Dancy Jimena G, Wadajkar Aniket S, Schneider Craig S, Mauban Joseph R H, Goloubeva Olga G, Woodworth Graeme F, Winkles Jeffrey A, Kim Anthony J
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
J Control Release. 2016 Sep 28;238:139-148. doi: 10.1016/j.jconrel.2016.07.034. Epub 2016 Jul 25.
Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62nm, but less than 110nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non-PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration.
已获批用于实体瘤治疗临床应用的治疗性纳米颗粒（NPs）仅在一定程度上提高了患者生存率，部分原因是生理屏障限制了颗粒在整个肿瘤中的递送。在此，我们探究了纳米颗粒大小和表面聚乙二醇（PEG）密度在肿瘤组织细胞外基质（ECM）中渗透的阈值。我们发现，直径达62nm但小于110nm的纳米颗粒能在肿瘤ECM制剂（基质胶）和离体乳腺肿瘤异种移植切片中快速扩散。对PEG密度的研究表明，增加PEG密度可增强纳米颗粒扩散，且低于临界值的PEG密度会导致纳米颗粒与ECM黏附。通过表面等离子体共振（SPR）评估纳米颗粒与肿瘤ECM成分的非特异性结合，结果显示其与颗粒扩散结果具有良好的相关性。对纳米颗粒在乳腺肿瘤组织中扩散的活体显微镜观察证实，62nm和110nm的PEG包被纳米颗粒之间以及PEG包被和未包被纳米颗粒之间在肿瘤组织渗透方面存在显著差异。SPR分析还表明，用于癌症治疗的FDA批准的非PEG化纳米颗粒制剂Abraxane与肿瘤ECM结合。我们的结果确定了在肿瘤组织内实现均匀广泛分散所需的大小和表面PEG密度参数的限制，并突出了SPR作为筛选具有肿瘤穿透性纳米颗粒的高通量方法的实用性。
