A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates solid tumors and induces systemic antitumor immunity
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ABSTRACT:
PROVIDER: PRJNA741771 | ENA |
REPOSITORIES: ENA
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Project description:Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors. We hypothesize that a local carrier of immunotherapeutics is critical to the effective activation of in-situ antitumor immunity. Here, we develop a polyethyleneimine derivative (2E’), which activates immune cells and co-delivers hydrophobic immunogenic cell death inducers and immunomodulatory nucleic acids/nucleotides. A single local administration of 2E’ or its combination with paclitaxel and PD-L1 siRNA or cyclic dinucleotide induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, and the resistance to rechallenge and metastasis in different models. This study supports that effective in-situ induction of antitumor immunity can lead to systemic protection from distant and recurrent diseases, where 2E’ plays multiple roles as a simple and versatile carrier of immunotherapeutics.
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Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
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