Cancer is the leading cause of mortality worldwide and is generally attributed to limited treatment options. While nanotechnology is projected to revolutionize the treatment landscape, it comes with its own set of perils. As a viable solution, the advent of nanocarriers (NCs) has garnered the attention of researchers across the globe. However, conventional NCs are impeded by their lack of specificity and poor distribution properties. As a mitigation strategy, there has been a paradigm shift in the focus on cancer cell membrane-coated NCs (CCMCNCs), which ensure drug delivery directly to the tumor cells. Generally, CCMCNCs comprise active cancer cell surface adhesive molecules in combination with other functional proteins, which further ensure extended blood circulation, cell-specific targeting, higher tumor-specific accumulation, and enhanced intra-tumoral penetration. This article aims to explore the various facets of CCMCNCs while commenting on the utilities and future prospects of the same.
Introduction
Cancer is one of the deadliest diseases known to exist in humans and is undoubtedly the leading cause of mortality worldwide. The limited efficacy of the drug and the harmful side effects of conventional cancer therapy, such as surgical therapy, chemoradiotherapy, and immunotherapy, present a significant obstacle. This leads to the development of new technologies. A wide range of advancements in cancer treatment has been made possible by nanoparticle technology, from increased immunogenicity in cancer vaccines to more effective cancer drug delivery. Recently, taking advantage of our improved understanding of biological systems, there has been growing interest in the development of nanoparticles with novel and improved capabilities. Nanomedicine has developed a new technology based on nanoparticles for drug delivery coated with different cell membranes. Although they were initially developed to use red blood cell membranes to extend their blood circulation time and stability, their versatility has since expanded to membranes from other cell types, including white blood cells, platelets, and cancer cells, among others (Harris et al., 2019). Researchers have been able to improve synthetic components for specific applications by adding biomimetic aspects owing to the identification of unique membrane elements. For example, membrane-bound tumor antigens have been used to train the immune system to recognize and combat malignancies. In addition to improving their biocompatibility, the cell membrane-coated NPs also achieve efficient and prolonged in vivo circulation, enabling the execution of targeted functions.
Synthesis and Characterization
A straightforward process containing three main steps can be used to synthesize cancer cell membrane-coated nanocarriers (CCMCNCs) on a laboratory scale: (1) extraction of the source cell membrane; (2) the particle core is an anticancer treatment or theranostic which is integrated into the nanocarriers (NCs); (3) the membrane and the particle core fused together to create membrane-coated nanocarriers. Large amounts of cells from culture plates or blood and tissue samples must be taken for the membrane extraction method. Many other methods, such as freeze-thaw cycling, and osmosis-based lysis coupled with physical homogenization, have been used to carry out this operation. For freeze-thaw procedures, cells are repeatedly frozen at 80 °C and thawed either at 37 °C or room temperature. Due to the breaking of ice crystals during these cycles, cell membranes are damaged, causing the cytosol to be removed while the membranes are retained. Since the freeze processes may result in damage such as loss of membrane structure, decreased protein stability, subsequent protein unfolding, and reduced membrane function, this procedure is best suited for non-nucleated cells, such as RBCs or platelets. The most common technique for removing cancer cell membranes is mild hypotonic cell lysis via osmosis, followed by membrane disruption using a homogenizer (Bose et al., 2018). Membrane vesicles are produced by washing the membrane-rich fraction with isotonic buffers after multiple centrifugation stages to remove intracellular biomacromolecules, vesicles, and nuclei. To create vesicles of the right size, these vesicles can then be further fragmented or extruded through polycarbonate membranes. Compared to non-nucleated cells like red blood cells, cancer cells require gentler lysis conditions and faster ultracentrifugation speeds. Furthermore, a wide range of nanoparticle (NP) core designs may also be utilized to produce cell membrane-coated nanoparticles (CMCNPs), depending on the intended application where the key requirement is to achieve a negative zeta potential which will permit proper orientation of the membrane surrounding the NP. Although numerous synthetic NPs have been employed for cancer theranostics up to this point, Poly (lactic-co-glycolic acid) acid (PLGA) is one of the most widely used NP cores because of its biodegradability, FDA approval, and capacity to encapsulate a wide range of products. Metallic-based NPs are also frequently employed since they can assist with imaging and hence have several uses. Overall, while building CMCNPs, the composition of the nano vehicle core is crucial since it determines the release and efficacy once it has been directed to the desired cells by the membrane coating. Finally, extrusion or electrostatic attraction can be used to engineer the cell membrane's surface on the NCs. Microfluidics is a relatively new technique that enables membrane coating. RBC membranes have been effectively coated around magnetic NPs using this method, which combines electroporation with rapid mixing of NPs and membrane vesicles (Li et al., 2020). The physiochemical and biological properties of the resultant NP, however, could be greatly impacted by the several manual stages involved in laboratory-scale preparation techniques. Unfortunately, it is currently difficult to translate CCMCNCs into clinical use in a reproducible and scalable manner.
Applications
Effective cancer treatments continue to be a substantial issue despite tremendous advancements and developments in cancer nanomedicine. Since general nanoparticles have low bioavailability, homologous targeting, intra-tumoral penetration of NCs into the main tumor and NC proliferation have all been shown to be improved by cancer cell membrane-coating techniques, which have been proposed as a viable solution to this issue. In addition, CCMCNCs provide a useful strategy that may delay the premature release of medications into the bloodstream and increase tumor-specific accumulation, preventing adverse effects. The ability of nanoparticles to adapt to different membranes and their use for a range of purposes has been established by the use of the coating technique on several NC surfaces. Individual formulations can be altered and adapted to meet the unique requirements of cancer therapy. A novel approach to treating cancer is called theranostics, which integrates both diagnostic and therapeutic modalities based on nanotechnology. This combines techniques including positron emission tomography (PET), fluorescence imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PA), etc. into a single carrier to help control cancer. Theranostics has shown a multitude of benefits, including improved diagnosis, targeted drug administration to tumors, and lessened damage to healthy tissue (Jin &Bhujwalla, 2020). However, because of their surface characteristics, which are frequently detected and quickly eliminated by the body's immune cells, their biological applications have been restricted. Although it has been shown that RBC membrane coating increases circulation half-life, RBCs lack targeting molecules and therefore are unsuitable for tumor-specific targeting. CCMCNCs have been used as a potential remedy to improve circulation and target the effectiveness of cancer theranostics. Additionally, it has been demonstrated that co-delivery of anticancer medicines and diagnostics within CCMCNCs has promising synergistic anticancer effects.
In the area of immunotherapy, CCMCNCs have another potential. In the field of oncology, the use of technology to activate the immune system to fight tumor cells is gaining popularity. Both a cancer cure and a cancer vaccination can be achieved with immunotherapy. Due to its high specificity, low toxicity, and potential to stop the growth of many tumors, the immune system's inherent ability to recognize and destroy tumor cells is thought to be a significant advantage over cytotoxic medicines. Immunotherapies activate particular immune system cells or work against tumor-produced signals that inhibit immune responses. Extensive research is being done on immunotherapeutic approaches, including the use of oncolytic viruses, antibodies, or recombinant proteins that activate immune cells or block the immunological checkpoint pathway (Fang et al., 2014). Additionally, a new approach in the development of cancer vaccines is the use of nanovaccine platforms that replicate the essential characteristics of surface molecular structure and physiochemical properties, such as the size and shape of biological entities. This leads to the conclusion that the combination of synthetic NCs and CCMs has great potential for cancer immunotherapy.
Conclusion and future prospects
The main cancer applications that are emerging with this type of NPs include homologous targeting to deliver imaging and therapeutic substances, disrupting cancer cell-stromal cell interactions, and producing an immune response. Furthermore, for precision medicine, a range of different medicinal moieties can be incorporated into the NP-cores. In conclusion, they offer enormous promise as either therapeutic agents to treat tumors or vaccinations to protect patients from difficulties posed by tumor cells. However, techniques for manufacturing scale-up must be developed for CMCNPs to be effective in the clinic. Due to the complicated biological elements involved, particle replication on a small laboratory scale is already challenging, and issues with batch-to-batch uniformity need to be addressed. Another issue, in addition to producing the required amount of membrane material, is scaling up the NP cores, particularly if the design is more intricate or involves a multi-component system. However, the possibility of eliminating even one type of cancer, whether through therapy or vaccination, will continue to motivate the various lines of research in CCMCNCs, despite the challenges involved.
References
Bose, R. J., Paulmurugan, R., Moon, J., Lee, S. H., & Park, H. (2018). Cell membrane-coated nanocarriers: the emerging targeted delivery system for cancer theranostics. In Drug Discovery Today (Vol. 23, Issue 4). https://doi.org/10.1016/j.drudis.2018.02.001
Fang, R. H., Hu, C. M. J., Luk, B. T., Gao, W., Copp, J. A., Tai, Y., O’Connor, D. E., & Zhang, L. (2014). Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery. Nano Letters, 14(4). https://doi.org/10.1021/nl500618u
Harris, J. C., Scully, M. A., & Day, E. S. (2019). Cancer cell membrane-coated nanoparticles for cancer management. Cancers, 11(12). https://doi.org/10.3390/cancers11121836
Jin, J., &Bhujwalla, Z. M. (2020). Biomimetic Nanoparticles Camouflaged in Cancer Cell Membranes and Their Applications in Cancer Theranostics. Frontiers in Oncology, 9. https://doi.org/10.3389/fonc.2019.01560
Li, T., Qin, X., Li, Y., Shen, X., Li, S., Yang, H., Wu, C., Zheng, C., Zhu, J., You, F., & Liu, Y. (2020). Cell Membrane Coated-Biomimetic Nanoplatforms toward Cancer Theranostics. In Frontiers in Bioengineering and Biotechnology (Vol. 8). https://doi.org/10.3389/fbioe.2020.00371
Gargi Digholkar is associated with Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University. Her research interests include toxicology, nanomedicine, novel drug delivery systems, and bioinformatics. She has worked on a spectrum of topics including artificial intelligence, drug repurposing and delivery in Alzheimer's disease, cancer therapeutics, and nanotechnology. She is keenly driven by experience and her sheer interest to pursue a career in pharmaceutical sciences.
Jainam Karsiya is a clinical pharmacist and medical affairs executive associated with River Route Creative Group, India. His domain of work expands across the length and breadth of oncology, ranging from drug delivery and clinical therapeutics to precision oncology. He has prior experience in nanotechnology, theranostics, and health outcomes research. He has also contributed to the drafting of public policies in the healthcare sector.
Dileep Kumar is an assistant professor in the Department of Pharmaceutical Chemistry at Poona College of Pharmacy. He is a pioneer in his field with his forte in the treatment and novel drug delivery in Cancer and Alzheimer’s disease, especially adamantylanalogs as GluN2B selective NMDA receptor agonists. He is also an awardee of the Junior Research Fellowship from the National Medicinal Plant Board (NMPB) New Delhi, Senior Research Fellowship from the University Grants Commission (UGC), Teaching Assistantship, and Institute Post-Doctoral Fellowship from IIT (BHU) Varanasi. He is the Guest Editor of Prestigious journals like Current Topics in Medicinal Chemistry, CTMC, Current drug target, combinatorial chemistry, and molecules.
Ryan Varghese is a researcher affiliated with the Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, and Philadelphia, USA. His work spans a spectrum of topics from artificial intelligence to cancer theranostics and drug delivery in Alzheimer's disease. His specialization lies in the drug delivery modalities in chronic diseases. He has curated several articles on the lacunae in the Government’s public policies while providing solutions for the same. His recent work included the proposal on drug repurposing and affordable hospitalization to mitigate the risk stemming from COVID-19 in India. His current line of work lies in the efficient diagnosis and treatment of various cancers.
