Dual-functional bio-derived nanoparticulates for apoptotic antitumor therapy.
The application of bio-derived nanoparticulates has gained a remarkable degree of interest as a promising sustained-release, site-targeted and completely biodegradable delivery system for chemotherapeutics. We hereby introduce a dual-functionalized biomimetic nanovector, cell-penetrating peptide (CPP)-anchored recombinant high density lipoproteins (cp-rHDL), which affords high payload and improved targeting of gambogic acid (GA), a therapeutic agent for apoptotic antitumor therapy. GA-loaded cp-rHDL nanoparticles (cp-rHDL/GA) consisted of hydrophobic core modulating GA, apolipoprotein A-I (apo A-I) for attractive integrating and tumor-homing, and lipophilic anchored R6H4 (RRRRRRHHHH, a pH-responsive CPP) offering a pH-controlled penetrating potential. Upon stepwise incubation with apo A-I and R6H4, cp-rHDL/GA presented several merits, including desirable physicochemical properties, superior biostability, and favorable buffering capacity resulting in proton sponge effect. Synergistic intracellular mechanism for scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, and pH-responsive R6H4 associated endocytotic pathway with rapid endo-lysosomal escape was also observed. This tailored cp-rHDL/GA displayed remarkable cytotoxicity and apoptotic effect via triggering p53 pathway, and provided approximately 5-fold increase in IC50 compared to free GA. Moreover, this rational biomimetic therapeutic strategy attained superior tumor accumulation and significant inhibition of tumor growth in HepG2 xenograft tumor animal models without measurable adverse effect. Results of this study demonstrated that bio-derived cp-rHDL/GA presents pH-responsive penetrating potential and efficient cellular internalization. This dual-functionalization model will open an avenue for exploration of multi-functional bio-derived drug delivery, thereby rendering potential broad applications in apoptotic anticancer therapy.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: dydszyzf@163.com.
Yang
Y
Ding
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Yazhe
Y
Wang
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Yaw
Y
Opoku-Damoah
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Cheng
C
Wang
National Engineering and Research Center for Target Drugs, Jiangsu Hengrui Medicine Co., Ltd, 7 Kunlun Shan Road, Lianyungang 222000, China.
Lingjia
L
Shen
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Lifang
L
Yin
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhoujianp60@163.com.
Jianping
J
Zhou
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D003952:Diagnostic Imaging; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011817:Rabbits; D051381:Rats; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D008075:Lipoproteins, HDL; D044004:Xanthones; C052659:gambogic acid
Apoptotic antitumor therapy; Dual functionalization; High density lipoprotein-derived nanoparticulates; Synergistic intracellular mechanisms; pH-responsive cell-penetrating peptide