PMID- 35404619
OWN - NLM
STAT- MEDLINE
DCOM- 20220503
LR  - 20220509
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 19
IP  - 5
DP  - 2022 May 2
TI  - Enhanced Therapeutic Effect of Liposomal Doxorubicin via Bio-Orthogonal Chemical 
      Reactions in Tumors.
PG  - 1400-1409
LID - 10.1021/acs.molpharmaceut.1c00936 [doi]
AB  - Liposomes are highly biocompatible drug carriers in drug delivery systems (DDSs). 
      Preferential accumulation of liposomes and acceleration of drug release at target 
      tumor sites are essential for effective cancer therapy using liposomal 
      formulations; however, conventional liposomes are unsuitable for on-demand drug 
      release. We have previously reported that drug release can be accelerated via a 
      bio-orthogonal inverse electron demand Diels-Alder (IEDDA) reaction between 
      amphiphilic tetrazine (Tz)-containing liposomes and norbornene (NB) derivatives 
      in vitro. In this study, we prepared HSTz-liposomes composed of hydrogenated 
      soybean phosphatidylcholine (HSPC) and Tz compound 
      (2-hexadecyl-N-(6-(6-(pyridin-2-yl)-1,2,4,5-tetrazin-3-yl)pyridin-3-yl)octadecanamide) 
      with particle sizes of 60-80 nm and zeta-potentials of -5 to 0 mV. Similar to our 
      previous report, the addition of 5-norbornene-2-carboxylic acid (NBCOOH) to 
      HSTz-liposomes accelerated drug release from the liposomes in vitro. In the 
      biodistribution study using colon26 tumor-bearing mice, the radiolabeled 
      HSTz-liposomes were accumulated and retained in the tumor at 6-48 h 
      post-injection, whereas the radioactivity in the blood almost disappeared at 48 
      h. Therefore, the timing of the injection of NBCOOH was selected to be 48 h after 
      the injection of the HSTz-liposome to avoid the IEDDA reaction in the 
      bloodstream. We investigated the in vivo drug release by evaluating the 
      intratumoral localization of doxorubicin (DOX) encapsulated in HSTz-liposomes 
      labeled with fluorescent lipids. In the tumors treated with HSTz-liposomes and 
      NBCOOH, DOX was more widely dispersed in the tumor compared with fluorescent 
      lipid, suggesting that the release of encapsulated drugs (DOX) from 
      HSTz-liposomes was enhanced in the tumor tissue via the bio-orthogonal IEDDA 
      reaction. Furthermore, the combination of DOX-encapsulated HSTz-liposomes with 
      NBCOOH significantly suppressed tumor growth compared to conventional 
      DOX-encapsulated liposomes. In conclusion, the bio-orthogonal IEDDA reactions in 
      the liposomal membrane enabled the acceleration of drug release from 
      HSTz-liposomes in vivo, suggesting a promising strategy for effective cancer 
      therapy.
FAU - Kannaka, Kento
AU  - Kannaka K
AD  - Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 
      Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
FAU - Sano, Kohei
AU  - Sano K
AUID- ORCID: 0000-0001-8748-026X
AD  - Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 
      Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
FAU - Munekane, Masayuki
AU  - Munekane M
AUID- ORCID: 0000-0002-3405-4512
AD  - Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 
      Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
FAU - Yamasaki, Toshihide
AU  - Yamasaki T
AUID- ORCID: 0000-0001-8567-8213
AD  - Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 
      Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
FAU - Hagimori, Masayori
AU  - Hagimori M
AD  - Laboratory of Analytical Chemistry, School of Pharmacy and Pharmaceutical 
      Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, Nishinomiya 
      663-8179, Japan.
FAU - Mukai, Takahiro
AU  - Mukai T
AUID- ORCID: 0000-0001-6334-4466
AD  - Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 
      Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220411
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Liposomes)
RN  - 0 (Norbornanes)
RN  - 0 (liposomal doxorubicin)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic
MH  - Cell Line, Tumor
MH  - Doxorubicin/analogs & derivatives/chemistry
MH  - *Liposomes
MH  - Mice
MH  - *Neoplasms/drug therapy
MH  - Norbornanes
MH  - Polyethylene Glycols
MH  - Tissue Distribution
OTO - NOTNLM
OT  - bio-orthogonal IEDDA reactions
OT  - controlled release
OT  - doxorubicin
OT  - liposome
OT  - norbornene
OT  - tetrazine
EDAT- 2022/04/12 06:00
MHDA- 2022/05/04 06:00
CRDT- 2022/04/11 17:20
PHST- 2022/04/12 06:00 [pubmed]
PHST- 2022/05/04 06:00 [medline]
PHST- 2022/04/11 17:20 [entrez]
AID - 10.1021/acs.molpharmaceut.1c00936 [doi]
PST - ppublish
SO  - Mol Pharm. 2022 May 2;19(5):1400-1409. doi: 10.1021/acs.molpharmaceut.1c00936. 
      Epub 2022 Apr 11.