Development and mechanistic insight into enhanced cytotoxic potential of hyaluronic acid conjugated nanoparticles in CD44 overexpressing cancer cells

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• 作者：Ankit Saneja^a ; ^b ; ¹ ; Debasis Nayak^a ; ^c ; ¹ ; M. Srinivas^d ; Amit Kumar^d ; Vaibhav Khare^b ; Archana Katoch^c ; Anindya Goswami^a ; ^c ; ^{agoswami@iiim.ac.in} ; Ram A. Vishwakarma^a ; ^d ; Sanghapal D. Sawant^a ; ^d ; ^{sdsawant@iiim.ac.in} ; Prem N. Gupta^a ; ^b ; ^{pngupta@iiim.ac.in}
• 关键词：poly(dl-lactic-co-glycolic acid) (PubChem CID ; 23111554) ; Dicyclohexylcarbodiimide (PubChem CID ; 10868) ; N-hydroxysuccinimide (PubChem CID ; 80170) ; Sodium hyaluronate (PubChem CID ; 3084049) ; Triethylamine (PubChem CID ; 8471)
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：97
• 期：Complete
• 页码：79-91
• 全文大小：2276 K
• 卷排序：97

文摘

The overexpression of CD44 in cancer cells reroutes number of oncogenic pathways including the central Pi3K/Akt/NF-kB pathway leading to cancer progression and malignancy. Herein, we developed hyaluronic acid-modified poly(dl-lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles (PLGA-PEG-HA NPs) for targeted delivery of TTQ (thio-tetrazolyl analog of a clinical candidate, IC87114) to CD44 overexpressing cancer cells. The PLGA-PEG co-polymer was synthesized and characterized by NMR and FTIR. The co-polymer based nanoparticles were prepared by solvent evaporation method and hyaluronic acid (HA) was conjugated on to the nanoparticle surface via EDC/NHS chemistry. The PLGA-PEG–HA NPs had a desirable particle size (< 200 nm) with reduced polydispersibility and exhibited spherical shape under atomic force microscope (AFM). In vitro cytotoxicity and cellular uptake studies demonstrated higher cytotoxicity and enhanced intracellular accumulation of PLGA-PEG-HA NPs compared to PLGA-PEG NPs in high CD44 expressing MiaPaca-2 cells compared to MDA-MB-231 and MCF7 cells. At the molecular level, the PLGA-PEG-HA NPs were found to be inducing premature senescence with increase in senescence associated β-galactosidase activity and senescence specific marker p21 expression through modulation of Pi3K/Akt/NF-kB signaling pathway in MiaPaca-2 cells. These findings collectively indicated that HA-modified nanoparticles might serve as a promising nanocarrier for site-specific drug delivery, and can be explored further to increase the therapeutic efficacy of anticancer drugs via targeting to CD44 over-expressing cancer cells.