CD44 Mediated Tumor Targeting of Hyaluronan-Conjugated Liposomes

[From Chapter 1] Looking closely at the past literature and drawing parallels with studies with various other ligand targeted systems "we hypothesize that decreasing HA-nanoparticle interactions in the circulation, enhancing the systemic exposure are critical steps in addition to receptor-ligand interaction at the tumor site for HA-conjugated nanoparticle delivery". Our goal is to develop HA-conjugated nanoparticle system that behaves like PEGylated liposome all through its journey in body reaching the destination in similar amounts and then retain some active tumor cell internalization in vivo

Breast Cancer: Conventional Diagnosis and Treatment Modalities and Recent Patents and Technologies

Breast cancer is the most prevalent cancer among women worldwide. However, increased survival is due to the dramatic advances in the screening methods, early diagnosis, and breakthroughs in treatments. Over the course of the last decade, many acquisitions have taken place in this critical field of research in the pharmaceutical industry. Advances in molecular biology and pharmacology aided in better understanding of breast cancer, enabling the design of smarter therapeutics able to target cancer and respond to its microenvironment efficiently. Patents and research papers investigating diagnosis and treatment strategies for breast cancer using novel technologies have been surveyed for the past 15 years. Various nanocarriers have been introduced to improve the therapeutic efficacy of anticancer drugs, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of breast cancer, conventional therapy, novel technologies in the management of breast cancer, and rational approaches for targeting breast cancer. Highlights Breast cancer is the most common cancer in women worldwide. However, survival rates vary widely, optimistically heading toward a positive trend. Increased survival is due to the drastic shift in the screening methods, early diagnosis, and breakthroughs in treatments. Different strategies of breast cancer classification and staging have evolved over the years. Intrinsic (molecular) subtyping is essential in clinical trials and well understanding of the disease. Many novel technologies are being developed to detect distant metastases and recurrent disease as well as to assess response to breast cancer management. Intensive research efforts are actively ongoing to take novel breast cancer therapeutics to potential clinical application. Most of the recent research papers and patents discuss one of the following strategies: the development of new drug entities that specifically target the breast tumor cells; tailor designing a novel carrier system that can multitask and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a therapeutic drug moiety with a targeting moiety, diagnostic moiety or pharmacokinetics altering moiety; or the use of innovative nontraditional approaches such as genetic engineering, stem cells, or vaccinations

Hyaluronan Polymer Length, Grafting Density, and Surface Poly(ethylene glycol) Coating Influence <i>in Vivo</i> Circulation and Tumor Targeting of Hyaluronan-Grafted Liposomes

Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells <i>in vitro via</i> receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5–8, 50–60, and 175–350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175–350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5–8, 50–60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability <i>in vivo</i>. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of <i>ex vivo</i> tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery