To augment the antitumor efficacy and minimize the significant side effects of chemotherapeutic drugs on health organs, a novel albumin-mimicking nanodrug, which is based on zwitterionic poly(glutamatyl lysine-co-cysteine) peptides scaffold, is developed to enhance pH-triggered tumor targeting via prolonging circulation time and accelerating cellular internalization. Results showed that the internalization of the nanodrug by MCF-7 cells is much faster than that by Doxil and even comparable to that by free doxorubicin (Dox) at tumor microenvironmental pH 6.7, whereas the internalization of the nanodrug is only 27.4 ± 7.6% of the Doxil by RAW-264.7 cells. Moreover, the significantly prolonged circulation time of the "stealthy" nanodrug was also comparable to that of the long circulating Doxil. As a result, the accumulation of the nanodrug in the tumor is much higher than that in the liver and kidney before the circulation half-life, which is significantly different from most other nanodrugs accumulated in the liver and kidney in this time scale. The tumor inhibition rate of the nanodrug was much higher than that of Doxil (93.2 ± 3.0% vs 54.2 ± 6.5%) after 18 day treatment, while the average bodyweight of the mice treated by the nanodrug was 26.9 ± 6.7% higher than that by Doxil. This indicated that the synergetic effect of long circulation time and fast cellular internalization of the nanodrug can significantly augment tumor targeting. This method might rejuvenate the traditional chemotherapeutic treatment.
Zwitterionic
materials have been employed to achieve excellent
biocompatibility and the well-suppressed nonspecific protein adsorption
of nanoparticles. However, a thick and compact zwitterionic layer
may prevent the modified nanoparticles from entering tumor cells,
resulting in low cellular internalization efficiency. To address this
problem, new biocompatible micelles (PPIMYC) with a thin zwitterionic
layer were designed and prepared. Zwitterionic generation 2 polypropyleneimine
dendrimers (G2 PPI) serve as the hydrophilic external shell, and N-(2-mercaptoethyl)oleamide serves as the hydrophobic internal
core. Drug-loaded dendritic micelles (PPIMYC-DOX-Ce6) were also prepared
by self-assembly of PPIMYC with doxorubicin (DOX) and chlorin e6 (Ce6)
to demonstrate chemo-photodynamic dual therapy. As potential drug
delivery systems for antitumor therapy, PPIMYC-DOX-Ce6 exhibited sustained
drug release under acidic conditions and high stability in fibrinogen
solution. In addition, cytotoxicity studies showed an enhanced efficiency
of PPIMYC-DOX-Ce6 in killing HeLa cells as compared to free DOX with
or without irradiation (660 nm laser). More importantly, both flow
cytometry and fluorescence microscopy results indicated that the cellular
uptake efficiency of DOX was significantly enhanced in PPIMYC-DOX-Ce6-treated
cells relative to free DOX treated cells. The intracellular internalization
of PPIMYC-DOX-Ce6 was more efficient under acidic pH, representing
the tumor environment, as compared to normal pH. This results from
the pH sensitivity of the zwitterionic layer. Temperature was the
only environmental factor affecting the cellular internalization process.
It is believed that the enhanced intracellular internalization efficiency
is due to the thin zwitterionic layer of PPIMYC-DOX-Ce6. The preparation
scheme of zwitterionic micelles would offer a new strategy to design
novel antitumor drug delivery systems with enhanced cellular internalization
efficiency and high stability in a complex medium.
An electrospun scaffold-reinforced zwitterionic hydrogel achieved both high tensile strength and mechano-induced self-enhancement while maintaining excellent hemocompatibility.
Albumin mimics could be an attractive platform for nanodrug carriers through systematic administration because of high safety and plentiful properties to be adjusted for a high drug efficacy, such as pH-triggered targeting cellular uptake and drug release. In this work, negative-biased zwitterionic nanodrug carriers based on zwitterionic polypeptide chains that mimic albumin were prepared, which have an outermost layer of zwitterionic glutamic acid (E) and lysine (K) pairs with a small amount of aspartic acid (D) to adjust the overall ζ potential. On the other hand, doxorubicin (Dox) was encapsulated in a hydrophobic core by 11-maleimidoundecanoic acid covalently linked with additional cysteine (C) residues on the polypeptide. The results show that the negative-biased zwitterionic nanodrug carriers can sensitively enhance the cellular uptake in responding to a pH change from 7.4 to 6.7 without reversing the ζ potential to a positive charge, leading to accelerating the Dox release rate in a slightly acidic environment through the polypeptide secondary structure change. Moreover, the anionic nanodrug carrier can also be easily enzymatically digested by trypsin for quick drug release. In short, this negative-biased zwitterionic nanodrug delivery vector could be an ideal candidate for a safer tumor inhibition with a high efficacy than conventional synthetic polymer-based ones.
Long-term resistance of biomaterials to the bacterial biofilm formation without antibiotic or biocide is highly demanded for biomedical applications. In this work, a novel biodegradable biomaterial with excellent capability to prevent long-term bacterial biofilm formation is prepared by the following two steps. Ethylcarboxybetaine ester analogue methacrylate (ECBEMA), poly(ethylene glycol) monomethacrylate (PEGMA), and 3methacryloxypropyletris(trimethylsiloxy)silane (TRIS) were copolymerized to obtain p(ECBEMA-PEGMA-TRIS) (PEPT). Then, PEPT was cross-linked by isocyanate-terminated polylactic acid (IPDI-PLA-IPDI) to obtain the final PEPTx-PLAy (x and y are the number-average molecular weights (M n ) of PEPT and PLA, respectively) with optimal mechanical strength and adjustable surface regeneration rate. Static contact angle measurement, protein adsorption measurement, and attenuated total reflectance infrared (ATR-IR) results show that the PEPT19800-PLA800 film surface can generate a zwitterionic layer to resist nonspecific protein adsorption after surface hydrolysis. Quartz crystal microbalance with dissipation (QCM-D) results indicates that the PEPT19800-PLA800 film can undergo gradual degradation of the surface layer at the lowest swelling rate. Particularly, this material can efficiently resist the bacterial biofilm formation of both Gram-positive bacteria and Gram-negative bacteria over 14 and 6 days, respectively. Moreover, the material also shows an ideal self-healing feature to adapt to harsh conditions. Thus, this nonfouling material shows great potential in biomedical applications and marine antifouling coatings without antibiotic or biocide.
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