Docetaxel-Loaded Methoxy poly(ethylene glycol)-poly (L-lactic Acid) Nanoparticles for Breast Cancer: Synthesis, Characterization, Method Validation, and Cytotoxicity
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ABSTRACT:
SUBMITTER: Miraj S
PROVIDER: S-EPMC10675362 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Stability and narrow size distribution are among the main requirements that apply to drug formulations based on polymeric nanoparticles. In this study, we obtained a series of particles based on biodegradable poly(D,L-lactide)-b-poly(ethylene glycol) (P(D,L)LAn-b-PEG113) copolymers with varied hydrophobic P(D,L)LA block length n from 50 to 1230 monomer units stabilized by poly(vinyl alcohol) (PVA) by a simple "oil-in-water" emulsion method. We found that nanoparticles of P(D,L)LAn-b-PEG113 copolymers with relatively short P(D,L)LA block (n ≤ 180) are prone to aggregate in water. P(D,L)LAn-b-PEG113 copolymers with n ≥ 680 can form spherical unimodal particles with values of hydrodynamic diameter less than 250 nm and polydispersity less than 0.2. The aggregation behavior of P(D,L)LAn-b-PEG113 particles was elucidated in terms of tethering density and conformation of PEG chains at the P(D,L)LA core. Docetaxel (DTX) loaded nanoparticles based on P(D,L)LA680-b-PEG113 and P(D,L)LA1230-b-PEG113 copolymers were formulated and studied. It was observed that DTX-loaded P(D,L)LAn-b-PEG113 (n = 680, 1230) particles are characterized by high thermodynamic and kinetic stability in aqueous medium. The cumulative release of DTX from the P(D,L)LAn-b-PEG113 (n = 680, 1230) particles is sustained. An increase in P(D,L)LA block length results in a decrease in DTX release rate. The in vitro antiproliferative activity and selectivity studies revealed that DTX-loaded P(D,L)LA1230-b-PEG113 nanoparticles demonstrate better anticancer performance than free DTX. Favorable freeze-drying conditions for DTX nanoformulation based on P(D,L)LA1230-b-PEG113 particles were also established.
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Project description:PurposeNanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA.MethodsIn this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo.ResultsNPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier.ConclusionOur data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.
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Project description:Amphiphilic polymers can be used to form micelles to deliver water-insoluble drugs. A biodegradable poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE)-PEG triblock copolymer was developed that is useful for drug delivery. It was shown to successfully encapsulate and pH-dependently release a water-insoluble, small molecule anticancer drug, verteporfin. PEG-PBAE-PEG micelle morphology was also controlled through variations to the hydrophobicity of the central PBAE block of the copolymer in order to evade macrophage uptake. Spherical micelles were 50 nm in diameter, while filamentous micelles were 31 nm in width with an average aspect ratio of 20. When delivered to RAW 264.7 mouse macrophages, filamentous micelles exhibited a 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean cellular uptake compared to spherical micelles. This demonstrates the potential of high-aspect-ratio, anisotropically shaped PEG-PBAE-PEG micelles to evade macrophage-mediated clearance. Both spherical and filamentous micelles also showed therapeutic efficacy in human triple-negative breast cancer and small cell lung cancer cells without requiring photodynamic therapy to achieve an anticancer effect. Both spherical and filamentous micelles were more effective in killing lung cancer cells than breast cancer cells at equivalent verteporfin concentrations, while spherical micelles were shown to be more effective than filamentous micelles against both cancer cells. Spherical and filamentous micelles at 5 and 10 μM respective verteporfin concentration resulted in 100% cell killing of lung cancer cells, but both micelles required a higher verteporfin concentration of 20 μM to kill breast cancer cells at the levels of 80% and 50% respectively. This work demonstrates the potential of PEG-PBAE-PEG as a biodegradable, anisotropic drug delivery system as well as the in vitro use of verteporfin-loaded micelles for cancer therapy.
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Project description:Poly(ethylene glycol) (PEG) side-chain functionalized lactide analogues have been synthesized in four steps from commercially available L-lactide. The key step in the synthesis is the 1,3-dipolar cycloaddition between PEG-azides and a highly strained spirolactide-heptene monomer, which proceeds in high conversions. The PEG-grafted lactides analogues were polymerized via ring-opening polymerization using triazacyclodecene as organocatalyst to give well-defined tri- and hepta-(ethylene glycol)-poly(lactide)s (PLA) with molecular weights above 10 kDa and polydispersity indices between 1.6 and 2.1. PEG-poly(lactide) (PLA) with PEG chain M(n) 2000 was also prepared but GPC analysis showed a bimodal profile indicating the presence of starting macromonomer. Cell adhesion assays were performed using MC3T3 E-1 osteoblast-like cells demonstrating that PEG-containing PLA reduces cell adhesion significantly when compared to unfunctionalized PLA.
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Project description:Half mustard (CEES) and nitrogen mustard (NM) are commonly used surrogates and vesicant analogs of the chemical warfare agent sulfur mustard. In the current study, in situ forming poly(ethylene glycol) (PEG)-based doxycycline hydrogels are developed and evaluated for their wound healing efficacy in CEES and NM-exposed rabbit corneas in organ culture. The hydrogels, characterized by UV-Vis spectrophotometry, rheometry, and swelling kinetics, showed that the hydrogels are optically transparent, have good mechanical strength and a relatively low degree of swelling (<7%). In vitro doxycycline release from the hydrogel disks (0.25% w/v) was found to be biphasic with release half times of approximately 12 and 72h, respectively, with 80-100% released over a 7-day period. Permeation of doxycycline through vesicant wounded corneas was found to be 2.5 to 3.4 fold higher than non-wounded corneas. Histology and immunofluorescence studies showed a significant reduction of matrix metalloproteinase-9 (MMP-9) and improved healing of vesicant-exposed corneas by doxycycline hydrogels compared to a similar dose of doxycycline delivered in phosphate buffered saline (PBS, pH 7.4). In conclusion, the current studies demonstrate that the doxycycline-PEG hydrogels accelerate corneal wound healing after vesicant injury offering a therapeutic option for ocular mustard injuries.
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