We hypothesised that synthetic HDL nanoparticles carrying a gemcitabine prodrug and apolipoprotein A-II (sHDLGemA2) would target scavenger receptor-B1 (SR-B1) to preferentially and safely deliver gemcitabine into pancreatic ductal adenocarcinoma (PDAC).

We designed, manufactured and characterised sHDLGemA2 nanoparticles sized ~130 nm, incorporating 20 mol% of a gemcitabine prodrug within the lipid bilayer, which strengthens on adding ApoA-II. We measured their ability to inhibit growth in cell lines and cell-derived and patient-derived murine PDAC xenografts.

Fluorescent-labelled sHDLGemA2 delivered gemcitabine inside xenografts. Xenograft levels of active gemcitabine after sHDLGemA2 were similar to levels after high-dose free gemcitabine. Growth inhibition in mice receiving 4.5 mg gemcitabine/kg/d, carried in sHDLGemA2, was equivalent to inhibition after high-dose (75 mg/kg/d) free gemcitabine, and greater than inhibition after low-dose (4.5 mg/kg/d) free gemcitabine. sHDLGemA2 slowed growth in semi-resistant cells and a resistant human xenograft.

sHDLGemA2 targeted xenografts more effectively than sHDLGemA1. SR-B1 was over-expressed in PDAC cells and xenografts. Targeting by ApoA-II was suppressed by anti-SR-B1.

Because sHDLGemA2 provided only ~6% of the free gemcitabine dose for an equivalent response, patient side effects can be greatly reduced, and the sHDLGemA2 concept should be developed through clinical trials.

我们假设携带吉西他滨前药和载脂蛋白A-II（sHDLGemA2）的合成HDL纳米粒子将靶向清道夫受体B1（SR-B1），以优先安全地将吉西他滨递送入胰腺导管腺癌（PDAC）。

我们设计，制造和表征了约130 nm的sHDLGemA2纳米颗粒，在脂质双层中掺入了20 mol％的吉西他滨前药，这在添加ApoA-II时会增强。我们测量了它们抑制细胞系以及细胞源性和患者源性鼠类PDAC异种移植物中生长的能力。

荧光标记的sHDLGemA2在异种移植物中递送吉西他滨。sHDLGemA2后活性吉西他滨的异种移植水平与大剂量游离吉西他滨后的异种移植水平相似。接受sHDLGemA2接受4.5 mg吉西他滨/ kg / d的小鼠的生长抑制作用等同于高剂量（75 mg / kg / d）游离吉西他滨后的抑制作用，大于低剂量（4.5 mg / kg / d）后的抑制作用d）免费吉西他滨。sHDLGemA2减慢了半耐药细胞和耐药人类异种移植物中的生长。

sHDLGemA2比sHDLGemA1更有效地靶向异种移植物。SR-B1在PDAC细胞和异种移植物中过表达。ApoA-II的靶向被抗SR-B1抑制。

由于sHDLGemA2仅提供约6％的吉西他滨游离剂量以产生等效反应，因此可以大大降低患者的副作用，因此应通过临床试验开发sHDLGemA2概念。