Strategies to Increase Drug Penetration in Solid Tumors

Abstract

Despite significant improvement in modalities for treatment of cancer that led to a longer survival period, the death rate of patients with solid tumors has not changed during the last decades. Emerging studies have identified several physical barriers that limit the therapeutic efficacy of cancer therapeutic agents such as monoclonal antibodies, chemotherapeutic agents, anti-tumor immune cells, and gene therapeutics. Most solid tumors are of epithelial origin and, although malignant cells are de-differentiated, they maintain intercellular junctions, a key feature of epithelial cells, both in the primary tumor as well as in metastatic lesions. Furthermore, nests of malignant epithelial tumor cells are shielded by layers of extracellular matrix (ECM) proteins (e.g., collagen, elastin, fibronectin, laminin) whereby tumor vasculature rarely penetrates into the tumor nests. In this chapter, we will review potential strategies to modulate the ECM and epithelial junctions to enhance the intratumoral diffusion and/or to remove physical masking of target receptors on malignant cells. We will focus on peptides that bind to the junction protein desmoglein 2 and trigger intracellular signaling, resulting in the transient opening of intercellular junctions. Intravenous injection of these junction openers increased the efficacy and safety of therapies with monoclonal antibodies, chemotherapeutics, and T cells in mouse tumor models and was safe in non-human primates. Furthermore, we will summarize approaches to transiently degrade ECM proteins or downregulate their expression. Among these approaches is the intratumoral expression of relaxin or decorin after adenovirus- or stem cell-mediated gene transfer. We will provide examples that relaxin-based approaches increase the anti-tumor efficacy of oncolytic viruses, monoclonal antibodies, and T cells.

Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis

“…A longer serum-half life is a beneficial property of tumor-penetration promoting agents for their co-administered or conjugated drugs [1,49]. The TPP11 fusion to Fc did not compromise the serum half-life of Fc (Fig.…”

Comparison of Nanoparticle Penetration into Solid Tumors and Sites of Inflammation: Studies Using Targeted and Nontargeted Liposomes

“…While the application of nanomedicines to cancer therapy can obviously boast success, more detailed scrutiny of the formulations has revealed that their large sizes may compromise their abilities to penetrate deep into a tumor mass [5,[8][9]. Thus, Torchilin and Jain disclosed in 1995 that tumor permeability was inversely proportional to NP radius [10].…”

“…The folate receptor (FR) is a 38-kDa glycosylphosphatidylinositol anchored protein Comparison of nanoparticle penetration into solid tumors and sites of inflammation: studies using targeted and nontargeted liposomes [2,[16][17][18]. Because many cancer cell types overexpress FRs, it is possible to selectively target folate-derivatized cargoes to malignant cells within FR+ tumors [3,9,[18][19]. Similarly, because activated macrophages (but not resting macrophages or other hematopoietic cells) also overexpress FRs, folate-linked liposomes can also be targeted to sites of inflammation that characterize many autoimmune diseases [17,20].…”

Antibody drug conjugates

“…However, while therapeutic mAbs have had a high success rate in treatment of hematologic tumors, targeting solid tumors has been relatively difficult because of their lack of sufficient permeability (Choi et al 2013). Most solid tumors are derived from epithelial cells and their tissues pose significant barriers to drug penetration due to their high interstitial fluid pressure (IFP), high cell density, excessive deposition of extracellular matrix (ECM), and physical barriers composed of stroma proteins.…”