Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation

Abstract

Background: Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform.

Methods: We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model.

Results: We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity.

Conclusion: This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy.

Keywords: camptothecin; cancer; gold porphyrin; lipid nanoparticles; neuroblastoma.

Figure 1

Tissue residence of free GP, GPNP, and GPNP-PEG at 6 and 24 hours. Notes: Data are presented as the ppb Au/g tissue ± standard deviation (*P < 0.05, n = 3). Abbreviations: GP, gold porphyrin; GPNP, gold porphyrin nanoparticles; GPNP-PEG, gold porphyrin nanoparticles surface-coated with PEG.

Figure 2

(A) Dose-dependent antitumor activity against N2 A for GP and camptothecin with or without the lipophilic carrier formulation (n = 4, *P < 0.05 when comparing nanoparticle formulation with free GP or camptothecin). (B) Comparison of surface-coated lipophilic nanoparticle carrier with different molecular weights (750 Da and 2000 Da) of PEG. Notes: Results are presented as the mean ± standard deviation (n = 4, *P < 0.05 for C-PEG 750 or C-PEG 2000 in comparison with C). Abbreviations: C, camptothecin; GP, gold porphyrin; GPNP, gold porphyrin nanoparticles; GPNP-PEG, gold porphyrin nanoparticles surface-coated with PEG.

Figure 3

Tumor volume measurements after N2A-bearing A/J mice had received intraperitoneal injections of GPNP-PEG 3, 4, or 5 mg/kg. Notes: n = 5–6, *P < 0.05. Abbreviation: GPNP-PEG, gold porphyrin nanoparticles surface-coated with PEG.

Figure 4

Apoptotic activity of (A) GP formulations and (B) camptothecin formulations using Tunel assay in neuroblastoma tissue harvested at 21 days after treatment. Notes: Green represents positive apoptotic cells and blue represents the DAPI nuclei stain. Magnification 100× (left column) or 200× (right column); n = 5, *P < 0.05 for 4 mg/kg or 5 mg/kg of GPNP-PEG in comparison with untreated controls in Figure 4A. Abbreviations: GP, gold porphyrin; GPNP-PEG, gold porphyrin nanoparticles surface-coated with PEG.

Figure 5

Dose-dependent antitumor activity against D54. Notes: Results are presented as the mean ± standard deviation (n = 4, *P < 0.05 for C-NP or C-PEG 2000 compared with C).