am9b19373_si_001.pdf (627.44 kB)
Novel Chitosan Derivatives with Reversible Cationization and Hydrophobicization for Tumor Cytoplasm-Specific Burst Co-delivery of siRNA and Chemotherapeutics
journal contribution
posted on 2020-03-18, 15:41 authored by Tingjie Yin, Yanqi Liu, Mengnan Yang, Lei Wang, Jianping Zhou, Meirong HuoDespite
the great potential of combination therapy based on siRNA
and chemotherapeutics, an efficient vehicle with abilities of well
drug co-loading, synchronizing in vivo trafficking,
and target-specific co-burst release remains elusive, which results
in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile
(PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization
and hydrophobicization by polyethylenimine (PEI) and octylamine (OA),
respectively, was developed for this purpose. HSPO spontaneously assembled
in aqueous solution to be a micellar system and effectively co-encapsulated
the two drugs with an adjustable dosage ratio. With a surface charge
inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery
micelles with a negative surface charge (−21.45 ± 1.44
mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated
into CD44 overexpressed A549 tumors through a combination of passive
and active targeting mechanism. Then, tumor cytoplasm-selective co-burst
release was obtained through GSH triggered collapse of the amphiphilic
assembly alongside a decrease of positive charge condensation, finally
leading to an enhanced synergistic antitumor effect with a superior
inhibition ratio of 86.63%. Overall, this study validated the great
promise of HSPO as an efficient site-specific rapid co-trafficking
vehicle of siRNA and chemotherapeutics for a remarkable synergistic
tumor inhibition.
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Keywords
GSHchemotherapeuticTumor Cytoplasm-Specificcombination therapy549 tumorstarget-specific co-burst releaseOAsurface charge inversion strategyPEIantitumor effectinhibition ratiovivo traffickingReversible CationizationHSPOdrug co-loadingNovel Chitosan DerivativesCD 44 overexpressedmicellar systemco-trafficking vehiclesiRNAHAnovel chitosan amphiphiletumor cytoplasm-selective co-burst releasedosage ratiotumor inhibitionamphiphilic assemblycharge condensation
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