TY - JOUR
T1 - Lactosome-Conjugated siRNA Nanoparticles for Photo-Enhanced Gene Silencing in Cancer Cells
AU - Lim, Melissa Siaw Han
AU - Nishiyama, Yuki
AU - Ohtsuki, Takashi
AU - Watanabe, Kazunori
AU - Kobuchi, Hirotsugu
AU - Kobayashi, Kazuko
AU - Matsuura, Eiji
N1 - Funding Information:
This study was supported by a grant from the Japan Agency for Medical Research and Development , Japan, Project for Cancer Research and Therapeutic Evolution (P-DIRECT and P-CREATE). We thank S. Inokawa and M. Ohshima (Okayama University) for their preliminary studies of the siRNA-loaded lactosome preparation.
Funding Information:
This study was supported by a grant from the Japan Agency for Medical Research and Development, Japan, Project for Cancer Research and Therapeutic Evolution (P-DIRECT and P-CREATE). We thank S. Inokawa and M. Ohshima (Okayama University) for their preliminary studies of the siRNA-loaded lactosome preparation.
Publisher Copyright:
© 2021
PY - 2021/4
Y1 - 2021/4
N2 - The A3B-type Lactosome comprised of poly(sarcosine)3-block-poly(L-lactic acid), a biocompatible and biodegradable polymeric nanomicelle, was reported to accumulate in tumors in vivo via the enhanced permeability and retention (EPR) effect. Recently, the cellular uptake of Lactosome particles was enhanced through the incorporation of a cell-penetrating peptide (CPP), L7EB1. However, the ability of Lactosome as a drug delivery carrier has not been established. Herein, we have developed a method to conjugate the A3B-type Lactosome with ATP-binding cassette transporter G2 (ABCG2) siRNA for inducing in vitro apoptosis in the cancer cell lines PANC-1 and NCI-H226. The L7EB1 peptide facilitates the cellular uptake efficiency of Lactosome but does not deliver siRNA into cytosol. To establish the photoinduced cytosolic dispersion of siRNA, a photosensitizer loaded L7EB1-Lactosome was prepared, and the photosensitizer 5,10,15,20-tetra-kis(pentafluorophenyl)porphyrin (TPFPP) showed superiority in photoinduced cytosolic dispersion. We exploited the combined effects of enhanced cellular uptake by L7EB1 and photoinduced endosomal escape by TPFPP to efficiently deliver ABCG2 siRNA into the cytosol for gene silencing. Moreover, the silencing of ABCG2, a protoporphyrin IX (PpIX) transporter, also mediated photoinduced cell death via 5-aminolevulinic acid (ALA)-mediated PpIX accumulated photodynamic therapy (PDT). The synergistic capability of the L7EB1/TPFPP/siRNA-Lactosome complex enabled both gene silencing and PDT.
AB - The A3B-type Lactosome comprised of poly(sarcosine)3-block-poly(L-lactic acid), a biocompatible and biodegradable polymeric nanomicelle, was reported to accumulate in tumors in vivo via the enhanced permeability and retention (EPR) effect. Recently, the cellular uptake of Lactosome particles was enhanced through the incorporation of a cell-penetrating peptide (CPP), L7EB1. However, the ability of Lactosome as a drug delivery carrier has not been established. Herein, we have developed a method to conjugate the A3B-type Lactosome with ATP-binding cassette transporter G2 (ABCG2) siRNA for inducing in vitro apoptosis in the cancer cell lines PANC-1 and NCI-H226. The L7EB1 peptide facilitates the cellular uptake efficiency of Lactosome but does not deliver siRNA into cytosol. To establish the photoinduced cytosolic dispersion of siRNA, a photosensitizer loaded L7EB1-Lactosome was prepared, and the photosensitizer 5,10,15,20-tetra-kis(pentafluorophenyl)porphyrin (TPFPP) showed superiority in photoinduced cytosolic dispersion. We exploited the combined effects of enhanced cellular uptake by L7EB1 and photoinduced endosomal escape by TPFPP to efficiently deliver ABCG2 siRNA into the cytosol for gene silencing. Moreover, the silencing of ABCG2, a protoporphyrin IX (PpIX) transporter, also mediated photoinduced cell death via 5-aminolevulinic acid (ALA)-mediated PpIX accumulated photodynamic therapy (PDT). The synergistic capability of the L7EB1/TPFPP/siRNA-Lactosome complex enabled both gene silencing and PDT.
KW - ABCG2
KW - Cancer
KW - Lactosome
KW - Photochemical internalization
KW - Photodynamic therapy
KW - Photosensitizer
KW - Polymeric micelle
KW - siRNA
KW - siRNA delivery
UR - http://www.scopus.com/inward/record.url?scp=85100696420&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100696420&partnerID=8YFLogxK
U2 - 10.1016/j.xphs.2021.01.026
DO - 10.1016/j.xphs.2021.01.026
M3 - Article
C2 - 33529684
AN - SCOPUS:85100696420
VL - 110
SP - 1788
EP - 1798
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 4
ER -
