Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors

Blood vessels in solid tumors possess larger intra-endothelial gaps, and they are leakier than normal blood vessels [1,2]. In addition, lymphatic vessels are generally underdeveloped in solid tumors [3]. Consequently, nano-sized materials accumulate preferentially in solid tumors, an effect referred to as the enhanced permeability and retention (EPR) effect [4,5]. Nanoparticle-based formulation strategies have been widely explored to leverage the EPR effect and deliver encapsulated anti-cancer drugs into tumors [6,7]. Numerous studies have reported on the use of nanoparticles for treating tumors, and some of them have entered the clinic or clinical development. For instance, liposome-based nanomedicines have been extensively used in the clinic to treat several cancers, whereas many other nanoparticle-based formulations are currently in clinical trials [8,9]. While some nanoparticles have demonstrated success in the clinic, many studies have demonstrated that the actual accumulation of nanoparticles in solid tumor is extremely low, typical <1% of the injected dose [10]. This is due partly to the dense and rigid extracellular matrix (ECM) comprising collagen, hyaluronic acid (HA), and fibrin in the tumor [[11], [12], [13]] which serves as a physical barrier for the penetration of nanoparticles into the tumor core. Enzymes such as hyaluronidases, collagenases, and bromelain have been used in pre-clinical studies to breakdown the ECM structure, facilitating intratumoral diffusion of nanoparticles [11,[14], [15], [16]]. For example, intratumoral injection of hyaluronidase has been shown to enhance the tumor accumulation of intravenously administrated liposomal doxorubicin [16]. However, adverse effects of breakdown of ECM in healthy tissues has limited their applicability [17]. Although many studies have reported ECM degradants to enhance the penetration of nanoparticles, none of the degradants were actively targeted to tumors. We suggest that the targeted delivery of ECM degrading enzymes into solid tumors is a promising strategy to overcome the tumor ECM barrier with reducing systemic adverse effects.

Various strategies have been reported to achieve tumor targeting using tumor ECM as the target [18,19]. Anti-collagen type IV antibodies have been shown to localize within the tumor, thus offering a potential means to target via covalent drug conjugation [20]. In another study, tenascin-C was used as a target within cancer stroma, and antibody drug conjugate (ADC) using anti-tenascin-C antibody exhibited a significant anti-tumor effect in the human epidermoid carcinoma xenograft mice model [21]. These approaches have led to the development of cancer stroma targeting (CAST) therapies [22].

Here, we propose a novel approach to deliver an ECM degrading enzyme to cancer stroma with the aim of enhancing intratumoral penetration of a concurrently delivered nanomedicine. In this study, we first selected peptides that can target the ECM of triple-negative breast cancer (TNBC) tissue, followed by designing a construct to present these peptides on an ECM degrading enzyme. We used hyaluronic acid (HA), a polysaccharide component of the ECM, as a linker to associate the enzymes and targeting peptides. HA is often used as a drug carrier because of its ease of chemical modification, stealth properties, and affinity for CD44, which is usually over-expressed on cancer cell membranes [[23], [24], [25]]. The ECM-degrading enzyme used in this study was bromelain. It is a mixture of cysteine and sulfhydryl proteases, which has enzymatic activity over a wide pH range and could degrade a variety of proteins that comprise the ECM [26]. Previous work on PEGylated bromelain [27,28] and bromelain-modified mesoporous silica nanoparticles [27,28] has demonstrated its potential for degrading ECM and enhancing nanoparticle penetration [27,28].

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