, or pinocytosis, they have been studied as intracellular drug carriers. Janus particles have an anisotropic structure composed of two or more distinct domains and have been proposed for use in various applications, including use as imaging agents or nanosensors. This study aimed to clarify the influence of the type of nanoparticles on their distribution in a human Caucasian colon adenocarcinoma (Caco-2) cell monolayer. We fabricated Janus and conventional spherical nanoparticles composed of pharmaceutically applicable ingredients. Janus and spherical nanoparticles composed of a cationic polymer and surfactant lipids were prepared by controlling the solvent removal pattern from the oil phase in the solvent removal process using the solvent evaporation and solvent diffusion methods. The distribution of nanoparticles in the Caco-2 cell monolayer was then evaluated using confocal laser microscopy. The mean hydrodynamic size of the fabricated Janus nanoparticles was 119.2 ± 4.6 nm. Distribution analysis using Caco-2 cells suggested that Janus nanoparticles were localized around the adherens junctions located just below the tight junction. Clear localization was not observed in non-Janus nanoparticles with the same composition. The clear localization of the Janus nanoparticles around the adherens junction may be due to their positive charge and asymmetric structure. Our results suggest the considerable potential for the development of nanoparticulate drug carriers to target cellular gaps.

Turnover of non-polymeric leaf lipids in a loamy grassland soil

BackgroundLeaves constitute a large input of lipids to soil, yet comparatively little is known about the fate of leaf lipids in soil. Our aim was to explore the initial stages of degradation of leaf lipids, both the loss of intact lipid and subsequent mineralisation. We focussed on intracellular lipids – triacylglycerols implicated in storage, membrane lipids such as phospholipids and galactolipids, and pigments – because they collectively constitute more than 1% of leaf mass.MethodsA mixture of U-13C lipids was extracted from leaves of wheat grown with 13CO2. The lipid mixture included the range of plant lipids soluble in organic solvent (e.g. free fatty acids, acylglycerols, pigments) but not polymeric lipids such as cutin and suberin. Mineralisation was deduced from 13CO2 efflux, while LC–MS examined degradation of intact 13C lipids.ResultsThere was no delay before lipids were mineralised. Instead, mineralisation was significant within minutes and reached a maximum within three hours. There was rapid loss (i.e. degradation) of a broad range of intact lipids including phospholipids, galactolipids, pigments (chlorophylls), and triacylglycerols. Around two-thirds of added lipid-C was respired over the course of 15 days, with one-third of lipid-C persisting in soil.ConclusionsOur study indicates that non-polymeric leaf lipids degrade quickly in soil, yet a fraction of lipid-C likely persisted in degradation products and/or microbial biomass. Persistence of lipid-C probably also reflected the presence of lipids that are more resistant to degradation (e.g. phaeophytins), and a fraction of added lipid being protected (e.g. by interaction with clays).Graphical abstract

Lipid-Polymer Hybrid Nanoparticles for Topical Drug Delivery System

Human skin not only functions as a permeation barrier (mainly due to the stratum corneum layer), but also provides a unique delivery pathway for therapeutic and other active agents. These compounds penetrate via intercellular, intracellular and transappendageal routes, resulting in topical delivery (into skin strata) and transdermal delivery (to subcutaneous tissues and into the systemic circulation). Lipid–polymer hybrid nanoparticles (LPHNPs) are next-generation core–shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent.&#x0D; Keywords: Lipid–polymer hybrid nanoparticle, Topical delivery, Drug delivery, Gene delivery.

Enhanced Skin Permeation and Controlled Release of β-Sitosterol Using Cubosomes Encrusted with Dissolving Microneedles for the Management of Alopecia.

The use of synthetic medication for treating alopecia is restricted because of systemic exposure and related negative effects. Beta-sitosterol (β-ST), a natural chemical, has lately been studied for its potential to promote hair development. The cubosomes with dissolving microneedles (CUBs-MND) created in this study may be a useful starting point for the creation of a sophisticated dermal delivery system for β-ST. Cubosomes (CUBs) were prepared by the emulsification method, using glyceryl monooleate (GMO) as a lipid polymer. CUBs were loaded with dissolving microneedles (MND) fabricated with HA and a PVP-K90 matrix. An ex vivo skin permeation study and an in vivo hair growth efficacy test of β-ST were performed with both CUB and CUB-MND. The average particle size of the CUBs was determined to be 173.67 ± 0.52 nm, with a low polydispersity index (0.3) and a high zeta potential value that prevents the aggregate formation of dispersed particles. When compared to CUBs alone, CUBs-MND displayed higher permeating levels of β-ST at all-time points. In the animals from the CUB-MND group, significant hair development was observed. According to the results of the current investigation, CUBs that integrate dissolving microneedles of β-ST are superior in terms of transdermal skin penetration and activity for the treatment of alopecia.

Mechanical Model for Super-Anisotropic Swelling of the Multi-Cylindrical PDGI/PAAm Gels

MC-PDGI/PAAm gels are cylindrical composite gels containing poly(dodecyl glyceryl itaconate) (PDGI) as a polymerized lipid oriented in a multilayer tubular shape within a polyacrylamide (PAAm) network. The most unique feature of the MC-PDGI/PAAm gel is its super-anisotropic swelling, wherein the diameter of the gel increases, but the length decreases with an increase in the volume of the gel. Through swelling and small-angle X-ray diffraction experiments, we investigated the effects of PDGI lipid bilayers and polymer network on the swelling of the MC-PDGI/PAAm gel, which suggests that the swelling anisotropy of the MC-PDGI/PAAm gel is dominated by the elasticity of the PDGI bilayers. Furthermore, we investigated the equation of state of the gel that roughly reproduced the experimental swelling results. These findings are crucial for realizing the controlled super-anisotropic swelling of MC-PDGI/PAAm gels and their applications as anisotropic actuation devices.

SMALPs Are Not Simply Nanodiscs: The Polymer-to-Lipid Ratios of Fractionated SMALPs Underline Their Heterogeneous Nature.

Amphipathic styrene-maleic acid (SMA) copolymers directly solubilize biomembranes into SMA-lipid particles, or SMALPs, that are often regarded as nanodiscs and hailed as a native membrane platform. The promising outlook of SMALPs inspires the discovery of many SMA-like copolymers that also solubilize biomembranes into putative nanodiscs, but a fundamental question remains on how much the SMALPs or SMALP analogues truly resemble the bilayer structure of nanodiscs. This unfortunate ambiguity undermines the utility of SMA or SMA-like copolymers in membrane biology because the structure and function of many membrane proteins depend critically on their surrounding matrices. Here, we report the structural heterogeneity of SMALPs revealed through fractionating SMALPs comprised of lipids and well-defined SMAs via size-exclusion chromatography followed by quantitative determination of the polymer-to-lipid (P/L) stoichiometric ratios in individual fractions. Through the lens of P/L stoichiometric ratios, different self-assembled polymer-lipid nanostructures are inferred, such as polymer-remodeled liposomes, polymer-encased nanodiscs, polymer-lipid mixed micelles, and lipid-doped polymer micellar aggregates. We attribute the structural heterogeneity of SMALPs to the microstructure variations amongst individual polymer chains that give rise to their polydisperse detergency. As an example, we demonstrate that SMAs with a similar S/MA ratio but different chain sizes participate preferentially in different polymer-lipid nanostructures. We further demonstrate that proteorhodopsin, a light-driven proton pump solubilized within the same SMALPs is distributed amongst different self-assembled nanostructures to display different photocycle kinetics. Our discovery challenges the native nanodisc notion of SMALPs or SMALP analogues and highlights the necessity to separate and identify the structurally dissimilar polymer-lipid particles in membrane biology studies.

Curcumin in the treatment of liver cancer: From mechanisms of action to nanoformulations

Liver cancer is the sixth most prevalent cancer and ranks third in cancer-related death, after lung and colorectal cancer. Various natural products have been discovered as alternatives to conventional cancer therapy strategies, including radiotherapy, chemotherapy, and surgery. Curcumin (CUR) with antiinflammatory, antioxidant, and antitumor activities has been associated with therapeutic benefits against various cancers. It can regulate multiple signaling pathways, such as PI3K/Akt, Wnt/β-catenin, JAK/STAT, p53, MAPKs, and NF-ĸB, which are involved in cancer cell proliferation, metastasis, apoptosis, angiogenesis, and autophagy. Due to its rapid metabolism, poor oral bioavailability, and low solubility in water, CUR application in clinical practices is restricted. To overcome these limitations, nanotechnology-based delivery systems have been applied to use CUR nanoformulations with added benefits, such as reducing toxicity, improving cellular uptake, and targeting tumor sites. Besides the anticancer activities of CUR in combating various cancers, especially liver cancer, here we focused on the CUR nanoformulations, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, and others, in the treatment of liver cancer.

Development and in-vitro evaluation of chitosan and glyceryl monostearate based matrix lipid polymer hybrid nanoparticles (LPHNPs) for oral delivery of itraconazole

Itraconazole (ICZ) is a broad spectrum antifungal drug, but used as second or third line therapy due to its low and erratic oral bioavailability. This work was carried out to prepare and characterize matrix type lipid-polymer hybrid nanoparticles (LPHNPs) for dissolution enhancement of ICZ. LPHNPs were prepared using solvent diffusion/emulsification technique. Matrix LPHNPs were composed of chitosan (polymer), glyceryl monostearate (lipid) and poloxamer 188 (stabilizer). LPHNPs loaded with ICZ (LPHNPs-1, LPHNPs-2, LPHNPs-3 and LPHNPs-4) were developed using varying concentration of chitosan whereas LPHNPs (LPHNPs-5, LPHNPs-6, LPHNPs-7 and LPHNPs-8) were prepared using varying concentrations of poloxamer 188. LPHNPs loaded with ICZ were further evaluated for entrapment efficiency, particle size, polydispersity index (PDI), zeta potential and dissolution profiles at biorelevant pH conditions. The particle size (LPHNPs-1 to LPHNPs-4) was found to be in range of 421–588 nm with PDI values 0.34–0.41. The particles size of LPHNPs-5 to LPHNPs-8 was found to be in range of 489–725 nm with PDI 0.34–0.74. The entrapment efficiency of LPHNPs-1 to LPHNPs-4 was found to be in range of 85.21%–91.34%. The entrapment efficiency of LPHNPs-5 to LPHNPs-8 was found to be in range 78.32%–90.44%. . The scanning electron microscopy of optimized formulations LPHNPs-1 and LPHNPs-5 indicated formation of oval shaped nanoparticles. DSC thermogram of ICZ loaded LPHNPs also depicted the conversion of crystalline form of ICZ into amorphous form demonstrating the internalization and dissolution enhancement of drug in the hybrid matrix. The cumulative drug dissolved at acidic pH 1.2 was found to be 23.3% and 19.8% for LPHNPs-1 and LPHNPs-5 respectively. Similarly at basic pH values 7.4, cumulative amount of drug dissolved was 90.2% and 83.4% for LPHNPs-1 and LPHNPs-5 respectively. Drug dissolution kinetics exhibited fickian diffusion best described by Korse-meyer Peppas model. The results suggested that chitosan and glyceryl monostearate based matrix LPHNPs could be used as promising approach for dissolution enhancement of ICZ which could further increase its bioavailability.

Effect of Cholesterol on the Structure and Composition of Glyco-DIBMA Lipid Particles.

Different amphiphilic co-polymers have been introduced to produce polymer-lipid particles with nanodisc structure composed of an inner lipid bilayer and polymer chains self-assembled as an outer belt. These particles can be used to stabilize membrane proteins in solution and enable their characterization by means of biophysical methods, including small-angle X-ray scattering (SAXS). Some of these co-polymers have also been used to directly extract membrane proteins together with their associated lipids from native membranes. Styrene/maleic acid and diisobutylene/maleic acid are among the most commonly used co-polymers for producing polymer-lipid particles, named SMALPs and DIBMALPs, respectively. Recently, a new co-polymer, named Glyco-DIBMA, was produced by partial amidation of DIBMA with the amino sugar N-methyl-d-glucosamine. Polymer-lipid particles produced with Glyco-DIBMA, named Glyco-DIBMALPs, exhibit improved structural properties and stability compared to those of SMALPs and DIBMALPs while retaining the capability of directly extracting membrane proteins from native membranes. Here, we characterize the structure and lipid composition of Glyco-DIBMALPs produced with either 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Glyco-DIBMALPs were also prepared with mixtures of either POPC or DMPC and cholesterol at different mole fractions. We estimated the lipid content in the Glyco-DIBMALPs and determined the particle structure and morphology by SAXS. We show that the Glyco-DIBMALPs are nanodisc-like particles whose size and shape depend on the polymer/lipid ratio. This is relevant for designing nanodisc particles with a tunable diameter according to the size of the membrane protein to be incorporated. We also report that the addition of >20 mol % cholesterol strongly perturbed the formation of Glyco-DIBMALPs. Altogether, we describe a detailed characterization of the Glyco-DIBMALPs, which provides relevant inputs for future application of these particles in the biophysical investigation of membrane proteins.

The development of highly dense highly protected surfactant ionizable lipid RNA loaded nanoparticles.

The long quest for efficient drug administration has been looking for a universal carrier that can precisely transport traditional drugs, new genomic and proteic therapeutic agents. Today, researchers have found conditions to overcome the two main drug delivery dilemmas. On the one side, the versatility of the vehicle to efficiently load, protect and transport the drug and then release it at the target place. On the other hand, the questions related to the degree of PEGylation which are needed to avoid nanoparticle (NP) aggregation and opsonization while preventing cellular uptake. The development of different kinds of lipidic drug delivery vehicles and particles has resulted in the development of ionizable lipid nanoparticles (iLNPs), which can overcome most of the typical drug delivery problems. Proof of their success is the late approval and massive administration as the prophylactic vaccine for SARS-CoV-2. These ILNPs are built by electrostatic aggregation of surfactants, the therapeutic agent, and lipids that self-segregate from an aqueous solution, forming nanoparticles stabilized with lipid polymers, such as PEG. These vehicles overcome previous limitations such as low loading and high toxicity, likely thanks to low charge at the working pH and reduced size, and their entry into the cells via endocytosis rather than membrane perforation or fusion, always associated with higher toxicity. We herein revise their primary features, synthetic methods to prepare and characterize them, pharmacokinetic (administration, distribution, metabolization and excretion) aspects, and biodistribution and fate. Owing to their advantages, iLNPs are potential drug delivery systems to improve the management of various diseases and widely available for clinical use.