Theranostics 2020; 10(3):1136-1150. doi:10.7150/thno.38287

Research Paper

High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy

Jingjing Sun1,2*✉, Yichao Chen1,2*, Jieni Xu1,2*, Xiangping Song3,4, Zhuoya Wan1,2, Yuqian Du1,2, Weina Ma1,2, Xizhen Li1,2, Lin Zhang3,4, Song Li1,2✉

1. Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
3. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
4. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
* These authors contributed equally to this paper.

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Citation:
Sun J, Chen Y, Xu J, Song X, Wan Z, Du Y, Ma W, Li X, Zhang L, Li S. High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy. Theranostics 2020; 10(3):1136-1150. doi:10.7150/thno.38287. Available from http://www.thno.org/v10p1136.htm

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Abstract

Development of small-sized nanoformulations for effective tumor penetration, particularly for those tumors with dense stroma is a major challenge in cancer nanomedicine. It is even more challenging to achieve effective co-loading of both hydrophobic and hydrophilic anticancer agents through a small-sized nanocarrier. In this work, we designed a novel redox-responsive gemcitabine (GEM)-conjugated polymer POEG-co-PVDGEM (PGEM) as a small-sized nanocarrier to co-deliver hydrophilic GEM and hydrophobic paclitaxel (PTX).

Methods: The in vitro physicochemical and biological properties of PTX/PGEM NPs were characterized. The efficiency of the PGEM carrier in selective codelivery of GEM and PTX in two murine tumor models as well as a patient derived xenograft model (PDX) was also evaluated. In addition, we investigated the changes in tumor immune microenvironment after treatment with PTX/PGEM nanoparticles.

Results: We discovered that GEM conjugation could significantly decrease the nanoparticle size from 160 nm to 13 nm. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. More importantly, our strategy could be extended to various nucleotides-based drugs such as azacytidine, decitabine and cytarabine, suggesting a new platform for co-delivery of various first line hydrophilic and hydrophobic anticancer agents. Imaging showed that our small-sized carrier was much more effective in tumor accumulation and penetration compared to the relatively large-sized drug carrier. The PGEM prodrug-based carrier not only well retained the pharmacological activity of GEM, but also boosted T-cell immune response. Furthermore, delivery of PTX via PGEM led to significantly improved antitumor activity in several murine cancer models and a PDX model of colon cancer.

Conclusion: This work not only provided a small-sized carrier platform that was able to load multiple hydrophilic and hydrophobic drugs with high loading capacity, but also provided an effective regimen for enhanced tumor penetration and improved anti-tumor immunity.

Keywords: tumor penetration, high loading capacity, T-cell immune response, patient derived xenograft (PDX)