Reticuloendothelial System Uptake Research Articles

Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation

Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin’s self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dose in vivo (hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.

Biomimetic nanodecoys deliver cholesterol-modified heteroduplex oligonucleotide to target dopaminergic neurons for the treatment of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) aggregates called Lewy bodies leading to the gradual loss of dopaminergic (DA) neurons in the substantia nigra. Although α-syn expression can be attenuated by antisense oligonucleotides (ASOs) and heteroduplex oligonucleotide (HDO) by intracerebroventricular (ICV) injection, the challenge to peripheral targeted delivery of oligonucleotide safely and effectively into DA neurons remains unresolved. Here, we designed a new DNA/DNA double-stranded (complementary DNA, coDNA) molecule with cholesterol conjugation (Chol-HDO (coDNA)) based on an α-syn-ASO sequence and evaluated its silence efficiency. Further, Chol-HDO@LMNPs, Chol-HDO-loaded, cerebrovascular endothelial cell membrane with DSPE-PEG2000-levodopa modification (L-DOPA-CECm)-coated nanoparticles (NPs), were developed for the targeted treatment of PD by tail intravenous injection. CECm facilitated the blood-brain barrier (BBB) penetration of NPs, together with cholesterol escaped from reticuloendothelial system uptake, as well as L-DOPA was decarboxylated into dopamine which promoted the NPs toward the PD site for DA neuron regeneration. The behavioral tests demonstrated that the nanodecoys improved the efficacy of HDO on PD mice. These findings provide insights into the development of biomimetic nanodecoys loading HDO for precise therapy of PD. Statement of significanceThe accumulation of α-synuclein (α-syn) aggregates is a hallmark of PD. Our previous study designed a specific antisense oligonucleotide (ASO) targeting human SNCA, but the traumatic intracerebroventricular (ICV) is not conducive to clinical application. Here, we further optimize the ASO by creating a DNA/DNA double-stranded molecule with cholesterol-conjugated, named Chol-HDO (coDNA), and develop a DA-targeted biomimetic nanodecoy Chol-HDO@LMNPs by engineering cerebrovascular endothelial cells membranes (CECm) with DSPE-PEG2000 and L-DOPA. The in vivo results demonstrated that tail vein injection of Chol-HDO@LMNPs could target DA neurons in the brain and ameliorate motor deficits in a PD mouse model. This investigation provides a promising peripheral delivery platform of L-DOPA-CECm nanodecoy loaded with a new Chol-HDO (coDNA) targeting DA neurons in PD therapy.

The Sojourn of Polymeric Micelles for Effective Brain Drug Delivery System.

The brain is a delicate organ and targeting neurological diseases with conventional approaches is still a daunting task. This is due to the presence of necessary physiological barriers, mainly the blood-brain barrier, that blocks the entry of dangerous and poisonous substances from the bloodstream, thus helping in maintaining homeostasis. Furthermore, the presence of multidrug resistance transporters which act by prohibiting the entry of drugs across the cell membrane and by channelizing them to the outside environment is another defense mechanism. Despite the advancements in the understanding of disease pathology, only a restricted number of drugs and drug therapies can treat and target neurological diseases. To overcome this shortcoming, the therapeutic approach using amphiphilic block copolymers - using polymeric micelles has gained momentum because of its wide applications like drug targeting, delivery, and imaging. Polymeric micelles are nanocarriers that arise when amphiphilic block copolymers spontaneously assemble in aqueous solutions. The hydrophobic core-hydrophilic shell configuration of these nanoparticles makes it easier to load hydrophobic drugs into the core and as a result, the solubility of these medications is improved. Micelle-based drug delivery carriers can target the brain with reticuloendothelial system uptake and produce a long-circulating effect. PMs can also be combined with targeting ligands that increase their uptake by specific cells and thus decreasing off-target effects. In the present review, we primarily focused on polymeric micelles for brain delivery along with the method of preparation, mechanism of micelle formulation, and the ongoing formulations under clinical trials for brain delivery.

O-02 - Evaluation of the combinationally glycated albumin nanoplatform for targeting the tumor microenvironment with minimized reticuloendothelial system uptake using PET imaging

O-02 - Evaluation of the combinationally glycated albumin nanoplatform for targeting the tumor microenvironment with minimized reticuloendothelial system uptake using PET imaging

Application of Nanoparticles in Cancer Treatment: A Concise Review.

Timely diagnosis and appropriate antitumoral treatments remain of utmost importance, since cancer remains a leading cause of death worldwide. Within this context, nanotechnology offers specific benefits in terms of cancer therapy by reducing its adverse effects and guiding drugs to selectively target cancer cells. In this comprehensive review, we have summarized the most relevant novel outcomes in the range of 2010-2023, covering the design and application of nanosystems for cancer therapy. We have established the general requirements for nanoparticles to be used in drug delivery and strategies for their uptake in tumor microenvironment and vasculature, including the reticuloendothelial system uptake and surface functionalization with protein corona. After a brief review of the classes of nanovectors, we have covered different classes of nanoparticles used in cancer therapies. First, the advances in the encapsulation of drugs (such as paclitaxel and fisetin) into nanoliposomes and nanoemulsions are described, as well as their relevance in current clinical trials. Then, polymeric nanoparticles are presented, namely the ones comprising poly lactic-co-glycolic acid, polyethylene glycol (and PEG dilemma) and dendrimers. The relevance of quantum dots in bioimaging is also covered, namely the systems with zinc sulfide and indium phosphide. Afterwards, we have reviewed gold nanoparticles (spheres and anisotropic) and their application in plasmon-induced photothermal therapy. The clinical relevance of iron oxide nanoparticles, such as magnetite and maghemite, has been analyzed in different fields, namely for magnetic resonance imaging, immunotherapy, hyperthermia, and drug delivery. Lastly, we have covered the recent advances in the systems using carbon nanomaterials, namely graphene oxide, carbon nanotubes, fullerenes, and carbon dots. Finally, we have compared the strategies of passive and active targeting of nanoparticles and their relevance in cancer theranostics. This review aims to be a (nano)mark on the ongoing journey towards realizing the remarkable potential of different nanoparticles in the realm of cancer therapeutics.

Design, development, and in-vitro/in-vivo evaluation of docetaxel-loaded PEGylated solid lipid nanoparticles in prostate cancer therapy

Docetaxel (DOC) is a potent anticancer molecule widely used to treat various cancers. However, its therapeutic efficacy as a potential anticancer agent has been limited owing to poor aqueous solubility, short circulation time, rapid reticuloendothelial system uptake, and high renal clearance, which consecutively showed poor bioavailability. In the present investigation, we developed polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLN) using the solvent diffusion method to increase the biopharmaceutical properties of DOC. PEG monostearate (SA-PEG2000) was initially synthesized and characterized using various analytical techniques. Afterwards, DOC-loaded SLN was synthesized with and without SA-PEG2000and systematically characterized for in-vitro and in-vivo properties. Spherical-shaped SA-PEG2000-DOC SLN showed hydrodynamic diameter and zeta potential of 177 nm and −13 mV, respectively. During the in-vitro release study DOC-loaded SLN showed a controlledrelease of approximately 54.35 % ± 5.46 within 12 h with Higuchi release kinetics in the tumor microenvironment (pH 5.5).In an in-vitro cytotoxicity study,SA-PEG2000-DOC SLN showedsignificantlylower IC50values(p < 0.001)compared to DOC-SLN and DOC aloneagainst prostate cancer cell lines (PC-3). Similarly, an in-vitro cellular uptake study showed a significant increase in intracellular DOC concentration for SA-PEG2000-DOC SLN. Additionally, inin-vivostudies,PEGylated SLN of DOC showed around 2- and 15-fold increase in the maximum concentration of drug (Cmax) and area under the curve (AUC), respectively, as compared to plain DOC solution due to the uniquehydrophilicity and hydrophobicity balance and electrical neutrality of specially designed PEG architect. The biological half-life (t1/2) and mean residence time (MRT) was found to increase from 8.55 and 11.43 to 34.96 and 47.68 h, respectively, with SA-PEG2000-DOC SLN. Moreover, the bio-distribution study indicates high DOC concentration in the plasma which signifies the more pronounced blood residence time of SA-PEG2000-DOC SLN. In a nutshell, SA-PEG2000-DOC SLNwasfound to bea promising and efficient drug delivery platform for the management of Metastatic Prostate cancer.

Biomimetic camouflaged nanoparticle-based folfirinox platform for optimizing clinical pancreatic cancer treatment

The most effective treatment of pancreatic cancer (PC) is known as mFOLFIRINOX scheme. However, this regimen has relatively severe toxic effects and are commonly restricted to patients with sound physique, which is poor in drug-selectivity, non-specific causing serious toxicity, greatly limits clinical application. Safer and more effective strategy seamlessly and synchronously is needed as advanced treatments for pancreatic cancer in future. In this report, we exploit a biomimetic nanoparticle-based platform for optimizing mFOLFIRINOX regimen. By coating pancreatic cancer cell membrane (PCCM) onto the surface of polymeric cores that loaded with mFOLFIRINOX, we prepare PCCM-cloaked nanoparticles, namely CNP@folfirinox, which inherit the antigenic exterior structure and associated functions of PC cells. The resulting CNP@folfirinox displays a core-shell nanostructure, which consisting of polymeric core and cancer cell membrane shell with suitable size and surface charge. Particularly, owing to inheriting the inherent membrane protein expressions profile, CNP@folfirinox exhibits prominent advantages in homologous homing to tumor tissue and deep penetration. It also shows lower side effects compared to extensive mFOLFIRINOX i.v. administration with no appreciable toxicity in other organs outside the tumor in vivo. Meanwhile, CNP@folfirinox is endowed with the “Don’t eat me” privilege, hard for the immune system to recognize and less reticuloendothelial system uptake, with prolonged blood circulation, therefore improving delivery efficiency of drug after intravenous administration. Thus, this work reshapes a promising paradigm for more safe and more effective mFOLFIRINOX strategy for further clinical pancreatic cancer treatment.

Brain-Targeted Biomimetic Nanodecoys with Neuroprotective Effects for Precise Therapy of Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates called Lewy bodies. Here, nanodecoys were designed from a rabies virus polypeptide with a 29 amino acid (RVG29)-modified red blood cell membrane (RBCm) to encapsulate curcumin nanocrystals (Cur-NCs), which could effectively protect dopaminergic neurons. The RVG29-RBCm/Cur-NCs nanodecoys effectively escaped from reticuloendothelial system (RES) uptake, enabled prolonged blood circulation, and enhanced blood–brain barrier (BBB) crossing after systemic administration. Cur-NCs loaded inside the nanodecoys exhibited the recovery of dopamine levels, inhibition of α-synuclein aggregation, and reversal of mitochondrial dysfunction in PD mice. These findings indicate the promising potential of biomimetic nanodecoys in treating PD and other neurodegenerative diseases.

Hybrid-Membrane-Decorated Prussian Blue for Effective Cancer Immunotherapy via Tumor-Associated Macrophages Polarization and Hypoxia Relief.

Both tumor-associated macrophages (TAMs) and hypoxia condition severely restrict the antitumor potency during cancer immunotherapy. It is essential to overcome the two issues for improving therapeutic efficacy. In this study, a hollow mesoporous Prussian blue (HMPB) nanosystem with mannose decoration and hydroxychloroquine (HCQ) adsorption is built, to form Man-HMPB/HCQ. It can facilitate cellular internalization via mannose-receptor mediated endocytosis and induce TAM polarization via iron ion/HCQ release with HMPB degradation. The hybrid macrophage and thylakoid (TK) membrane is camouflaged on the Man-HMPB/HCQ surface, denoted as TK-M@Man-HMPB/HCQ, to reduce in vivo reticuloendothelial system uptake, enhance tumor accumulation, and mitigate hypoxia. The in vivo results indicate that TK-M@Man-HMPB/HCQ notably inhibits tumor growth, induces TAM polarization, facilitates cytotoxic T lymphocytes infiltration, and alleviates hypoxia microenvironment. The rational design may provide a new pathway to modulate the tumor microenvironment for promoting cancer immunotherapy effects.

Pretargeting articulation for improving the deliverance of injected dose to the tumor: An evaluation of In vivo study for enhanced tumor uptake

Background: Radiobioconjugate targeting using monoclonal antibodies linked to a high-energy radionuclide is a promising approach for treating metastatic cancer. The central problem of radiobioconjugate targeting is the small fraction of radiobioconjugate localized in the tumor. Pretargeting based on avidin–biotin approach has been recommended to maximize tumor targeting. The current study was conceded with an aim to assess a selective targeting strategy for the site-specific deliverance of an injected radioactive dose to the tumor cells. Methods: Two labeling protocols were tested and evaluated, both for the direct and indirect radiolabeling of antibodies with radionuclide technetium. A comparative evaluation of biodistribution studies relating to the deposition of injected dose in different organs was carried out in tumor-bearing nude mice both for a direct single-step and indirect multistep pretargeting approach. Results: High concentration of the injected dose was accounted in the nontarget organs and blood for a direct targeting mode, as compared to indirect multistep pretargeting with high tumor uptake. Better tumor visibility and high tumor/nontumor ratio were observed at 24 h and 48 h. However, a considerable deposition of radioactivity in the organs such as liver, spleen, kidney, and lungs as a nonspecific, reticuloendothelial system uptake was observed as a cause of concern and the use of certain blocking agents were explored, effective for reducing the same. Conclusions: The study demonstrates a successful targeting efficiency of the radiolabeled bioconjugate for technetium (Tc-99m), through a multistep pretargeting approach, and the same can be applied for other related therapy radionuclides also.

NIR/MRI-Guided Oxygen-Independent Carrier-Free Anti-Tumor Nano-Theranostics.

Imaging-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer treatment are beneficial for precise localization of the malignant lesions and combination of multiple cell killing mechanisms in eradicating stubborn thermal-resistant cancer cells. However, overcoming the adverse impact of tumor hypoxia on PDT efficacy remains a challenge. Here, carrier-free nano-theranostic agents are developed (AIBME@IR780-APM NPs) for magnetic resonance imaging (MRI)-guided synergistic PTT/thermodynamic therapy (TDT). Two IR780 derivatives are synthesized as the subject of nanomedicine to confer the advantages for the nanomedicine, which are by feat of amphiphilic IR780-PEG to enhance the sterical stability and reduce the risk from reticuloendothelial system uptake, and IR780-ATU to chelate Mn2+ for T1 -weighted MRI. Dimethyl 2,2'-azobis(2-methylpropionate) (AIBME), acting as thermally decomposable radical initiators, are further introduced into nanosystems with the purpose of generating highly cytotoxic alkyl radicals upon PTT launched by IR780 under 808nm laser irradiation. Therefore, the sequentially generated heat and alkyl radicals synergistically induce cell death via synergistic PTT/TDT, ignoring tumor hypoxia. Moreover, these carrier-free nano-theranostic agents present satisfactory biocompatibility, which could be employed as a powerful weapon to hit hypoxic tumors via MRI-guided oxygen-independent PTT and photonic TDT.

Prognostic value of F-18 fluorodeoxyglucose uptake in primary tumor and reticuloendothelial system in patients with head and neck cancer

Aim: The aim of this study was to investigate the prognostic value of FDG uptake in primary tumor and reticuloendothelial system at 18 Fluorine-fluorodeoxyglucose positron emission tomography / computed tomography (18F-FDG PET / CT) in patients with head and neck cancer.Materials and Methods: A total of 56 head and neck cancer patients who underwent 18F-FDG PET / CT imaging in our clinic for staging were included in study. A circular volume of interest (VOI) was drawn which include tumor tissue on axial images and thereafter SUVmax value of the primary tumor was measured. Bone marrow SUVmax was measured at Lumbal 3-5 th vertebraes. Bone marrow-to-liver uptake ratio (BLR) value was calculated by dividing the bone marrow SUVmax value to liver SUVmax. Bone marrow-to-spleen uptake ratio (BSR) ratio value was calculated by dividing bone marrow SUVmax value to the spleen SUVmax.Results: Forty-five were male and 11 were female of the 56 patients included in the study. The average age was 62.71 ± 14.3. The SUVmax value of primary tumor and age had a significant predictive value in terms of overall survival (p = 0.027 and p = 0.037, respectively). There was a significant difference in overall survival when using 13.6 cut off for SUVmax and 65.5 cut off for age (p = 0.005, p = 0.019, respectively). Age (≥65.5), distant metastasis and SUVmax of primary tumor (≥13.6) values were independent prognostic factors in the multivariate analysis. The bone marrow SUVmax value and BLR and BSR ratios of the patients did not have a significant prognostic value in both univariate and multivariate analysis.Conclusion: The SUVmax value of the primary tumor in 18F-FDG PET / CT in patients with head and neck cancer, had both predictive and independent prognostic value. Bone marrow SUVmax, BLR and BSR values which shows FDG uptake on RES system, were not predictive and prognostic.

Distinct Proteins in Protein Corona of Nanoparticles Represent a Promising Venue for Endogenous Targeting - Part II: In vitro and in vivo Kinetics Study.

IntroductionNanoparticles (NPs), upon introduction to the biological systems, become wrapped by serum and cellular proteins constituting the protein corona (PC). This PC contributes largely to the NPs’ interaction with the biological systems and their subsequent functions. On the one hand, PC can decrease the efficiency of targeting by directing the NPs to the reticuloendothelial system (RES) or by masking the active targeting moieties and decreasing their ability to bind to their target receptors. On the other hand, some components of PC have offered hopes for achieving endogenous targeting.MethodsIn this study, we aimed at the investigation of the role of the PC in determining the behavior of cRGDyk peptide-unconjugated and -conjugated NPs (uNPs and cNPs) exhibiting different physicochemical properties and their interaction with melanoma on in vitro and in vivo levels. Mathematical modeling has been utilized to understand the kinetics of the interaction of NPs with the tumor cells and different organs, respectively.ResultsEndocytosis and exocytosis were reported to occur simultaneously for the utilized NPs. The balance was largely dependent on the NPs’ physicochemical properties and the role of the PC. In addition, distinct proteins present in the PC (illustrated in the results of the PC analysis in part I) have also determined the patterns of the NPs’ distribution in different organs and tissues of the vascular system, the RES system and the target tumot tissue. Vitronectin (VN) was found to mediate higher accumulation in integrin receptor-expressing melanoma cells, while complement 3 protein (C3) and clusterin (CLU), as an opsonin and dysopsonin, respectively, regulated the balance between the RES uptake and blood circulation.DiscussionPC, if properly modulated by tuning NPs’ physicochemical properties, can serve as a potential venue for optimum utilization of NPs in cancer therapy.

Surface modified silk fibroin nanoparticles for improved delivery of doxorubicin: Development, characterization, in-vitro studies

Silk fibroin nanoparticles possess the hydrophobic nature which assists them to become a good substrate for reticulo-endothelial system (RES) and macrophageal uptake. Surface coating of these nanoparticles with hydrophilic stabilizers, like Tween-80 make them long circulating and facilitate their uptake by low density lipoprotein (LDL) receptors to cross blood brain barrier (BBB). Surface modified silk fibroin nanoparticles bearing anti-cancer agent doxorubicin (DOX) were fabricated by desolvation method and coated with Tween-80 as surface modifier. The prepared nanoparticles were characterized for various physicochemical parameters, like particle size, surface charge, surface morphology by scanning electron microscope (SEM) and transmission electron microscopy (TEM), and in vitro drug release along with in vitro cell cytotoxicity, flow cytometry and cellular uptake studies by flourocytometry on glioblastoma cell lines. Entrapment efficiency for the silk fibroin nanoparticles were found to be >85% for coated and uncoated nanoparticles. Nanoparticles with average diameter less than 150 nm having negative charge were found to show no toxicity of its own. The pro-inflammatory response of nanoparticles was observed by determining the cytokines level, such as TNF-α and IL-1β. Sustained drug release pattern from the nanoparticles with better cytotoxicty as compared to free drug was observed, signifying their potential ability to work as a drug delivery system.

Design of Dense Brush Conformation Bearing Gold Nanoparticles as Theranostic Agent for Cancer.

Dense brush conformation-bearing theranostic agents are emerging as drug delivery systems due to their higher ability to escape from reticuloendothelial system uptake which prolongs their in vivo circulation time. With the aim of developing dual therapy agent, 13-nm gold nanoparticles' (AuNPs) surfaces were coated with different amounts of polyethylene glycol (PEG) (SH-PEG-NH2) to obtain dense brush conformation-bearing theranostic agents. Among the 14 different theranostic agent candidates prepared, the one hosting 1819 PEG per particle was selected as the most promising theranostic agent candidate based on structural conformation, stability, size, zeta potential, hemocompatibility, cell inhibition, and cell death pathway towards MCF-7 cell line. To test drug delivery efficiency of the developed PEGylated AuNP and to improve efficacy of the treatment, apoptotic peptide (AP) was covalently conjugated to NH2 terminus of the PEG in various ratios to yield AuNP-AP conjugate. Among the prepared conjugates, the one having 1nmol of peptide per milliliter of AuNP yielded the most promising results based on the same criteria as employed for PEGylated AuNPs. Besides, incorporation of AP to AuNP returned in superior efficacy of AP since it was possible to achieve 50% cell death with 1000 times less amount of AP alone.

Biodistribution and PET imaging of 89-zirconium labeled cerium oxide nanoparticles synthesized with several surface coatings

Cerium oxide nanoparticles (CONPs) have unique surface chemistry allowing catalyst-like antioxidant properties, and are being investigated for several disease indications in medicine. Studies have utilized surface modified CONPs toward this application, but have been lacking in comprehensive biodistribution and pharmacokinetic data and a direct comparison to uncoated CONPs. We developed an enhanced single-pot synthesis of several coated CONPs and an efficient intrinsic core labeling of CONPs with the clinical PET isotope, zirconium-89, allowing detailed PET imaging and ex vivo biodistribution. All coated [89Zr]-CONPs showed benefit in terms of biodistribution compared to uncoated [89Zr]-CONPs, while retaining the intrinsic antioxidant properties. Among these, poly(acrylic acid) coated CONPs demonstrated excellent candidacy for clinical implementation due to their enhanced renal clearance and low reticuloendothelial system uptake. This work also demonstrates the value of intrinsic core labeling and PET imaging for evaluation of nanoparticle constructs to better inform future studies towards clinical use.

Enhanced Antiatherosclerotic Efficacy of Statin-Loaded Reconstituted High-Density Lipoprotein via Ganglioside GM1 Modification.

Atherosclerosis remains one of the leading causes of morbidity and mortality globally. Recently, reconstituted high-density lipoprotein (rHDL), the synthetic form of endogenous plasma HDL, has been utilized as a therapeutic delivery system for statins, a class of lipid-lowering drugs, to treat atherosclerosis. Accumulating evidence suggests that ganglioside GM1 modification can induce an increased stability, a prolonged circulation time, and a decreased reticuloendothelial system uptake of liposomes. Therefore, we hypothesized that GM1 modification probably has similar effects on statin-loaded rHDL and finally enhances its inhibitory effect on atherogenesis. To test this hypothesis, we prepared GM1-modified lovastatin (LT)-loaded rHDL (LT-GM1-rHDL), as well as LT-loaded rHDL (LT-rHDL) and LT-loaded nanostructured lipid carriers (LT-NLC) for comparison, via thin film dispersion followed by physicochemical characterization, in vitro LT release assay, and in vitro cellular experiments. Subsequently, the pharmacokinetic behavior, tissue distribution, and in vivo antiatherosclerotic effect of all LT-loaded nanocarriers were evaluated by using ApoE-/- mice fed with a high-fat diet. We found that LT-GM1-rHDL has a more efficient LT sustained-release, a longer circulation time, a lower liver uptake, a better atherosclerotic plaque targeting efficiency, and a stronger inhibitory effect on atherogenesis compared with LT-NLC and LT-rHDL. The data verified our hypothesis that GM1 modification of statin-loaded rHDL can induce an enhanced inhibitory effect on atherogenesis and imply that statin-GM1-rHDL can potentially be recruited as a promising drug delivery system for the treatment of atherosclerosis.

Polymeric Lipid Hybrid Nanoparticles: Properties and Therapeutic Applications.

Some of the criteria for selection of a viable nanocarrier formulation currently being explored are the development of a site-specific and bioavailable formulation. Although the literature reports a variety of techniques for fabrication of nanocarrier systems, their stability and scale-up issues are a concern for their prominence in the pharmaceutical industry. The other widely recognized drawbacks of nanoparticulates, i.e., polymeric nanoparticles and lipid vesicular nanoparticles (liposomes), are low circulatory half-lives due to reticuloendothelial system (RES) uptake and leaky architecture leading to burst kinetics. Polymeric lipid hybrid nanoparticles (PLHNs) or lipomers are the recent advancement in nanodrug delivery systems composed of a polymeric core and lipid shell which imparts physicochemical stability and biocompatibility to the nanoparticles. The lipomers are a blend of positive attributes of both liposomes and polymeric nanoparticles wherein their individual innate flaws are negated. An extensive study of PLHN was engineered using single/two or multiple methods carried out for encapsulation efficiency, physicochemical properties, and stability. The influence of shape and composition of PLHN has also shown promising results in terms of reticuloendothelial uptake. These PLHNs have shown to hold a promising place in designing drug delivery systems for the treatment of cancer and infectious diseases as well as for theranostic purposes. The present review article encompasses various types of PLHNs, their physicochemical characteristics, and their applications as future perspectives in strategizing drug delivery to their desired sites of action.

A New Approach to Deliver Anti-cancer Nanodrugs with Reduced Off-target Toxicities and Improved Efficiency by Temporarily Blunting the Reticuloendothelial System with Intralipid

We have developed a new strategy to temporarily blunt the reticuloendothelial system uptake of nanodrugs, a major challenge for nanodrug delivery and causing off-target toxicities, using an FDA approved nutrition supplement, Intralipid. We have tested our methodology in rats using an experimental platinum-containing anti-cancer nanodrug and three FDA approved nanodrugs, Abraxane, Marqibo, and Onivyde, to determine their toxicities in liver, spleen, and kidney, with and without the addition of Intralipid. Our method illustrates its potentials to deliver nanodrugs with an increase in the bioavailability and a decrease in toxicities. Our study shows that Intralipid treatment exhibits no harmful effect on tumor growing and no negative effect on the anti-tumor efficacy of the platinum-containing nanodrug, as well as animal survival rate in a HT-29 xenograft mouse model. Our methodology could also be a valuable complement/supplement to the “stealth” strategies. Our approach is a general one applicable to any approved and in-development nanodrugs without additional modification of the nanodrugs, thus facilitating its translation to clinical settings.

Orthogonal near-infrared upconversion co-regulated site-specific O2 delivery and photodynamic therapy for hypoxia tumor by using red blood cell microcarriers.

Pre-existing hypoxia in tumors can result in an inadequate oxygen supply during photodynamic therapy (PDT), which in turn hampers photodynamic efficacy. To overcome this problem, we developed an orthogonal near-infrared upconversion controlled red blood cell (RBC) microcarriers to selectively deliver O2 in hypoxia area. Moreover, this RBC microcarriers are able to overcome a series of complex biological barriers which include transporting across the inflamed endothelium, evading mononuclear phagocyte system, reducing reticuloendothelial system uptake. Based on these abilities, RBC microcarriers have efficient tumors accumulation and are capable of delivery a large amount of O2 for PDT under near-infrared (NIR) irradiation to realize effective solid tumor eradication.