Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO ...manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.
To determine whether trace amounts of ethylene glycol (EG), diethylene glycol (DEG), or triethylene glycol (TEG) in PEG 3350 are associated with increased blood levels of EG, DEG, or TEG in children ...receiving daily PEG 3350 therapy.
Blood samples were drawn from 9 children who were being treated for constipation with PEG 3350 (6-12 years old) before and every 30 minutes for 3 hours after receiving 17 g of PEG 3350. PEG 3350, tap water, and blood samples from 18 age- and sex-matched controls also were analyzed.
Baseline blood levels of EG and TEG did not differ between control and treated groups. DEG levels (median IQR) were lower in the PEG 3350 group (40.13 ng/mL 36.69, 63.94 vs 92.83 ng/mL 51.06, 128.93, P = .008). After PEG 3350 dose, levels of EG (390.51 ng/mL 326.06, 624.55) and TEG (2.21 ng/mL 0, 4.5) peaked at 90 minutes at 1032.81 ng/mL (826.84, 1486.13) (P = .009) and 35.17 ng/mL (15.81, 45.13) (P = .0005), respectively. DEG levels did not significantly change. Standard 17-g doses of PEG 3350 in 8 oz (237 mL) of water resulted in concentrations (mean ± SD) of EG, DEG, and TEG of 1.32 ± 0.23 µg/mL, 0.18 ± 0.03 µg/mL, and 0.12 ± 0.01 µg/mL, respectively. EG, DEG, and TEG levels in public water supply were 0.07 µg/mL, 0.21 µg/mL, and 0.02 µg/mL, respectively.
Daily PEG 3350 therapy in children was not associated with sustained elevation of EG, DEG, or TEG blood levels over levels in matched controls. Although EG and TEG levels increased after a standard dose of PEG 3350, their peak values remained well below toxic levels.
•Ethylene glycol compounds share acute toxicity modes of action.•Only monoethylene and diethylene glycol show evidence of developmental toxicity.•Similarities and differences across these compounds ...are explained by metabolic pathways.•A matrix of toxicological commonalities and differences is presented.•No significant risk of the ethylene glycols is expected under normal use patterns.
This review summarizes the hazards, exposure and risk that are associated with ethylene glycols (EGs) in their intended applications. Ethylene glycol (EG; CAS RN 107-21-1) and its related oligomers include mono-, di-, tri-, tetra-, and penta-EG. All of the EGs are quickly and extensively absorbed following ingestion and inhalation, but not by the dermal route. Metabolism involves oxidation to the mono- and dicarboxylic acids. Elimination is primarily through the urine as the parent compound or the monoacid, and, in the case of EG, also as exhaled carbon dioxide. All EGs exert acute toxicity in a similar manner, characterized by CNS depression and metabolic acidosis in humans and rodents; the larger molecules being proportionally less acutely toxic on a strict mg/kg basis. Species differences exist in the metabolism and distribution of toxic metabolites, particularly with the formation of glycolic acids and oxalates (OX) from EG and diethylene glycol (DEG); OX are not formed to a significant degree in higher ethylene glycols. Among rodents, rats are more sensitive than mice, and males more sensitive than females to the acute and repeated-dose toxicity of EG. The metabolic formation of glycolic acid (GA), diglycolic acid (DGA), and OX are associated with nephrotoxicity in humans and rodents following single and repeated exposures. However, physiological and metabolic differences in the rate of formation of GA, DGA and OX and their distribution result in EG and DEG causing embryotoxicity in rats, but not rabbits. This rodent-specific sensitivity indicates that EG and its higher oligomers are not anticipated to be embryotoxic in humans at environmentally relevant doses. None of the compounds present developmental toxicity concerns at doses that do not also cause significant maternal toxicity, nor do any of the EGs cause adverse effects on fertility. The EGs are neither genotoxic nor carcinogenic. A read-across matrix is presented, which considers the common and distinct toxicological properties of each compound. It is concluded that EGs pose no risk to human health as a result of their intended use patterns.
Modification of biopharmaceutical molecules by covalent conjugation of polyethylene glycol (PEG) molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large ...molecules and has been used successfully in 12 approved drugs. Both linear and branched-chain PEG reagents with molecular sizes of up to 40 kDa have been used with a variety of different PEG derivatives with different linker chemistries. This review describes the properties of PEG itself, the history and evolution of PEGylation chemistry, and provides examples of PEGylated drugs with an established medical history. A trend toward the use of complex PEG architectures and larger PEG polymers, but with very pure and well-characterized PEG reagents is described. Nonclinical toxicology findings related to PEG in approved PEGylated biopharmaceuticals are summarized. The effect attributed to the PEG part of the molecules as observed in 5 of the 12 marketed products was cellular vacuolation seen microscopically mainly in phagocytic cells which is likely related to their biological function to absorb and remove particles and macromolecules from blood and tissues. Experience with marketed PEGylated products indicates that adverse effects in toxicology studies are usually related to the active part of the drug but not to the PEG moiety.
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Cyclic RGD peptide-functionalized reversibly core-crosslinked biodegradable poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) micelles (cRGD-RCCMs) were designed and developed ...for highly potent and targeted glioma chemotherapy. To achieve crosslinkable core, dithiolane-functionalized trimethylene carbonate (DTC) was incorporated into PCL block. Interestingly, cRGD-RCCMs displayed a high doxorubicin (DOX) loading content of ∼18wt%, small hydrodynamic size of ∼50nm, and excellent colloidal stability with minimum drug leakage under physiological conditions while fast DOX release under cytoplasmic-mimicking reductive environments. MTT, confocal microscopy and flow cytometry measurement results pointed out that cRGD-RCCMs with 30% cRGD surface density (cRGD30-RCCMs) showed an evident selectivity, efficient cytoplasmic drug release, and superior antitumor activity to clinically used pegylated liposomal doxorubicin (DOX-LPs) in αvβ3 integrin overexpressing U87MG glioblastoma cells. Strikingly, DOX-loaded cRGD30-RCCMs demonstrated a prolonged circulation time showing an elimination half-life of ∼4.7h, three times exceeding that of the non-crosslinked counterparts, and a remarkably enhanced tumor accumulation of 7.7%ID/g. Furthermore, in vivo therapeutic studies revealed that DOX-loaded cRGD30-RCCMs effectively suppressed tumor growth, significantly prolonged survival time, and lessened side effects in subcutaneous U87MG glioblastoma-bearing nude mice. These reversibly core-crosslinked multifunctional biodegradable micelles might be developed into advanced and clinically viable targeted anticancer nanomedicines.
Nanomedicines based on biodegradable micelles and nanoparticles offer a most promising treatment for malignant tumors. The therapeutic outcomes of current nanomedicines are, however, trimmed by their instability, low tumor retention, inefficient tumor cell uptake, and inferior drug release control. We report herein that cRGD-functionalized, rapidly glutathione-responsive, and reversibly core-crosslinked biodegradable micellar doxorubicin based on PEG-PCL block copolymer mediates potent and targeted glioma chemotherapy, affording significantly better treatment efficacy and lower systemic toxicity than the non-crosslinked micellar doxorubicin and clinically used pegylated liposomal doxorubicin controls. These reversibly core-crosslinked multifunctional biodegradable micelles have emerged as a robust, simple, versatile, and safe nanoplatform that might elegantly bridge the gap between the scientific and translational anticancer nanomedicine research.
The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small ...hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.
Development of self-nanoemulsifying drug delivery systems (SNEDDS) of polypeptide-k (PPK) is reported with the aim to achieve its oral delivery. Box-Behnken design (BBD) was adopted to develop and ...optimize the composition of SNEDDS. Oleoyl polyoxyl-6 glycerides (A), Tween 80 (B), and diethylene glycol monoethyl ether (C) were used as oil, surfactant and co-surfactant, respectively as independent variables. The effect of variation in their composition was observed on the mean droplet size (y1), polydispersity index (PDI) (y2), % drug loading (y3) and zeta potential (y4). As per the optimal design, seventeen SNEDDS prototypes were prepared. The optimized composition of SNEDDS formulation was 25% v/v Oleoyl polyoxyl-6 glycerides, 37% v/v Tween 80, 38% v/v diethylene glycol monoethyl ether, and 3% w/v PPK. The optimized formulation revealed values of y1, y2, y3, and y4 as 31.89nm, 0.16, 73.15%, and −15.65mV, respectively. Further the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, disintegration and dissolution properties. Both, liquid and solid-SNEDDS have shown release of >90% within 10min. The formulation was found stable with change in pH, dilution, temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline PPK was observed in amorphous state in solid SNEDDS when characterized through DSC and PXRD studies. The biochemical, hematological and histopathological results of streptozotocin induced diabetic rats shown promising antidiabetic potential of PPK loaded in SNEDDS at its both the doses (i.e. 400mg/kg and 800mg/kg) as compared to its naïve form at both the doses. The study revealed successful formulation of SNEDDS for oral delivery of PPK.
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Poly(propylene fumarate) (PPF)-based nanocomposites incorporating different amounts of polyethylene glycol-functionalized graphene oxide (PEG-GO) have been prepared via sonication and thermal ...curing, and their surface morphology, structure, thermal stability, hydrophilicity, water absorption, biodegradation, cytotoxicity, mechanical, viscoelastic and antibacterial properties have been investigated. SEM and TEM images corroborated that the noncovalent functionalization with PEG caused the exfoliation of GO into thinner flakes. IR spectra suggested the presence of strong hydrogen-bonding interactions between the nanocomposite components. A gradual rise in the level of hydrophilicity, water uptake, biodegradation rate, surface roughness, protein absorption capability and thermal stability was found upon increasing GO concentration in the composites. Tensile tests revealed improved stiffness, strength and toughness for the composites compared to unfilled PPF, ascribed to a homogeneous GO dispersion within the matrix along with a strong PPF/PEG-GO interfacial adhesion via polar and hydrogen bonding interactions. Further, the nanocomposites retained enough stiffness and strength under a biological state to provide effective support for bone tissue formation. The antibacterial activity was investigated against Gram-positive Staphylococcus aureus and Staphylococcus epidermidis as well as Gram-negative Pseudomonas aeruginosa and Escherichia coli microorganisms, and it rose sharply upon increasing GO concentration; systematically, the biocide effect was stronger versus Gram-positive bacteria. Cell viability data demonstrated that PPF/PEG-GO composites do not induce toxicity over human dermal fibroblasts. These novel materials show great potential to be applied in the bone tissue engineering field.
The work describes systematic development of nanomicellar cationic supersaturable self-nanoemulsifying drug delivery systems (CS-SNEDDS) for augmenting oral biopharmaceutical performance of ...raloxifene hydrochloride. Plain SNEDDS formulation containing Capryol 90, Cremophor RH 40, and Transcutol HP was optimized using D-optimal mixture design. SNEDDS were characterized for emulsification time, globule size, in vitro drug release, and ex vivo permeation. The CS-SNEDDS formulation was prepared from the optimized SNEDDS by adding oleylamine as the cationic charge inducer and HPMC as the polymeric precipitation inhibitor. Evaluation of CS-SNEDDS was carried out through in vitro cell line studies on Caco-2 and MCF-7 cells, in situ perfusion, and in vivo pharmacokinetic studies, which indicated significant improvement in biopharmaceutical attributes of the drug from CS-SNEDDS over plain drug.
Highlights ► Microbial production of 1,3-propanediol from glucose is a major achievement of industrial biotechnology. ► Raw glycerol as a by-product of biofuel production is attractive for production ...of diol. ► The use of raw glycerol for the bioproduction of 1,3-propanediol is technically feasible and economically competitive. ► Unsterile or mixed culture fermentation of glycerol can significantly reduce the investment and operation costs for microbial 1,3-propanediol. ► The concentration and yield of 2,3-buatnediol from biomass have been significantly improved in the last years.
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