7MO - Photoreactive and intratumorally injectable dendrimer matrix improves survival in multiple xenograft mouse models

Background

Adverse events occur in majority of patients receiving systemic cancer therapies. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration in the tumor. The active agent is typically required to stay in contact with the tumor. This requires attachment directly into the tumor or to the surrounding tissue. Dendrimers are well-defined, multivalent molecules having branched structure of nanometer size, which can be used to form injectable gels. Dendrimers have been used to encapsulate and release drugs with the aid of external stimuli at physiological pH.

Methods

We prepared a dendrimeric drug delivery matrix based on a PEG-core. The model drug (5-fluorouracil, docetaxel, capecitabine, cisplatin) was encapsulated in the matrix. The outer shell of the matrix was modified with photoreactive groups, injected inside the tumor, and attached to the tumor by activation of the photoreactive groups with the aid of interstitial photodynamic therapy. We compared the pharmacokinetics, tissue distribution and antitumor efficacy of conventional systemic therapy and the intratumoral therapy in xenograft-bearing mice. The tumor growth curve was plotted and tumor, spleen, lymph nodes, and lungs were collected at the study endpoint for further flow cytometry and histological analysis.

Results

The dendrimer-based therapy showed significantly decreased tumor growth rates over standard systemic therapies. Mice treated with the intratumoral dendrimer showed decreased toxicity when compared to those receiving systemic therapies. The matrix enabled a significant increase in drug accumulation in tumors, and markedly extended the survival of mice compared with conventional systemic treatments.

Conclusions

Local sustained intratumoral systemic therapy is a potential strategy for improving treatment of solid tumors while minimizing adverse side effects. The photoreactive dendrimer matrix enhances antitumor activity by improving intratumoral drug accumulation and increases efficacy in comparison to conventional systemic therapies. These results highlight the potential use of photoreactive dendrimers in the treatment of several cancer types.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Chembrain LTD.

Funding

Chembrain LTD research organization.

Disclosure

S. Vuoti: Full/Part-time employment, currently works at Sanofi Genzyme, however, the presented research is not related to Sanofi but was conducted in 2017-2018 before joining Sanofi: Sanofi Genzyme. All other authors have declared no conflicts of interest.