Mononuclear Phagocyte System Uptake Research Articles

HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

Intranasal delivery: An attractive route for the administration of nucleic acid based therapeutics for CNS disorders.

The etiologies of several cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases have implicated changes in the genetic set up or genetic mutations as the root cause. Nucleic acid based therapeutics (NBTs) is a new class of biologics that are known to regulate gene expression at the transcriptional and post-transcriptional level. The NBTs include oligonucleotides, nucleosides, antisense RNA, small interfering RNAs, micro RNA etc. In recent times, this new category of biologics has found enormous potential in the management of cardiovascular, inflammatory, neurological disorders, cancer, infectious diseases and organ transplantation. However, the delivery of NBTs is highly challenging in terms of target specificity (intracellular delivery), mononuclear phagocyte system uptake, stability and biodistribution. Additionally, management of the above mentioned disorders require regular and intrusive therapy making non-invasive routes preferable in comparison to invasive routes like parenteral. The nasal route is garnering focus in delivery of NBTs to the brain in the management of several CNS disorders due to the associated merits such as non-invasiveness, possibility of chronic delivery, improved patient compliance, avoidance of hepatic and gastrointestinal metabolism as well as ability to bypass the BBB. Hence in recent times, this route has been sought by the reserachers as an alternative to parenteral therapy for the delivery of several NBTs. This review shall focus on an array of NBTs delivered through nasal route, their challenges, applications and opportunities. The novel delivery systems for incorporating NBTs; their targeting strategies shall be critically reviewed. The challenges towards regulatory approvals and commercialization shall also be discussed at large. Comparison of learnings derived from the success and barriers in nasal delivery of NBTs will help in identification of futuristic opportunities for their translation from bench to bedside.

Surface modification of polymer nanoparticles with native albumin for enhancing drug delivery to solid tumors

Albumin is a promising surface modifier of nanoparticulate drug delivery systems. Serving as a dysopsonin, albumin can protect circulating nanoparticles (NPs) from the recognition and clearance by the mononuclear phagocytic system (MPS). Albumin may also help transport the NPs to solid tumors based on the increased consumption by cancer cells and interactions with the tumor microenvironment. Several studies have explored the benefits of surface-bound albumin to enhance NP delivery to tumors. However, it remains unknown how the surface modification process affects the conformation of albumin and the performance of the albumin-modified NPs. We use three different surface modification methods including two prevalent approaches (physisorption and interfacial embedding) and a new method based on dopamine polymerization to modify the surface of poly(lactic-co-glycolic acid) NPs with albumin and compare the extent of albumin binding, conformation of the surface-bound albumin, and biological performances of the albumin-coated NPs. We find that the dopamine polymerization method preserves the albumin structure, forming a surface layer that facilitates NP transport and drug delivery into tumors via the interaction with albumin-binding proteins. In contrast, the interfacial embedding method creates NPs with denatured albumin that offers no particular benefit to the interaction with cancer cells but rather promotes the MPS uptake via direct and indirect interactions with scavenger receptor A. This study demonstrates that the surface-bound albumin can bring distinct effects according to the way they interact with NP surface and thus needs to be controlled in order to achieve favorable therapeutic outcomes.

Suppressing Nanoparticle-Mononuclear Phagocyte System Interactions of Two-Dimensional Gold Nanorings for Improved Tumor Accumulation and Photothermal Ablation of Tumors

The clearance of nanoparticles (NPs) by mononuclear phagocyte system (MPS) from blood leads to high liver and spleen uptake and negatively impacts their tumor delivery efficiency. Here we systematically evaluated the in vitro and in vivo nanobio interactions of a two-dimensional (2D) model, gold (Au) nanorings, which were compared with Au nanospheres and Au nanoplates of similar size. Among different shapes, Au nanorings achieved the lowest MPS uptake and highest tumor accumulation. Among different sizes, 50 nm Au nanorings showed the highest tumor delivery efficiency. In addition, we demonstrated the potential use of Au naonrings in photoacoustic imaging and photothermal therapy. Thus, engineering the shape, surface area, and size of Au nanostructures is important in controlling NP-MPS interactions and improving the tumor uptake efficiency.

Surface Distribution and Biophysicochemical Properties of Polymeric Micelles Bearing Gemini Cationic and Hydrophilic Groups.

Polymeric micelles containing cationic gemini quaternary ammonium (GQA) groups have shown enhanced cellular uptake and efficient drug delivery, while the incorporation of poly(ethylene glycol) (PEG) corona can potentially reduce the absorption of cationic carriers by opsonic proteins and subsequent uptake by mononuclear phagocytic system (MPS). To understand the interactions of GQA and PEG groups and their effects on the biophysicochemical characteristics of nanocarriers, a series of polyurethane micelles containing GQA and different molecular weights of PEG were prepared and carefully characterized. It was found that the GQA and PEG groups are unevenly distributed on the micellar surface to form two kinds of hydrophilic domains. As a result, the particle surface with some defects cannot be completely shielded by the PEG corona. Despite this, the longer PEG chains with a brush conformation provide superior stabilization and steric repulsion against the absorption of proteins and, thus, can reduce the cytotoxicity, protein absorption, and MPS uptake of micelles to some extent. This study provides a new understanding on the interactions between PEG chains and cationic groups and a guideline for the design and fabrication of safe and effective drug delivery systems.

Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA–mPEG nanoparticles

The effect of nanoparticle dose on the biodistribution and pharmacokinetics of conventional PLGA and stealth poly(Lactide-co-glycolide)–monomethoxypoly(ethyleneglycol) (PLGA–mPEG) nanoparticles was investigated. The precipitation-solvent diffusion method was used to prepare PLGA and PLGA–mPEG nanoparticles labeled with 125I-cholesterylaniline. These were administered intravenously (i.v.) in mice and at predetermined time intervals the animals were sacrificed and their tissues were excised and assayed for radioactivity. Within the dose range applied in this study, blood clearance and mononuclear phagocyte system (MPS) uptake of the PLGA nanoparticles depended on dose whereas they were independent of dose in the case of the PLGA–mPEG nanoparticles. Increasing the dose, decreased the rates of blood clearance and MPS uptake of the PLGA nanoparticles, indicating a certain degree of MPS saturation at higher doses of PLGA nanoparticles. The dose affected the distribution of PLGA nanoparticles between blood and MPS (liver) but it did not affect the nanoparticle levels in the other tissues. Within the range of doses applied here, the PLGA nanoparticles followed non-linear and dose-dependent pharmacokinetics whereas the PLGA–mPEG nanoparticles followed linear and dose-independent pharmacokinetics. In addition to the prolonged blood residence, the dosage-independence of the pharmacokinetics of the PLGA–mPEG nanoparticles would provide further advantages for their application in controlled drug delivery and in drug targeting.

Lipid nanoparticles for delivering antitumor drugs

Lipid nanoparticles (LNs) in oil-in-water formulations were investigated for selective targeting of anticancer agents to tumor tissues and prolonged accumulation in tumor area. Simple and inexpensive lipid derivatives of polyethylene glycol (PEG) in order to decrease uptake of particles into the mononuclear phagocyte system (MPS) and highly lipophilic prodrug 4′- O-tetrahydropyranyl adriamycin (THP-ADM) in order to be entrapped into the lipid nanoparticles were synthesized and tested for their ability in tumor bearing mice. A simple PEG (1900)-lipid derivative with two long alkyl chains as the lipophilic moiety demonstrated substantial ability to form lipid nanoparticles (30–50 nm) together with phosphatidylcholine (PC), to decrease MPS uptake and to prolong circulation half-life. Plasma levels and the tissue distribution of the prodrug and anticancer active metabolites (THP-ADM and adriamycin (ADM)) were investigated after intravenous administration of LN into BALB/c mice bearing the Meth A fibrosarcoma. The blood half-life of the prodrug in LNs with PEG (1900)-lipid derivatives with two long alkyl chains (LN-E) was approximately 4.3 h. In tumor tissues, the peak height of the sum of drug concentrations [lipophilic prodrugs + metabolites (THP-ADM + ADM)] after LN-E injection did not markedly differ from that of drug concentrations [THP-ADM + metabolite (ADM)] after injection of THP-ADM itself, but a pronounced prolongation of tumor cell exposure to the drugs could be achieved. From the data on the pharmacokinetic properties of the nanoparticles, we conclude that new synthetic PEG derivatives with two long simple alkyl chains as the lipophilic moiety are useful emulsifiers for development of nanoparticles as vehicles to deliver chemotherapeutic agents to tumor.

Studies of the organ distribution in mice of teniposide liposomes designed for treatment of diseases in the mononuclear phagocytic system.

Liposomes can be used for the delivery of drugs in cancer chemotherapy. After i.v. injection liposomes are to a large extent taken up by the mononuclear phagocytic system (MPS). When treating diseases in the MPS, such as the histiocytic syndromes, this property is of potential value for drug targeting and may lead to a more efficient therapy with less systemic toxicity. Teniposide (VM-26) is a potent anti-tumor drug. Its lipophilicity makes it suitable for liposomal formulation. Teniposide liposomes were prepared by dissolving egg phosphatidylcholine and dioleoyl phosphatidic acid (19:1 molar ratio) in methylene chloride together with teniposide. After solvent evaporation, the dry lipid film was dispersed in a glucose solution (50 mg/mL), and size calibration was obtained by filtration through polycarbonate filters. The amount of teniposide incorporated was 2.5 mol%. To investigate the organ distribution, teniposide liposomes containing radiolabeled teniposide or phospholipid were given i.v. to mice. By increasing the size of the vesicles, the MPS uptake could be modulated. When vesicles of 200 nm and 1 and 3 microns were injected, the drug levels in the spleen were increased 2.6-, 6.8-, and 21-fold 40 min after injection, compared with levels after injection of the commercial teniposide formulation. It was concluded that organ distribution of teniposide in mice could be modified by administering the drug in liposomal form with the potential of improved treatment of diseases engaging the MPS.

99mTc-labeling of lipid vesicles containing the lipophilic chelator PE-DTTA: Effect of tin-to-chelate ratio, chelate content and surface polymer on labeling efficiency and biodistribution behavior

When injected intravenously, lipid vesicles labeled with 99mTc by means of a lipophilic chelator dipalmitoylphosphatidylethanolamine-diethylenetriaminetetraacetic acid (PE-DTTA) are rapidly accumulated by the mononuclear phagocytic system (MPS). By derivatizing the membrane surface with the lipid-polymer complex dipalmitoylphosphatidylethanolamine-monomethoxy polyethylene glycol 5000 (PE-MPEG), MPS uptake can be suppressed and loss of 99mTc label from the lipid surface reduced depending upon both PE-DTTA and PE-MPEG content. For vesicles containing 20% PE-DTTA, addition of PE-MPEG makes no difference to their rate of clearance from the circulation. However for vesicles containing 2% PE-DTTA, addition of more than 0.8% PE-MPEG increases circulation half-life, suppresses liver uptake and reduces renal clearance of the 99mTc label. The molar ratio of reducing agent (Sn) to chelator (PE-DTTA) is critical to efficient and reproducible labeling. For vesicles containing 2% PE-DTTA at a lipid concentration of 100 mM, a Sn/DTTA ratio of 0.35 gives close to optimal labeling. Variation in the Sn/DTTA ratio by a factor of two negatively impacts upon both labeling efficiency in vitro and circulation half-life in vivo. Potential uses for technetium-labeled lipid vesicles with extended circulation half-life are discussed.

Versatility in lipid compositions showing prolonged circulation with sterically stabilized liposomes

Efforts to overcome rapid uptake of liposomes by cells of the mononuclear phagocytic system (MPS) have identified that lipids derivatized with the hydrophilic polymer poly(ethylene glycol) (PEG) have many advantages. The structure-function relationship of PEG-derivatized phosphatidylethanolamine (PEG-PE) has been examined by studies of blood lifetime and tissue distribution in both mice and rats. Liposomes composed of phosphatidylcholine (PC), cholesterol, and 7.5 mol% of PEG-PE show prolonged circulation and reduced MPS uptake when the PEG has a molecular weight in the range of 1000 to 5000. Up to 35% of the injected dose remains in the blood and less than 10% is taken up by the MPS (liver plus spleen) after 24 h in the best cases as compared to 1% and 40%, respectively, for liposomes without PEG-PE. Prolonged circulation with PEG-PE is independent of cholesterol, degree of saturation in either the PC or the PE lipid anchor, lipid dose, or addition of other negatively charged lifetime or tissue distribution is essential for controlling drug dosage and release properties in a liposome-based therapeutic agent.

Pharmacokinetics of stealth versus conventional liposomes: effect of dose

Liposomes which substantially avoid uptake into the mononuclear phagocyte system (MPS), termed Stealth® liposomes, have recently been formulated (Allen, T.M. and Chona, A., (1987) FEBS Lett. 223, 42–46). The pharmacokinetics of stealth liposomes as a function of liposome dose and a comparison to conventional liposome pharmacokinetics, was the subject of the present study. We have examined the tissue distribution of two different formulations of stealth liposomes, i.e., sphingomyelin: egg phosphatidylcholine: cholesterol: monosialoganglioside GM 1 (SM: PC: CHOL: GM 1) 1:1:1:0.2 and SM: PC: CHOL: polyethylene glycol distearoylphosphatidylethanolamine (PEG(1900)-DSPE) 1:1:1:0.2, and compared them with the tissue distributions seen for a lipsomal formulation which is avidly removed from circulation by the cells of the MP system (PC:CHOL, 2:1). Tissue distribution in mice was examined over a 100-fold concentration range (0.1 to 10μmol phospholipid/mouse) and at several time points over a 48 h time period. Liposome size ranged from 92–123 nm in diameter for all compositions. Clearance from blood of PC: CHOL liposomes following intravensous adminstration showed a marked dose dependence (i.e., saturation-type or Michaelis-Menten kinetics), with MPS uptake decreasing and% of injected dose in blood increasing as dose increased, over the entire dosage range. Injection of stealth liposome, on the other hand, resulted in % of injected doses of liposomes in MPS, blood and carcass which were dose-independent and log-linear (first order kinetics) over the entire dosage range. The doses of stealth liposomes containing PEG (1900)-DSPE required for MPS saturation was higher than 10μ mol phospholipid/mouse or 400 μmol/kg. The dosage-independence of the pharmacokinetics of stealth liposomes and their lack of MPS saturation within the therapeutic dose range are two more assets, in addition to the prolonged circulation half-lives, leading towards their eventual use as drug delivery systems in the clinic.