Cell-Mediated and Cell Membrane-Coated Nanoparticles for Drug Delivery and Cancer Therapy

Yaman et al. Cancer Drug Resist 2020;3:879-911 Cancer DOI: 10.20517/cdr.2020.55 Drug Resistance Review Open Access Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy Serkan Yaman1,2,#, Uday Chintapula1,2,#, Edgar Rodriguez1, Harish Ramachandramoorthy1,2, Kytai T. Nguyen1,2 1Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76010, USA. 2Joint Bioengineering Program, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. #Yaman S and Chintapula U contributed equally to this work. Correspondence to: Dr. Kytai T. Nguyen, Department of Bioengineering, University of Texas at Arlington, 500 UTA Blvd ERB244, Arlington, TX 76010, USA. E-mail: [email protected] How to cite this article: Yaman S, Chintapula U, Rodriguez E, Ramachandramoorthy H, Nguyen KT. Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy. Cancer Drug Resist 2020;3:879-911. http://dx.doi.org/10.20517/cdr.2020.55 Received: 24 Jul 2020 First Decision: 25 Aug 2020 Revised: 16 Sep 2020 Accepted: 21 Sep 2020 Available online: 3 Nov 2020 Academic Editor: Vladimir P. Torchilin Copy Editor: Cai-Hong Wang Production Editor: Jing Yu Abstract Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability. Despite recent advancement in nanotechnology platforms, this approach still falls short to meet the complexity of biological systems and diseases, such as avoiding systemic side effects, manipulating biological interactions and overcoming drug resistance, which hinders the therapeutic outcomes of the NP-based drug delivery systems. To address these issues, various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers. Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions, targeting, and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest. In this context, we comprehensively discuss various cell- and cell membrane-based drug delivery approaches towards cancer therapy, the therapeutic potential of these strategies, and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers. Finally, we review various cell types and cell membrane receptors for their potential in targeting, immunomodulation and overcoming drug resistance in cancer. Keywords: Cell membrane-based drug delivery, cell-mediated drug delivery, membrane receptors, drug carriers, cancer drug resistance, nanoparticles © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. www.cdrjournal.com Page 880 Yaman et al. Cancer Drug Resist 2020;3:879-911 I http://dx.doi.org/10.20517/cdr.2020.55 INTRODUCTION Based on recent trends, cancer is expected to become the leading cause of death in the world and effective treatment strategies are needed to address the increasing trend in incidents of cancer[1]. Chemotherapy has been established as a standard treatment in various cancer therapies with hundreds of antitumor drugs developed and approved for human use. However, drug sensitivity in cancer cells has been reduced due to the emergence of multiple drug resistance (MDR) induced by various factors including ATP-dependent drug efflux out of the cell, selective stress of drugs, altered DNA repair mechanisms, cellular heterogeneity in the tumors, and other drug barriers[2]. Several nanotechnology-based drug delivery systems utilize biomaterials including polymers, metals and lipids to improve the therapeutic index by improving drug loading efficacy, controlling drug release kinetics to address the challenges associated with free drugs such as systemic side effects, pharmacokinetic diversity, and physiological variety, as well as achieving ideal dose regimen and other antagonistic effects of combinatorial drug therapies used in addressing MDR. But the efficient bioavailability with those platforms has not yet been achieved due to their relatively simple structure compared to complex biomolecule interactive systems in vivo and they still suffer from the “foreign-body” aspects, leading to side effects, immune clearance and poor targeting abilities due to the protein corona formation in vivo, making them unable to meet clinical expectations[3]. Nanoparticles (NPs) as a carrier loaded with drugs can be directed towards a specific target by the use of various surface moieties involved in the complex biological mechanisms[4]. A bottom-up approach of surface functionalization is commonly adopted in the preparation of NPs for targeted drug delivery. Surface functionalization incorporates functional moieties such as antibodies, enzymes, ligands, and other functional target molecules onto the surface of drug delivery carriers via various chemical and non-chemical interactions. Though NPs have shown optimal therapeutic results, they still lack in multifunctional applications such as improved circulation, targeting, homing, immunomodulation, and/ or in combination. Although more than 80% of NP systems published are designed to treat cancer through their enhanced permeability and retention (EPR) effects, only a few tumors have been reported to achieve NP accumulation through EPR effects[5,6]. Various cells, due to their innate features, can reach tumor sites via their membrane components which may help in reducing toxicities arising from the current one-size- fits-all approach. Patient-to-patient in vivo biology varies in immune responsiveness and disease pathology; for example, tumor heterogeneity in cancers requires a bio-interfacing approach to address limitations of synthetic NP drug delivery systems. Together, the challenges faced in NP drug carriers demands more efficient and safer approaches to achieve therapeutic potential and to meet clinical expectations. Cell- and cell membrane-based NPs possess multifunctional abilities, which make them ideal in NP-based cancer therapies. Cell membrane-coated NP (CMCNPs) have been increasingly studied for their mimicry of cell surface functionality, which can aid in reducing the immune responses of synthetic NPs in vivo and introduce the ability to combine both natural and synthetic materials concisely as shown in Figure 1. Cell- and cell membrane-based drug carriers exhibiting intrinsic properties of in vivo biology have been shown to overcome the challenges faced by synthetic NP-based drug carriers and achieve acceptable toxicity and better biocompatibility than their synthetic counterparts[7-12]. Major advantages of using cell- and cell membrane-based drug carriers include provision of immune escape and specific tumor targeting imparted by the cell membrane proteins leading to improved EPR in cancer therapies, and an ability to generate desired cytotoxic immunomodulatory effects via cell surface engineering, leading to tumor regression[13-18]. Cancer is a complex disease involving various cells and their membrane interactions in the tumor microenvironment, such as immune suppression via PD-1/PD-L1 axis in T cells, recruitment of stem cells via membrane receptor-mediated CXCR4/CXCL2 chemokine axis, maturation of immune cells via membrane interactions, and various other chemical interactions, which uncover the potential of using cells in cell- and cell membrane-based drug delivery. Recently, discovered mechanisms of these interactions Yaman et al. Cancer Drug Resist 2020;3:879-911 I http://dx.doi.org/10.20517/cdr.2020.55 Page 881 Figure 1. Preparation of cell/cell membrane-based payload delivery and its applications. CRISPR: clustered regularly interspaced short palindromic repeats; Cas9: CRISPR associated protein 9; IPTG: isopropyl β-D-1-thiogalactopyranoside are being explored by NP technology to develop various treatment strategies[19-21]. Efficient navigation, while maintaining the integrity of the drug carrier and physiologically pertinent interactions within complex biological environments, can be achieved using cell membrane-coated NPs with a relatively higher circulation-time[22]. Accordingly, researchers in NP-based drug delivery have shifted their focus to the use of engineering cells and/or cell-derived sources for cancer therapies and immunomodulation, as shown in Figure 2. Bioengineered components including whole cells, cell membranes, and exosomes are being employed in anticancer or immunomodulating drugs[23] and vaccine-loaded carriers[24,25]. Cell- and/ or cell membrane-based NP drug delivery platforms can be applied in numerous ways to alter biological functions and pathways and be used in targeting and manipulating their destination to achieve desired therapeutic responses. Therefore, it is of critical importance to understand the cell membrane mechanisms involved in targeting, altering immune responses, and eliciting therapeutic outcomes. Along with recent cell- and cell membrane-based drug carriers in cancer and immunomodulation, we provide an up-to-date review of current and potential cell types and cell membrane receptors involved

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