PEGylated Lipid Nanoparticles Research Articles

Selective induction of apoptotic cell death in lung carcinoma cells by curcumin-loaded PEGylated lipid nanoparticles with minimal normal tissue toxicity: in vitro and in vivo toxicity evaluation by oral delivery

Selective induction of apoptotic cancer cell death by curcumin-loaded PEGylated lipid nanoparticles.

JNK2 silencing lipid nanoparticles for elastic matrix repair.

The over-expression of c-Jun N-terminal kinase (JNK2), a stress activated mitogen kinase, in the aortic wall plays a critical role in the formation and progression of abdominal aortic aneurysm (AAA). This triggers chronic downstream upregulation of elastolytic matrix metalloproteinases (MMPs), MMPs2 and 9 to cause progressive proteolytic breakdown of the wall elastic matrix. We have previously shown that siNRA knockdown of JNK2 gene expression in an AAA culture model stimulates downstream elastin gene expression, elastic fiber formation, crosslinking and reduces elastolytic MMPs2 and 9. Since naked siRNA poorly routes to intracellular targets, has poor stability in blood, and could be potentially toxic and immunogenic, this project is aimed to develop PEGylated lipid nanoparticles (LNPs) for delivery of JNK siRNA and to generate evidence of successful JNK2 knockdown and downstream attenuation of MMP2 gene and protein expressions. LNPs were formulated using thin-film hydration technique and had the size of 100-200 nm with zeta-potential ranging between 30 and 40 mV. JNK siRNA loaded PEGylated LNPs successfully knocked down JNK2 in cytokine-activated rat aneurysmal smooth muscle (EaRASMC) cultures. This resulted in a downstream decrease in MMP2 gene and protein expression and an upward trend in expression of genes for proteins critical for elastic fiber assembly such as elastin (ELN) and lysyl oxidase (LOX). Our result indicates cationic LNPs to be potential carriers for JNK siRNA delivery improving potency for elastin homeostasis required for AAA repair which could possibly provide benefits in preventing the progression of small AAAs.

Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route.

Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system.

Investigating the mechanism of action of DNA-loaded PEGylated lipid nanoparticles

PEGylated lipid nanoparticles (LNPs) are commonly used to deliver bioactive molecules, but the role of PEGylation in DNA-loaded LNP interactions at the cellular and subcellular levels remains poorly understood. In this study, we investigated the mechanism of action of DNA-loaded PEGylated LNPs using gene reporter technologies, dynamic light scattering (DLS), synchrotron small angle X-ray scattering (SAXS), and fluorescence confocal microscopy (FCS). We found that PEG has no significant impact on the size or nanostructure of DNA LNPs but reduces their zeta potential and interaction with anionic cell membranes. PEGylation increases the structural stability of LNPs and results in lower DNA unloading. FCS experiments revealed that PEGylated LNPs are internalized intact inside cells and largely shuttled to lysosomes, while unPEGylated LNPs undergo massive destabilization on the plasma membrane. These findings can inform the design, optimization, and validation of DNA-loaded LNPs for gene delivery and vaccine development.

Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products.

Polyethylene glycol (PEG) is a versatile polymer that is widely used as an additive in foods and cosmetics, and as a carrier in PEGylated therapeutics. Even though PEG is thought to be less immunogenic, or perhaps even non-immunogenic, with a variety of physicochemical properties, there is mounting evidence that PEG causes immunogenic responses when conjugated with other materials such as proteins and nanocarriers. Under these conditions, PEG with other materials can result in the production of anti-PEG antibodies after administration. The antibodies that are induced seem to have a deleterious impact on the therapeutic efficacy of subsequently administered PEGylated formulations. In addition, hypersensitivity to PEGylated formulations could be a significant barrier to the utility of PEGylated products. Several reports have linked the presence of anti-PEG antibodies to incidences of complement activation-related pseudoallergy (CARPA) following the administration of PEGylated formulations. The use of COVID-19 mRNA vaccines, which are composed mainly of PEGylated lipid nanoparticles (LNPs), has recently gained wide acceptance, although many cases of post-vaccination hypersensitivity have been documented. Therefore, our review focuses not only on the importance of PEGs and its great role in improving the therapeutic efficacy of various medications, but also on the hypersensitivity reactions attributed to the use of PEGylated products that include PEG-based mRNA COVID-19 vaccines.

Understanding the Role and Impact of Poly (Ethylene Glycol) (PEG) on Nanoparticle Formulation: Implications for COVID-19 Vaccines.

Poly (ethylene glycol) (PEG) is a widely used polymer in a variety of consumer products and in medicine. PEGylation refers to the conjugation of PEG to drugs or nanoparticles to increase circulation time and reduce unwanted host responses. PEG is viewed as being well-tolerated, but previous studies have identified anti-PEG antibodies and so-called pseudoallergic reactions in certain individuals. The increased use of nanoparticles as contrast agents or in drug delivery, along with the introduction of mRNA vaccines encapsulated in PEGylated lipid nanoparticles has brought this issue to the fore. Thus, while these vaccines have proven to be remarkably effective, rare cases of anaphylaxis have been reported, and this has been tentatively ascribed to the PEGylated carriers, which may trigger complement activation in susceptible individuals. Here, we provide a general overview of the use of PEGylated nanoparticles for pharmaceutical applications, and we discuss the activation of the complement cascade that might be caused by PEGylated nanomedicines for a better understanding of these immunological adverse reactions.

Potential enhancement of metformin hydrochloride in solidified reverse micellar solution-based PEGylated lipid nanoparticles targeting therapeutic efficacy in diabetes treatment

Metformin hydrochloride (MH) is a widely used oral biguanide antihyperglycemic (antidiabetic) drug with poor bioavailability which necessitates the development of novel drug delivery systems such as PEGylated solid lipid nanoparticles for improving its therapeutic activity. The aim of this study was to formulate, characterize and evaluate in vitro and in vivo pharmacodynamic properties of metformin–loaded PEGylated solid lipid nanoparticles (PEG-SLN) for improved delivery of MH. The lipid matrices (non-PEGylated lipid matrix and PEGylated lipid matrices) used in the formulation of both non-PEGylated (J0) and PEGylated SLNs (J10, J20, J40) were prepared by fusion using beeswax and Phospholipon ® 90H at 7:3 ratio with or without polyethylene glycol (PEG) 4000 (0, 10, 20 and 40% w/w), respectively. Representative lipid matrices (LM and PEG-LM) were loaded with MH by fusion and then characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The PEG-SLNs were prepared by high shear hot homogenization using the lipid matrices (5% w/w), drug (MH) (1.0% w/w), sorbitol (4% w/w) (cryoprotectant), Tween ® 80 (2% w/w) (surfactant) and distilled water (q.s to 100% w/w) (vehicle). The non-PEGylated and PEGylated SLNs (J0, J10, J20, J40)) were characterized with respect to encapsulation efficiency (EE%), loading capacity (LC), morphology by scanning electron microscopy (SEM), mean particle size (Zav) and polydispersity indices (PDI) by photon correlation spectroscopy (PCS), compatibility by FT-IR spectroscopy and in vitro drug release in biorelevant medium. Thereafter, in vivo antidiabetic study was carried out in alloxanized rats’ model and compared with controls (pure sample of MH and commercial MH- Glucophage®)). Solid state characterizations indicated the amorphous nature of MH in the drug loaded-lipid matrices. The PEG-SLNs were mostly smooth and spherical nanoformulations with Zav and PDI of 350.00 nm and 0.54, respectively, for non-PEGylated SLNs, and in the range of 386.80–783.10 nm and 0.592 to 0.752, respectively, for PEGylated SLNs. The highest EE% and LC were noted in batch J20 and were 99.28% and 16.57, respectively. There was no strong chemical interaction between the drug and excipients used in the preparation of the formulations. The PEGylated SLN (batch J40) exhibited the highest percentage drug released (60%) at 8 h. The PEGylated SLNs showed greater hyperglycemic control than the marketed formulation (Glucophage ®) after 24 h. This study has shown that metformin–loaded PEGylated solid lipid nanoparticles could be employed as a potential approach to improve the delivery of MH in oral diabetic management, thus encouraging further development of the formulations.

To PEGylate or not to PEGylate: Immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives.

Polyethylene glycol or PEG has a long history of use in medicine. Many conventional formulations utilize PEG as either an active ingredient or an excipient. PEG found its use in biotechnology therapeutics as a tool to slow down drug clearance and shield protein therapeutics from undesirable immunogenicity. Nanotechnology field applies PEG to create stealth drug carriers with prolonged circulation time and decreased recognition and clearance by the mononuclear phagocyte system (MPS). Most nanomedicines approved for clinical use and experimental nanotherapeutics contain PEG. Among the most recent successful examples are two mRNA-based COVID-19 vaccines that are delivered by PEGylated lipid nanoparticles. The breadth of PEG use in a wide variety of over the counter (OTC) medications as well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEG's immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives.

Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: A case series

Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: A case series

Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases.

Neurons within the tumor microenvironment promote cancer progression; thus, their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer cross-talk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration, and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer cell viability. In vivo, bupivacaine-loaded nanoparticles intravenously administered suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

ABC phenomenon in the development of PEGylated lipid nanoparticles encapsulating siRNA

ABC phenomenon in the development of PEGylated lipid nanoparticles encapsulating siRNA

Adhesion and Structural Changes of PEGylated Lipid Nanocarriers on Silica Surfaces

PEGylated lipid nanoparticles have a continuously expanding range of applications, particularly within pharmaceutical areas. Hereby, it is shown with the help of the Quartz Crystal Microbalance with Dissipation monitoring (QCM-D) and other surface sensitive techniques that, at room temperature, PEGylated liposomes and lipodisks adhere strongly to silica surfaces resulting in the displacement of the hydration layer of silica and the formation of immobilized nanoparticle films. Furthermore, it is shown that drastic changes in the structure of the immobilized films occur if the temperature is increased to >35 °C. Thus, intact immobilized PEGylated liposomes rupture and spread, even in the gel phase state; immobilized lipodisks undergo complete separation of their components (bilayer forming lipids and PEGylated lipids) resulting in a monolayer of adsorbed PEGylated lipids; and PEGylated supported lipid bilayers release part of the water trapped between the lipid membrane and the surface. It is hypothesized that these changes occur mainly due to the changes in the configuration of PEG chains and a drastic decrease of the affinity of the polymer for water. The observed phenomena can be applied, e.g., for the production of defect-free supported lipid bilayers in the gel or liquid ordered phase states.

Basophil reactivity to BNT162b2 is mediated by PEGylated lipid nanoparticles in patients with PEG allergy

The mechanisms underpinning allergic reactions to the BNT162b2 (Pfizer) COVID-19 vaccine remain unknown, with polyethylene glycol (PEG) contained in the lipid nanoparticle suspected as being the cause. Our aim was to evaluate the performance of skin testing and basophil activation testing to PEG, polysorbate 80, and the BNT162b2 (Pfizer) and AZD1222 (AstraZeneca) COVID-19 vaccines in patients with a history of PEG allergy. Three known individuals with PEG allergy and 3 healthy controls were recruited and evaluated for hypersensitivity to the BNT162b2 and AZD1222 vaccines, and to related compounds by skin testing and basophil activation, as measured by CD63 upregulation using flow cytometry. We found that the BNT162b2 vaccine induced positive skin test results in patients with PEG allergy, whereas the result of traditional PEG skin testing was negative in 2 of 3 patients. One patient was found to be cosensitized to both the BNT162b2 and AZD1222 vaccines because of cross-reactive PEG and polysorbate allergy. The BNT162b2 vaccine, but not PEG alone, induced dose-dependent activation of all patients' basophils exvivo. Similar basophil activation could be induced by PEGylated liposomal doxorubicin, suggesting that PEGylated lipids within nanoparticles, but not PEG in its native state, are able to efficiently induce degranulation. Our findings implicate PEG, as covalently modified and arranged on the vaccine lipid nanoparticle, as a potential trigger of anaphylaxis in response to BNT162b2, and highlight shortcomings of current skin testing protocols for allergy to PEGylated liposomal drugs.

Targeting the resolution pathway of inflammation using Ac2–26 peptide-loaded PEGylated lipid nanoparticles for the remission of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2–26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn‑glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2–26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2–26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.

Novel PEGylated Lipid Nanoparticles Have a High Encapsulation Efficiency and Effectively Deliver MRTF-B siRNA in Conjunctival Fibroblasts.

The master regulator of the fibrosis cascade is the myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway, making it a key target for anti-fibrotic therapeutics. In the past, inhibitors and small interfering RNAs (siRNAs) targeting the MRTF-B gene have been deployed to counter fibrosis in the eye, with the latter showing promising results. However, the biggest challenge in implementing siRNA therapeutics is the method of delivery. In this study, we utilised the novel, pH-sensitive, cationic lipid CL4H6, which has previously demonstrated potent targeting of hepatocytes and endosomal escape, to safely and efficiently deliver an MRTF-B siRNA into human conjunctival fibroblasts. We prepared two lipid nanoparticle (LNP) formulations, incorporating targeting cleavable peptide cY in one of them, and measured their physicochemical properties and silencing effect in human conjunctival fibroblasts. Both proved to be non-cytotoxic at a concentration of 50 nM and effectively silenced the MRTF-B gene in vitro, with the targeting cleavable peptide not affecting the silencing efficiency [LNP with cY: 62.1% and 81.5% versus LNP without cY: 77.7% and 80.2%, at siRNA concentrations of 50 nM (p = 0.06) and 100 nM (p = 0.09), respectively]. On the other hand, the addition of the targeting cleavable peptide significantly increased the encapsulation efficiency of the LNPs from 92.5% to 99.3% (p = 0.0005). In a 3D fibroblast-populated collagen matrix model, both LNP formulations significantly decreased fibroblast contraction after a single transfection. We conclude that the novel PEGylated CL4H6-MRTF-B siRNA-loaded LNPs represent a promising therapeutic approach to prevent conjunctival fibrosis after glaucoma filtration surgery.

PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: Faster PEG shedding attenuates anti-PEG IgM production

PEGylation-modification with polyethylene glycol (PEG)-is useful for stabilizing lipid nanoparticles (LNPs). However, such PEGylation can prevent small interfering RNA (siRNA) encapsulated in LNPs from exerting its gene-silencing effects by disrupting the interaction of LNPs with target cells and by inducing the accelerated blood clearance phenomenon via anti-PEG IgM. PEG-lipids with short acyl chains can be used to address these issues because they are quickly shed from LNPs after administration; however, there are few reports on the relationships among PEG shedding rate, anti-PEG IgM production, and the gene-silencing activity of siRNA upon repeated LNP administration. Here, in mice, we found that LNPs conjugated to a fast-shedding PEG-lipid (short acyl chain) induced less anti-PEG IgM compared with LNPs conjugated to a slow-shedding PEG-lipid (long acyl chain). Moreover, pretreatment of mice with LNPs conjugated to the slow-shedding PEG-lipid caused loss of RNA interference activity after subsequent LNP administration because the payload siRNA was delivered primarily to Kupffer cells rather than to hepatocytes. Together, these findings imply that manipulating PEG shedding rate and anti-PEG antibody production is enormously important in the development of RNA interference-based therapeutics utilizing LNP technology.

Matrix Metalloproteinase-Responsive PEGylated Lipid Nanoparticles for Controlled Drug Delivery in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder. It causes inflammation, swelling, and pain in the joints of the human body. Overexpressed matrix metalloproteinases (MMPs) at the inflammatory sites of RA are a target in the construction of inflammation-responsive drug delivery vehicles for enhancing the therapeutic effect of anti-inflammatory drugs in the treatment of RA. In this paper, we report MMP-responsive PEGylated lipid nanoparticles through the co-assembly of triglycerol monostearate (TGMS) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) in which the ester bond of TGMS is cleavable by MMPs and the PEG chain provides a stealth layer. The lipid nanoparticles show high biocompatibility, extended blood circulation, and preferential distribution in the inflammatory joints of RA. The loaded dexamethasone (Dex) can be rapidly released from the lipid nanoparticles in response to MMPs. After being intravenously administered to arthritic rats, Dex-loaded MMP-responsive PEGylated lipid nanoparticles significantly reduce the degree of joint swelling and inhibit the production of TNF-α and IL-1β in joint tissues. These results demonstrate that MMP-responsive PEGylated lipid nanoparticles are a smart drug vehicle for the treatment of RA with improved therapeutic efficacy.

RGD modified and PEGylated lipid nanoparticles loaded with puerarin: Formulation, characterization and protective effects on acute myocardial ischemia model.

Puerarin has been widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy. RGD modified and PEGylated solid lipid nanoparticles loaded with puerarin (RGD/PEG-PUE-SLN) were developed to improve bioavailability of PUE, to prolong retention time in vivo and to enhance its protective effect on acute myocardial ischemia model. In the present study, RGD-PEG-DSPE was synthesized. RGD/PEG-PUE-SLN were prepared by the solvent evaporation method with some modifications. The physicochemical properties of NPs were characterized, the pharmacokinetics, biodistribution, pharmacodynamic behavior of RGD/PEG-PUE-SLN were evaluated in acute MI rats. The mean diameter, zeta potential, entrapment efficiency and drug loading capacity for RGD/PEG-PUE-SLN were observed as 110.5nm, -26.2mV, 85.7% and 16.5% respectively. PUE from RGD/PEG-PUE-SLN exhibited sustained drug release with a burst release during the initial 12h and a followed sustained release. Pharmacokinetics results indicated that AUC increased from 52.93 (μg/mLh) for free PUE to 176.5 (μg/mLh) for RGD/PEG-PUE-SLN. Similarly, T1/2 increased from 0.73h for free PUE to 2.62h for RGD/PEG-PUE-SLN. RGD/PEG-PUE-SLN exhibited higher drug concentration in the heart and plasma compared with other PUE formulations. It can be clearly seen that the infarct size of RGD/PEG-PUE-SLN is the lowest among all the formulation. We conclude that RGD modified and PEGylated SLN are promising candidate delivery vehicles for cardioprotective drugs in treatment of myocardial infarction.

Clinically approved PEGylated nanoparticles are covered by a protein corona that boosts the uptake by cancer cells.

Today, liposomes are an advanced technology of drug carriers with a dozen drugs in clinical practice and many more in clinical trials. A bottleneck associated with the clinical translation of liposomes has long been 'opsonization', i.e. the adsorption of plasma proteins at the liposome surface resulting in their rapid clearance from circulation. For decades, the most popular way to avoid opsonization has been grafting polyethylene glycol (PEG) onto the liposome surface. Recent studies have clarified that grafting PEG onto the liposome surface reduces, but does not completely prevent protein binding. In this work, we employed dynamic light scattering, zeta-potential analysis, one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE), semi-quantitative densitometry and cell imaging to explore the bio-nano-interactions between human plasma (HP) and Onivyde, a PEGylated liposomal drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). To properly evaluate the role of PEGylation, an unPEGylated variant of Onivyde was used as a reference. Collectively, our findings suggest that: (i) although PEGylated, Onivyde is not "stealth" in HP; (ii) surface chemistry is more important than PEGylation in controlling the bio-nano-interactions between Onivyde and plasma components. Of note is that the PC was found to boost the cellular uptake of Onivyde in the pancreas ductal adenocarcinoma cell line (PANC-1) thus suggesting its prominent role in its indication for PDAC treatment. Relevant implications for drug delivery and drug design are discussed.

Baicalin-loaded PEGylated lipid nanoparticles: characterization, pharmacokinetics, and protective effects on acute myocardial ischemia in rats

Context: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy.Objective: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention time in vivo and to enhance its protective effect.Methods: In this study, BN-PEG-NLC were prepared by the emulsion-evaporation and low temperature-solidification method using a mixture of glycerol monostearate and polyethylene glycol monostearate as solid lipids, and oleic acid as the liquid lipid. The physicochemical properties of NLC were characterized. The pharmacokinetic and pharmacodynamic behaviors of BN-PEG-NLC or BN-NLC were evaluated in acute MI rats.Results and discussion: The particle size, zeta potential, and entrapment efficiency for BN-PEG-NLC were observed as 83.9 nm, −32.1 mV, and 83.5%, respectively. The release profiles of BN from both BN-PEG-NLC and BN-NLC were fitted to the Ritger–Peppas modal, which presented burst release initially and prolonged release afterwards. Pharmacokinetics results indicated that BN-PEG-NLC exhibited a 7.2-fold increase in AUC in comparison to BN solution, while a 3-fold increase in comparison to BN-NLC. Biodistribution results revealed that BN-PEG-NLC exhibited higher heart drug concentration compared with BN-NLC as well as BN solution. In the present study, BN-PEG-NLC significantly ameliorated infarct size.Conclusion: The results of the present study imply that PEG-NLC could be the biocompatible carriers for heart-targeted drug delivery to improve myocardial ischemia.