Distribution and Elimination of Coated Polymethyl [2-14C]Methacrylate Nanoparticles After Intravenous Injection in Rats

doi:10.1002/jps.2600731028

Journal of Pharmaceutical Sciences

Volume 73, Issue 10, October 1984, Pages 1433-1437

https://doi.org/10.1002/jps.2600731028 Get rights and content

Abstract

Surfactant-coated polymethyl [2-¹⁴C]methacrylate nanoparticles had significantly different time-course distribution patterns in rats than noncoated and albumin-coated particles. Blood concentrations of poloxamer 188-coated particles were 70-fold higher after 30 min, and the particles persisted at higher levels in the circulation for up to 2 h. The initial and final liver levels were significantly lower (38% after 30 min, 51% after 7 d) and spleen levels were significantly higher (21% after 30 min, 23% after 7 d) than non-coated particles (74% in the liver and 5% in the spleen after 7 d) and the albumin-coated particles (84% in the liver and 5% in the spleen after 7 d). Specific activity was somewhat higher for the surfactant-coated particles in other organs such as the lungs, kidneys, testicles, ovaries, and lymph nodes. The bovine serum albumin sorption behavior of polymethyl methacrylate nanoparticles was followed under various conditions, and adsorption was found to increase with increasing protein concentration and increasing temperature, reaching a maximum at the isoelectric point of pH 4.9 after ∼12 h of incubation. The zeta potential of the particles decreased with increasing pH, and the change was more pronounced with the albumin-coated particles.

REFERENCES (34)

G. Birrenbach et al.
J. Pharm. Sci.
(1976)
J. Kreuter et al.
J. Pharm. Sci.
(1979)
M. Kanke et al.
J. Pharm. Sci.
(1980)
H.G. Schroeder et al.
J. Pharm. Sci.
(1978)
L. Illum et al.
J. Pharm. Sci.
(1983)
O.H. Lowry et al.
J. Biol. Chem.
(1951)
M.E. Soderquist et al.
J. Colloid Interface Sci.
(1980)
J. Slack et al.
J. Pharm. Sci.
(1981)
W. Norde et al.
J. Colloid Interface Sci.
(1978)
P. Couvreur et al.
FEBS Lett.
(1977)

F. Brasseur et al.

Eur. J. Cancer

(1980)

T.M.S. Chang

Enzyme

(1972-1973)

K.F. O'Driscoll et al.

J. Pharmacol. Exp. Ther.

(1975)

J. Kreuter et al.

Infect. Immun.

(1976)

J.J. Marty et al.

Pharm. Acta Helv.

(1978)

J. Kreuter

Infect. Immun.

(1978)

J. Charnley

Acrylic Cement in Orthopaedic Surgery

(1970)

Cited by (80)

Core polymer optimization of ternary siRNA nanoparticles enhances in vivo safety, pharmacokinetics, and tumor gene silencing
2023, Biomaterials
Gene silencing with siRNA nanoparticles (si-NPs) is promising but still clinically unrealized for inhibition of tumor driver genes. Ternary si-NPs containing siRNA, a single block NP core-forming polymer poly[(2-(dimethylamino)ethyl methacrylate)-co-(butyl methacrylate)] (DMAEMA-co-BMA, 50B), and an NP surface-forming diblock polymer 20 kDa poly(ethylene glycol)-block-50B (20kPEG-50B) have the potential to improve silencing activity in tumors due to the participation of both 50B and 20kPEG-50B in siRNA electrostatic loading and endosome disruptive activity. Functionally, single block 50B provides more potent endosomolytic activity, while 20kPEG-50B colloidally stabilizes the si-NPs. Here, we systematically explored the role of the molecular weight (MW) of the core polymer and of the core:surface polymer ratio on ternary si-NP performance. A library of ternary si-NPs was formulated with variation in the MW of the 50B polymer and in the ratio of the core and surface forming polymeric components. Increasing 50B core polymer MW and ratio improved si-NP in vitro gene silencing potency, endosome disruptive activity, and stability, but these features also correlated with cytotoxicity. Concomitant optimization of 50B size and ratio resulted in the identification of lead ternary si-NPs 50B4-DP100, 50B8-DP100, and 50B12-DP25, with potent activity and minimal toxicity. Following intravenous treatment in vivo, all lead si-NPs displayed negligible toxicological effects and enhanced pharmacokinetics and tumor gene silencing relative to more canonical binary si-NPs. Critically, a single 1 mg/kg intravenous injection of 50B8-DP100 si-NPs silenced the tumor driver gene Rictor at the protein level by 80% in an orthotopic breast tumor model. 50B8-DP100 si-NPs delivering siRictor were assessed for therapeutic efficacy in an orthotopic HCC70 mammary tumor model. This formulation significantly inhibited tumor growth compared to siControl-NP treatment. 50B8-DP100 si-NPs were also evaluated for safety and were well-tolerated following a multi-dose treatment scheme. This work provides new insight on ternary si-NP structure-function relationships and identifies core polymer optimization strategies that can yield safe si-NP formulations with potent oncogene silencing.
Layered double hydroxide nanoparticles: Impact on vascular cells, blood cells and the complement system
2018, Journal of Colloid and Interface Science
Citation Excerpt :
Upon entering the bloodstream, all foreign materials are immediately recognized by the complement system [19], leading to the generation of potent activation products including opsonin C3b and anaphylatoxin C5a. Surface coating (‘opsonization’) of nanoparticles with C3b leads to recognition by myeloid cells (neutrophils, monocytes, macrophages) [28], subsequent removal by phagocytosis, pinocytosis or endocytosis [29], and clearance to lymphoid organs (liver, spleen, lymph nodes) [19]. The rapid uptake of nanoparticles by phagocytic cells reduces their circulation time and is thought to be a major cause of reduced therapeutic efficacy of injected nanoparticles [30].
The mounting interest in layered double hydroxide (LDH) nanoparticles as drug carriers and bio-imaging contrast agents makes biosafety evaluation of LDH essential. Considering the important role of blood circulation in bio-distribution of nanoparticles, the present work evaluated the impact of MgAl-LDHs on key components of the circulatory system, including vascular cells (vascular smooth muscle cells (SMCs) and endothelial cells (HUVECs)), red blood cells (RBCs), and complement activation. The results showed that LDH had no effects on SMCs and HUVECs at concentrations up to 500 and 10 µg/mL respectively, in terms of cell proliferation and viability. LDH (10 µg/mL) did not change either the migration distance or the number of migrating SMCs in culture. Moreover, LDH (400 µg/mL) had a negligible effect on RBCs’ lysis, and there was no significant increase in levels of complement activation product, C5a, in the presence of LDH (20 or 200 µg/mL). The low toxicity for vascular cells and blood cells combined with low immunogenicity sheds a light on the biosafety of LDH nanoparticles, and encourages further studies into their biomedical applications.
Nanobased Intravenous and Transdermal Drug Delivery Systems
2018, Applications of Targeted Nano Drugs and Delivery Systems: Nanoscience and Nanotechnology in Drug Delivery
Comprehensive study of the drug delivery properties of poly(L-lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice
2017, Journal of Controlled Release
Citation Excerpt :
Therefore, by 48 h post-injection, two-thirds to three-quarters of injected dose distributed to organs and tissues beyond the ones investigated by us. Literature data for polymeric nanoparticles, although non-biodegradable ones, show that only a few percent of injected nanoparticles get excreted from rodents within 2 days post-injection [34,35], so excretion of nanoparticles within the timeframe of our experiment is most likely to be negligible. The use of ultra-slow release VCR-loaded and PLA-Cy5-loaded nanoparticles has allowed us to demonstrate the differences in the biodistribution patterns of nanoparticles with varying PEG coverage in vivo and investigate the factors underlying those differences in vitro.
Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~ 100 nm size at injected doses of 30 to 140 mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API).
Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~ 20 h in rats and ~ 10 h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled.
Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits.
Parasite impairment by targeting Plasmodium-infected RBCs using glyceryl-dilaurate nanostructured lipid carriers
2014, Biomaterials
Citation Excerpt :
For biodistribution studies, animals were sacrificed 1 h after rGDL-NLC injection. Single-cell suspensions were prepared from the organs, the RBCs and leukocytes were separated and analysed [15]. To determine the kinetics of uptake, rGDL-NLCs-treated P. berghei-infected mice were bled at time points indicated and DAPI-stained iRBCs analysed.
Antimalarial therapy is a major contributor to declining malaria morbidity and mortality. However, the high toxicity and low bioavailability of current antimalarials and emerging drug resistance necessitates drug-delivery research. We have previously developed glyceryl-dilaurate nanolipid carriers (GDL-NLCs) for antimalarial drug delivery. Here, we show evidence that GDL-NLCs themselves selectively target Plasmodium-infected red blood cells (iRBCs), and cause severe parasite impairment. The glyceryl-dilaurate lipid-moiety was important in the targeting. GDL-NLCs localized to the parasite mitochondrion and uptake led to mitochondrial-membrane polarization and Ca²⁺ ion accumulation, ROS release, and stage-specific iRBC lysis. GDL-NLC treatment also resulted in externalization of iRBC-membrane phosphatidylserine and enhanced iRBC clearance by macrophages. GDL-NLC uptake disrupted the parasite-induced tubulovesicular network, which is vital for nutrient import by the parasite. Laser optical trap studies revealed that GDL-NLCs also restored iRBC flexibility. Such restoration of iRBC flexibility may help mitigate the vasculature clogging that can lead to cerebral malaria. We demonstrate the suitability of GDL-NLCs for intravenous delivery of antimalarial combinations artemether–clindamycin and artemether–lumefantrine in the murine model. Complete parasite clearance was achieved at 5−20% of the therapeutic dose of these combinations. Thus, this nanostructured lipid formulation can solubilize lipophilic drugs, selectively target and impair the parasite-infected red cell, and therefore constitutes a potent delivery vehicle for antimalarials.
Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs
2010, Advanced Drug Delivery Reviews
The impact of human immunodeficiency virus (HIV) infection has been devastating with nearly 7400 new infections every day. Although, the advent of highly active antiretroviral therapy (HAART) has made a tremendous contribution in reducing the morbidity and mortality in developed countries, the situation in developing countries is still grim with millions of people being infected by this disease. The new advancements in the field of nanotechnology based drug delivery systems hold promise to improve the situation. These nanoscale systems have been successfully employed in other diseases such as cancer, and therefore, we now have a better understanding of the practicalities and technicalities associated with their clinical development. Nanotechnology based approaches offer some unique opportunities specifically for the improvement of water solubility, stability, bioavailability and targeting of antiretroviral drugs. This review presents discussion on the contribution of pure drug and polymer based nanotechnologies for the delivery anti-HIV drugs.

View all citing articles on Scopus

View full text

Research ArticlesDistribution and Elimination of Coated Polymethyl [2-14C]Methacrylate Nanoparticles After Intravenous Injection in Rats

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Biol. Chem.

J. Colloid Interface Sci.

J. Pharm. Sci.

J. Colloid Interface Sci.

FEBS Lett.

Eur. J. Cancer

Enzyme

J. Pharmacol. Exp. Ther.

Infect. Immun.

Pharm. Acta Helv.

Infect. Immun.

Acrylic Cement in Orthopaedic Surgery

Research Articles
Distribution and Elimination of Coated Polymethyl [2-¹⁴C]Methacrylate Nanoparticles After Intravenous Injection in Rats