Abstract
In this work, micelles composed of doxorubicin-conjugated Y-shaped copolymers (YMs) linked via an acid-labile linker were constructed. Y-shaped copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin)2 and linear copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin) were synthesized and characterized. Particle size, size distribution, morphology, drug loading content (DLC) and drug release of the micelles were determined. Alterations in size and DLC of the micelles could be achieved by varying the hydrophobic block lengths. Moreover, at fixed DLCs, YMs showed a smaller diameter than micelles composed of linear copolymers (LMs). Also, all prepared micelles showed sustained release behaviors under physiological conditions over 72 h. DOX loaded in YMs was released more completely, with 30% more drug released in acid. The anti-tumor efficacy of the micelles against HeLa cells was evaluated by MTT assays, and YMs exhibited stronger cytotoxic effects than LMs in a dose- and time-dependent manner. Cellular uptake studied by CLSM indicated that YMs and LMs were readily taken up by HeLa cells. According to the results of this study, doxorubicin-conjugated Y-shaped PEG-(polypeptide)2 copolymers showed advantages over linear copolymers, like assembling into smaller nanoparticles, faster drug release in acid, which may correspond to higher cellular uptake and enhanced extracellular/intracellular drug release, indicating their potential in constructing nano-sized drug delivery systems.
Highlights
Benefitting from the advances in polymer science, more and more novel synthetic polymers are being used in the construction of nano-scale drug delivery systems (DDS) that target tumors by their enhanced permeation and retention (EPR) effects [1]
Y-shaped miktoarm-star mPEG-(PBLG)2 copolymers with different molecular weights were synthesized via ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxy anhydride (BLG-NCA) using α-methoxy-poly(ethylene glycol) with two primary amino groups at the ω-terminal as a macromolecular initiator [8]
Y-Shaped 3-Miktoarm Star-Block Copolymers mPEG-Poly(γ-benzyl-L-glutamate)(PBLG) diblock and mPEG-(PBLG)2 3-miktoarm star copolymer were synthesized by ring-opening polymerization (ROP) of BLG-NCA initiated by mPEG-NH2 or mPEG-S-(CH2CH2NH2)2 in anhydrous DCM with different feed ratios
Summary
Benefitting from the advances in polymer science, more and more novel synthetic polymers are being used in the construction of nano-scale drug delivery systems (DDS) that target tumors by their enhanced permeation and retention (EPR) effects [1]. The micellar stability might be limited due to the flexibility of the all-carbon backbone of the polymer, as reflected by a higher CAC value, while the secondary structure adopted by poly(amino acids) reduced chain mobility, thereby increasing the micellar stability to some extent. Another AB2 type copolymer (mPEG-b-PBLG2) was synthesized by Li et al [8], and the tamoxifen loaded micelles exhibited a sustained release pattern. For DDSs carrying DOX or other chemotherapeutic agents, the drug loading content (DLC) is a key parameter that is closely related to the anti-tumor efficacy and even multidrug resistance induction. Y-shaped and linear copolymers were prepared and their size, DLC, in vitro release and cytotoxicity were investigated
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