An injectable acellular matrix scaffold with absorbable permeable nanoparticles improves the therapeutic effects of docetaxel on glioblastoma.
Intratumoral drug delivery (IT) is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. However, for most chemotherapies, poor tumor penetration and short retention at the administration site limit their anti-tumor effects. In this work, we describe permeable nanoparticles (NPs) prepared with a novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL). The nanoparticles (NPs) of VES-g-ε-PLL exhibited an ultra-small hydrodynamic diameter (20.8 nm) and positive zeta potential (20.6 mV), which facilitate strong glioma spheroid penetration ability in vitro. Additionally, the hydrophobic model drug docetaxel (DTX) could be effectively encapsulated in the nanoparticles with 3.99% drug loading and 73.37% encapsulation efficiency. To prolong the retention time of DTX-loaded nanoparticles (DTX-NPs) in the tumor, intact decellularized brain extracellular matrix (dBECM) derived from healthy rats was used as a drug depot to adsorb the ultra-small DTX-NPs. The intact DTX-NPs-adsorbing dBECM scaffold was further homogenized into an injectable DTX-NPs-dBECM suspension for intratumoral administration. The DTX-NPs-dBECM suspension exhibited slower DTX release than naked DTX-NPs without compromising the tumor penetration ability of DTX-NPs. An antitumor study showed that the DTX-NPs-dBECM suspension exhibited more powerful in vitro inhibition of tumor spheroid growth than free DTX solution or DTX-NPs. Due to strong tumor penetration ability and prolonged retention, DTX-NPs-dBECM led to complete suppression of glioma growth in vivo at 28 days after treatment. The therapeutic mechanism was due to enhanced proliferation inhibition and apoptosis of tumor cells and angiogenesis inhibition of glioma after treatment with DTX-NPs-dBECM. Finally, the safety of DTX-NPs-dBECM at the therapeutic dose was demonstrated via pathological HE assay from heart, liver, spleen, lung and kidney tissues. In conclusion, permeable nanoparticle-absorbing dBECM is a potential carrier for intratumoral delivery of common chemotherapeutics.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
He-Lin
HL
Xu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Kai-Li
KL
Mao
The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China. Electronic address: lctuua@sina.com.
Cui-Tao
CT
Lu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Zi-Liang
ZL
Fan
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Jing-Jing
JJ
Yang
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Jie
J
Xu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Pian-Pian
PP
Chen
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
De-Li
DL
ZhuGe
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Bi-Xin
BX
Shen
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Bing-Hui
BH
Jin
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China. Electronic address: xfxj2000@126.com.
Jian
J
Xiao
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China; The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China. Electronic address: pharmtds@163.com.
Ying-Zheng
YZ
Zhao
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D000077143:Docetaxel; D004357:Drug Synergism; D004655:Emulsions / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D015552:Injections, Intralesional; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004655:Emulsions; D043823:Taxoids; D000077143:Docetaxel
Decellularized brain extracellular matrix; Glioma; Intratumoral injection; Permeable nanoparticles; Retention time; Sustained release