State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Biomaterials. 2015 Dec;72:90-103. doi: 10.1016/j.biomaterials.2015.08.051. Epub 2015 Aug 31.
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.
生物衍生纳米颗粒作为一种有前途的持续释放、靶向和完全可生物降解的化疗药物递送系统，已经引起了极大的关注。我们在此介绍一种双功能仿生纳米载体，即穿透肽（CPP）锚定的重组高密度脂蛋白（cp-rHDL），它能够高效负载并靶向藤黄酸（GA），GA 是一种用于凋亡抗肿瘤治疗的治疗剂。载有 GA 的 cp-rHDL 纳米颗粒（cp-rHDL/GA）由疏水性核心调节 GA、载脂蛋白 A-I（apo A-I）用于有吸引力的整合和肿瘤归巢以及疏水性锚定的 R6H4（RRRRRRHHHH，一种 pH 响应 CPP）提供 pH 控制的穿透潜力。cp-rHDL/GA 在与 apo A-I 和 R6H4 逐步孵育后，具有理想的物理化学性质、卓越的生物稳定性和有利的缓冲能力，从而产生质子海绵效应。还观察到协同的细胞内机制，包括清道夫受体 B 型 I（SR-BI）介导的直接跨膜递药和 pH 响应的 R6H4 相关的内吞途径以及快速的内溶酶体逃逸。这种定制的 cp-rHDL/GA 通过触发 p53 途径表现出显著的细胞毒性和凋亡作用，并与游离 GA 相比，IC50 增加了约 5 倍。此外，这种合理的仿生治疗策略在 HepG2 异种移植肿瘤动物模型中实现了优异的肿瘤积累和显著的肿瘤生长抑制，而没有可测量的不良反应。本研究结果表明，生物衍生的 cp-rHDL/GA 具有 pH 响应的穿透潜力和高效的细胞内化能力。这种双重功能化模型将为多功能生物衍生药物递送的探索开辟道路，从而为凋亡抗肿瘤治疗提供潜在的广泛应用。
