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Abstract
Due to increasing safety and intracellular delivery concerns about hydrophilic polymers in amphiphilic polymer-based nanoparticles (NPs), this study investigates small hydrophilic molecule-stabilized NPs for effective intracellular delivery with multiorganelle targetability and dual responsiveness to acidic pH/glutathione (GSH). In the construction of small hydrophilic molecule-stabilized NP (MSPCL-NP), the A-B-A-type amphiphilic polymer (MSPCL-P) is composed of two short hydrophilic carboxylate-capped disulfide derivatives (A) that replace hydrophilic polymers and assist in providing colloidal stability and preventing antibody (e.g., at least anti-PEG antibody)-mediated specific interactions and complement activation in the plasma and a hydrophobic multiple disulfide-containing poly(ε-caprolactone) block (B) that carries hydrophobic drugs. The carboxylates on the surface of MSPCL-NP target the acidic extratumoral/endolysosomal milieu by sensing and buffering acidic pH values, and the hydrophobic carboxylic acids improve adsorptive endocytosis and effective endosomal escape. Multiple disulfide linkages selectively target cytosolic GSH, resulting in rapid drug release from the destroyed MSPCL-NP via the cleavage of disulfide bonds in MSPCL-P. Doxorubicin (DOX)-loaded NP (DOX@MSPCL-NP) exerts strong effects on killing cells in vitro and inhibits tumor growth in HCT116 xenograft tumor-bearing mice. In conclusion, the multifunctionality and multispatial targetability of MSPCL-NP might effectively overcome various sequential drug delivery hurdles, ranging from blood circulation to drug release. Furthermore, the introduction of small hydrophilic molecules represents a potential strategy to make self-assembled NPs without the use of hydrophilic polymers.

Affiliations

Yeon Su Choi  1 , Hana Cho  1 , Won-Gu Choi  1 , Sung Su Lee  1 , Kang Moo Huh  2 , Min Suk Shim  3 , In Suh Park  4 , Yong-Yeon Cho  1 , Joo Young Lee  1 , Hye Suk Lee  5 , Han Chang Kang  6
1 Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
2 Department of Polymer Science and Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.
3 Division of Bioengineering, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon, 22012, Republic of Korea.
4 Department of Pathology, Inha University Hospital, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea.
5 Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea. Electronic address: sianalee@catholic.ac.kr.
6 Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea. Electronic address: hckang@catholic.ac.kr.