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De-differentiated liposarcoma (DDLPS) is a malignant soft tissue sarcoma known for its metastatic potential and high rate of local recurrence. Surgical resection remains the standard treatment for DDLPS due to the limited efficacy of systemic chemotherapy and radiation [1]. Chemotherapy is limited by systemic effects that prevent accumulation at the tumor site, thereby requiring higher dosages leading to adverse side effects. We started the development of a targeted drug delivery system that is responsive to specific signals in the tumor and its microenvironment to treat locally recurrent DDLPS. DDLPS is marked by amplification in the chromosomal locus 12q13-15 which is associated with amplifications of the oncoprotein mouse double minute 2 (MDM2) [2]. Mdm2 is found to be upregulated in nearly all cases of DDLPS and is associated with increased local recurrence rates [3]. Given that Mdm2 can serve as a reliable diagnostic marker, we wanted to find a downstream product that could be used to prompt controlled drug delivery. Matrix metalloproteinases (MMPs) are a family of endoproteases that contribute towards the degradation of the extracellular matrix (ECM). MMPs have previously been used in targeted drug delivery systems and are upregulated by increased levels of MDM2 [4]. Therefore, the relationship between MDM2 and MMPs demonstrated the potential to be exploited for a controlled drug delivery system. To make this system transferrable to a clinical setting, we began characterization of the MMPs being released from liposarcoma (LPS) cell lines. We used polymerase chain reaction (PCR) to gain a better understanding of how increased Mdm2 levels impacted MMP expression and found that MMP-1, -2, and -14 mRNA expression was significantly increased in cell lines with higher Mdm2 expression. Based on these results, we designed four peptide substrates that were amenable to degradation by the identified MMPs. Results indicated a trend in the QGIW and RSLS peptides that suggested preferential degradation by LPS cell lines with high levels of MDM2. To improve the design of these crosslinkers we used fluorescent peptide zymography to measure which MMPs might be contributing to the degradation of each peptide. We found that MMP-1 and -2 are driving the degradation of the selected substrates by LPS cell lines. Future work will aim to improve the design of the peptide substrates to make them more selective for degradation by MMP-1 and -2 specifically.