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Overcoming transport barrier to immunotherapies
Katharina Maisel
doi : 10.1007/s13346-021-01080-8
Drug Delivery and Translational Research volume 11, pages2271–2272 (2021)
Overcoming transport barriers to immunotherapy
Shann S. Yu, Jeffrey A. Hubbell & Melody A. Swartz
doi : 10.1007/s13346-021-01084-4
Drug Delivery and Translational Research volume 11, pages2273–2275 (2021)
Immunotherapies are designed to treat disease by modulating the activity of immune cells. Here, we consider how anatomy and microphysiology create transport barriers to immunotherapeutic delivery and retention at diseased sites, and summarize recent developments to overcome these barriers by exploiting immunobiology to engineer molecular and cellular engineering approaches. Creating impactful and practical solutions across these diseases requires the integration of the collective expertise of pathologists, clinicians, immunologists, biophysicists, immunoengineers, and more.
Overcoming biological barriers to improve solid tumor immunotherapy
Anvay Ukidve, Katharina Cu, Ninad Kumbhojkar, Joerg Lahann & Samir Mitragotri
doi : 10.1007/s13346-021-00923-8
Drug Delivery and Translational Research volume 11, pages2276–2301 (2021)
Cancer immunotherapy has been at the forefront of therapeutic interventions for many different tumor types over the last decade. While the discovery of immunotherapeutics continues to occur at an accelerated rate, their translation is often hindered by a lack of strategies to deliver them specifically into solid tumors. Accordingly, significant scientific efforts have been dedicated to understanding the underlying mechanisms that govern their delivery into tumors and the subsequent immune modulation. In this review, we aim to summarize the efforts focused on overcoming tumor-associated biological barriers and enhancing the potency of immunotherapy. We summarize the current understanding of biological barriers that limit the entry of intravascularly administered immunotherapies into the tumors, in vitro techniques developed to investigate the underlying transport processes, and delivery strategies developed to overcome the barriers. Overall, we aim to provide the reader with a framework that guides the rational development of technologies for improved solid tumor immunotherapy.
Overcoming delivery barriers in immunotherapy for glioblastoma
Yuan Rui & Jordan J. Green
doi : 10.1007/s13346-021-01008-2
Drug Delivery and Translational Research volume 11, pages2302–2316 (2021)
Glioblastoma is one of the deadliest forms of primary adult tumors, with median survival of 14.6 months post-diagnosis despite aggressive standard of care treatment. This grim prognosis for glioblastoma patients has changed little in the past two decades, necessitating novel treatment modalities. One potential treatment modality is cancer immunotherapy, which has shown remarkable progress in slowing disease progression or even potentially curing certain solid tumors. However, the transport barriers posed by the blood–brain barrier and the immune privileged status of the central nervous system pose drug delivery obstacles that are unique to brain tumors. In this review, we provide an overview of the various physiological, immunological, and drug delivery barriers that must be overcome for effective glioblastoma treatment. We discuss chemical modification strategies to enable nanomedicines to bypass the blood–brain barrier and reach intracranial tumors. Finally, we highlight recent advances in biomaterial-based strategies for cancer immunotherapy that can be adapted to glioblastoma treatment.
Rational combination of an immune checkpoint inhibitor with CSF1R inhibitor–loaded nanoparticle enhances anticancer efficacy
Anujan Ramesh, Vaishali Malik, Hayat Anu Ranjani, Harriet Smith & Ashish A. Kulkarni
doi : 10.1007/s13346-021-01040-2
Drug Delivery and Translational Research volume 11, pages2317–2327 (2021)
Since the advent of immune checkpoint inhibitors, rapid strides have been made in the realm of cancer immunotherapy. Of the abundance of infiltrating immune cells in the tumor microenvironment (TME), macrophages contribute a significant portion and make up to 50% of the tumor mass. In addition to this, the relative plasticity of macrophages makes it an attractive target to modulate macrophage functions to initiate an anti-tumor response. However, many challenges hinder this strategy. Macrophage colony-stimulating factor (MCSF) secreted by cancer cells binds to the colony-stimulating factor receptor present on macrophages and negatively influences macrophage functions. MCSF, along with a cocktail of immunosuppressive cytokines present in the TME, polarizes macrophages to an immunosuppressive pro-tumorigenic M2-like phenotype. M2-like macrophages dampen tumor response and are known to be associated with increased tumor progression and metastasis. Indeed, clinical interventions aimed to reprogram macrophage response from an M2-like tumor aiding phenotype to an M1-like tumor-killing phenotype using small-molecule inhibitors of the CSF1R axis have gathered much attention in the recent past. However, poor response and systemic toxicities observed in these therapies necessitate alternative therapeutic strategies. Furthermore, another key signaling pathway that has been recently implicated in aiding the CSF1R signaling in TAMs is the PDL1 signaling axis. Hence, in this study, we designed a self-assembled lipid nanoparticle system encompassing a potent small-molecule inhibitor of the CSF1R signaling axis, while the surface of the nanoparticle was tethered with anti-PDL1 mAb. The purpose of this is twofold; the nanoparticles can deliver the cargo in a targeted manner to PDL1 expressing M2-like macrophages while simultaneously blocking the receptor. The resulting nanoparticle system termed ?-PDL1-CSF-LNP showed enhanced repolarization of M2 like macrophages in vitro while also upregulating the phagocytic index. Furthermore, suboptimal dose administration of ?-PDL1-CSF-LNP in an aggressive melanoma mouse model resulted in superior anti-tumor efficacy with minimal toxicities. These results were validated by ex vivo mechanistic analysis showing that TAMs have successfully been repolarized to a predominantly M1-like phenotype. This, along with increased tumor infiltration of CD8+ T cells, worked in synergy to provide an effective anti-tumor strategy.
Quantitation of lymphatic transport mechanism and barrier influences on lymph node-resident leukocyte access to lymph-borne macromolecules and drug delivery systems
Paul A. Archer, Lauren F. Sestito, Margaret P. Manspeaker, Meghan J. O’Melia, Nathan A. Rohner, Alex Schudel, Yajun Mei & Susan N. Thomas
doi : 10.1007/s13346-021-01015-3
Drug Delivery and Translational Research volume 11, pages2328–2343 (2021)
Lymph nodes (LNs) are tissues of the immune system that house leukocytes, making them targets of interest for a variety of therapeutic immunomodulation applications. However, achieving accumulation of a therapeutic in the LN does not guarantee equal access to all leukocyte subsets. LNs are structured to enable sampling of lymph draining from peripheral tissues in a highly spatiotemporally regulated fashion in order to facilitate optimal adaptive immune responses. This structure results in restricted nanoscale drug delivery carrier access to specific leukocyte targets within the LN parenchyma. Herein, a framework is presented to assess the manner in which lymph-derived macromolecules and particles are sampled in the LN to reveal new insights into how therapeutic strategies or drug delivery systems may be designed to improve access to dLN-resident leukocytes. This summary analysis of previous reports from our group assesses model nanoscale fluorescent tracer association with various leukocyte populations across relevant time periods post administration, studies the effects of bioactive molecule NO on access of lymph-borne solutes to dLN leukocytes, and illustrates the benefits to leukocyte access afforded by lymphatic-targeted multistage drug delivery systems. Results reveal trends consistent with the consensus view of how lymph is sampled by LN leukocytes resulting from tissue structural barriers that regulate inter-LN transport and demonstrate how novel, engineered delivery systems may be designed to overcome these barriers to unlock the therapeutic potential of LN-resident cells as drug delivery targets.
Harnessing nanomedicine for enhanced immunotherapy for breast cancer brain metastases
Christine P. Carney, Nikhil Pandey, Anshika Kapur, Graeme F. Woodworth, Jeffrey A. Winkles & Anthony J. Kim
doi : 10.1007/s13346-021-01039-9
Drug Delivery and Translational Research volume 11, pages2344–2370 (2021)
Brain metastases (BMs) are the most common type of brain tumor, and the incidence among breast cancer (BC) patients has been steadily increasing over the past two decades. Indeed,?~?30% of all patients with metastatic BC will develop BMs, and due to few effective treatments, many will succumb to the disease within a year. Historically, patients with BMs have been largely excluded from clinical trials investigating systemic therapies including immunotherapies (ITs) due to limited brain penetration of systemically administered drugs combined with previous assumptions that BMs are poorly immunogenic. It is now understood that the central nervous system (CNS) is an immunologically distinct site and there is increasing evidence that enhancing immune responses to BCBMs will improve patient outcomes and the efficacy of current treatment regimens. Progress in IT for BCBMs, however, has been slow due to several intrinsic limitations to drug delivery within the brain, substantial safety concerns, and few known targets for BCBM IT. Emerging studies demonstrate that nanomedicine may be a powerful approach to overcome such limitations, and has the potential to greatly improve IT strategies for BMs specifically. This review summarizes the evidence for IT as an effective strategy for BCBM treatment and focuses on the nanotherapeutic strategies currently being explored for BCBMs including targeting the blood–brain/tumor barrier (BBB/BTB), tumor cells, and tumor-supporting immune cells for concentrated drug release within BCBMs, as well as use of nanoparticles (NPs) for delivering immunomodulatory agents, for inducing immunogenic cell death, or for potentiating anti-tumor T cell responses.
Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis
Allen B. Tu & Jamal S. Lewis
doi : 10.1007/s13346-021-01038-w
Drug Delivery and Translational Research volume 11, pages2371–2393 (2021)
Rheumatoid arthritis (RA) is an extremely painful autoimmune disease characterized by chronic joint inflammation leading to the erosion of adjacent cartilage and bone. Rheumatoid arthritis pathology is primarily driven by inappropriate infiltration and activation of immune cells within the synovium of the joint. There is no cure for RA. As such, manifestation of symptoms entails lifelong management via various therapies that aim to generally dampen the immune system or impede the function of immune mediators. However, these treatment strategies lead to adverse effects such as toxicity, general immunosuppression, and increased risk of infection. In pursuit of safer and more efficacious therapies, many emerging biomaterial-based strategies are being developed to improve payload delivery, specific targeting, and dose efficacy, and to mitigate adverse reactions and toxicity. In this review, we highlight biomaterial-based approaches that are currently under investigation to circumvent the limitations of conventional RA treatments.
Targeting the extracellular matrix for immunomodulation: applications in drug delivery and cell therapies
Samira Aghlara-Fotovat, Amanda Nash, Boram Kim, Robert Krencik & Omid Veiseh
doi : 10.1007/s13346-021-01018-0
Drug Delivery and Translational Research volume 11, pages2394–2413 (2021)
Host immune cells interact bi-directionally with their extracellular matrix (ECM) to receive and deposit molecular signals, which orchestrate cellular activation, proliferation, differentiation, and function to maintain healthy tissue homeostasis. In response to pathogens or damage, immune cells infiltrate diseased sites and synthesize critical ECM molecules such as glycoproteins, proteoglycans, and glycosaminoglycans to promote healing. When the immune system misidentifies pathogens or fails to survey damaged cells effectively, maladies such as chronic inflammation, autoimmune diseases, and cancer can develop. In these conditions, it is essential to restore balance to the body through modulation of the immune system and the ECM. This review details the components of dysregulated ECM implicated in pathogenic environments and therapeutic approaches to restore tissue homeostasis. We evaluate emerging strategies to overcome inflamed, immune inhibitory, and otherwise diseased microenvironments, including mechanical stimulation, targeted proteases, adoptive cell therapy, mechanomedicine, and biomaterial-based cell therapeutics. We highlight various strategies that have produced efficacious responses in both pre-clinical and human trials and identify additional opportunities to develop next-generation interventions. Significantly, we identify a need for therapies to address dense or fibrotic tissue for the treatment of organ tissue damage and various cancer subtypes. Finally, we conclude that therapeutic techniques that disrupt, evade, or specifically target the pathogenic microenvironment have a high potential for improving therapeutic outcomes and should be considered a priority for immediate exploration.
Microfluidic systems to study tissue barriers to immunotherapy
Ann Ramirez, Mayowa Amosu, Priscilla Lee & Katharina Maisel
doi : 10.1007/s13346-021-01016-2
Drug Delivery and Translational Research volume 11, pages2414–2429 (2021)
Immunotherapies have been heavily explored in the last decade, ranging from new treatments for cancer to allergic diseases. These therapies target the immune system, a complex organ system consisting of tissues with intricate structures and cells with a multitude of functions. To better understand immune functions and develop better therapeutics, many cellular and 2-dimensional (2D) tissue models have been developed. However, research has demonstrated that the 3-dimensional (3D) tissue structure can significantly affect cellular functions, and this is not recapitulated by more traditional 2D models. Microfluidics has been used to design 3D tissue models that allow for intricate arrangements of cells and extracellular spaces, thus allowing for more physiologically relevant in vitro model systems. Here, we summarize the multitude of microfluidic devices designed to study the immune system with the ultimate goal to improve existing and design new immunotherapies. We have included models of the different immune organs, including bone marrow and lymph node (LN), models of immunity in diseases such as cancer and inflammatory bowel disease, and therapeutic models to test or engineer new immune-modulatory treatments. We particularly emphasize research on how microfluidic devices are used to better understand different physiological states and how interactions within the immune microenvironment can influence the efficacy of immunotherapies.
Overcoming physical stromal barriers to cancer immunotherapy
Seung Woo Chung, Yunxuan Xie & Jung Soo Suk
doi : 10.1007/s13346-021-01036-y
Drug Delivery and Translational Research volume 11, pages2430–2447 (2021)
Immunotherapy has emerged as an unprecedented hope for the treatment of notoriously refractory cancers. Numerous investigational drugs and immunotherapy-including combination regimens are under preclinical and clinical investigation. However, only a small patient subpopulation across different types of cancer responds to the therapy due to the presence of several mechanisms of resistance. There have been extensive efforts to overcome this limitation and to expand the patient population that could be benefited by this state-of-the-art therapeutic modality. Among various causes of the resistance, we here focus on physical stromal barriers that impede the access of immunotherapeutic drug molecules and/or native and engineered immune cells to cancer tissues and cells. Two primary stromal barriers that contribute to the resistance include aberrant tumor vasculatures and excessive extracellular matrix build-ups that restrict extravasation and infiltration, respectively, of molecular and cellular immunotherapeutic agents into tumor tissues. Here, we review the features of these barriers that limit the efficacy of immunotherapy and discuss recent advances that could potentially help immunotherapy overcome the barriers and improve therapeutic outcomes.
Delivery strategies for cell-based therapies in the brain: overcoming multiple barriers
Olivia M. Turk, Ryan C. Woodall, Margarita Gutova, Christine E. Brown, Russell C. Rockne & Jennifer M. Munson
doi : 10.1007/s13346-021-01079-1
Drug Delivery and Translational Research volume 11, pages2448–2467 (2021)
Cell-based therapies to the brain are promising for the treatment of multiple brain disorders including neurodegeneration and cancers. In order to access the brain parenchyma, there are multiple physiological barriers that must be overcome depending on the route of delivery. Specifically, the blood–brain barrier has been a major difficulty in drug delivery for decades, and it still presents a challenge for the delivery of therapeutic cells. Other barriers, including the blood-cerebrospinal fluid barrier and lymphatic-brain barrier, are less explored, but may offer specific challenges or opportunities for therapeutic delivery. Here we discuss the barriers to the brain and the strategies currently in place to deliver cell-based therapies, including engineered T cells, dendritic cells, and stem cells, to treat diseases. With a particular focus on cancers, we also highlight the current ongoing clinical trials that use cell-based therapies to treat disease, many of which show promise at treating some of the deadliest illnesses.
Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways
Sean T. Carey, Joshua M. Gammon & Christopher M. Jewell
doi : 10.1007/s13346-021-01075-5
Drug Delivery and Translational Research volume 11, pages2468–2481 (2021)
Autoimmune diseases—where the immune system mistakenly targets self-tissue—remain hindered by non-specific therapies. For example, even molecularly specific monoclonal antibodies fail to distinguish between healthy cells and self-reactive cells. An experimental therapeutic approach involves delivery of self-molecules targeted by autoimmunity, along with immune modulatory signals to produce regulatory T cells (TREG) that selectively stop attack of host tissue. Much has been done to increase the efficiency of signal delivery using biomaterials, including encapsulation in polymer microparticles (MPs) to allow for co-delivery and cargo protection. However, less research has compared particles encapsulating drugs that target different TREG inducing pathways. In this paper, we use poly (lactic-co-glycolide) (PLGA) to co-encapsulate type 1 diabetes (T1D)-relevant antigen and 3 distinct TREG-inducing molecules — rapamycin (Rapa), all-trans retinoic acid (atRA), and butyrate (Buty) — that target the mechanistic target of Rapa (mTOR), the retinoid pathway, and histone deacetylase (HDAC) inhibition, respectively. We show all formulations are effectively taken up by antigen presenting cells (APCs) and that antigen-containing formulations are able to induce proliferation in antigen-specific T cells. Further, atRA and Rapa MP formulations co-loaded with antigen decrease APC activation levels, induce TREG differentiation, and reduce inflammatory cytokines in pancreatic-reactive T cells.
Modeled vascular microenvironments: immune-endothelial cell interactions in vitro
Justin Silberman, Aakanksha Jha, Holly Ryan, Talia Abbate & Erika Moore
doi : 10.1007/s13346-021-00970-1
Drug Delivery and Translational Research volume 11, pages2482–2495 (2021)
The advancement of in vitro techniques enables a better understanding of biological processes and improves drug screening platforms. In vitro studies allow for enhanced observation of cell behavior, control over the mimicked microenvironment, and the ability to use human cells. In particular, advances in vascular microenvironment recapitulation are of interest given vasculature influence in cardiovascular vascular diseases and cancer. These investigate alterations in endothelial cell behavior and immune cell interactions with endothelial cells. Specific immune cells such as monocytes, macrophages, neutrophils, and T cells influence endothelial cell behavior by promoting or inhibiting vasculogenesis through cell-cell interaction or soluble signaling. Results from these studies showcase cell behavior in vascular diseases and in the context of tumor metastasis. In this review, we discuss examples of in vitro studies modeling immune cell-endothelial cell interactions to present methods and recent findings in the field.
Synergistic and receptor-mediated targeting of arthritic joints via intra-articular injectable smart hydrogels containing leflunomide-loaded lipid nanocarriers
Mariam Zewail, Noha Nafee, Maged W. Helmy & Nabila Boraie
doi : 10.1007/s13346-021-00992-9
Drug Delivery and Translational Research volume 11, pages2496–2519 (2021)
Intra-articular drug delivery represents a tempting strategy for local treatment of rheumatoid arthritis. Targeting drugs to inflamed joints bypasses systemic-related side effects. Albeit, rapid drug clearance and short joint residence limit intra-articular administration. Herein, injectable smart hydrogels comprising free/nanoencapsulated leflunomide (LEF) were developed. Nanostructured lipid carriers (NLCs), 200–300 nm, were coated with either chondroitin sulfate (CHS), hyaluronic acid (HA), or chitosan (CS) to provide joint targetability. Coated NLCs were incorporated in either hyaluronic/pluronic (HP) or chitosan/?-glycerophosphate (CS/?GP) hydrogels. Optimized systems ensured convenient gelation time (14–100 s), injectability (5–15 s), formulation-dependent mechanical strength, and extended LEF release up to 51 days. In vivo intra-articular injection in induced arthritis rat model revealed that rats treated with HA-coated NLCs showed the fastest recovery. Histopathological examination demonstrated perfect joint healing in case of HA-coated LEF-NLCs in CS/?GP thermogel manifested as minor erosion of subchondral bone, improved intensity of extracellular matrix, cartilage thickness, and chondrocyte number. Both HA- and CHS-coated NLCs reduced TNF-? level 4–5-fold relative to positive control. The feat would be achieved via active targeting to CD44 receptors overexpressed in the articular tissue, limiting chondrocyte apoptosis together with innate synergistic targetability by promoting chondrocyte proliferation and neovascularization, inhibiting the production of pro-inflammatory cytokines, thus enhancing cartilaginous tissue repair.
Nanomedicine-based combination of dexamethasone palmitate and MCL-1 siRNA for synergistic therapeutic efficacy against rheumatoid arthritis
Yanmei Li, Shitong Wei, Yonghua Sun, Shihua Zong & Yameng Sui
doi : 10.1007/s13346-021-01037-x
Drug Delivery and Translational Research volume 11, pages2520–2529 (2021)
The main aim of this research was to design a MCL-1 siRNA and dexamethasone (DEX)-loaded folate modified poly(lactide-co-glycolide) (PLGA)-based polymeric micelles with an eventual goal to improve the therapeutic outcome in the rheumatoid arthritis (RA). Polymeric micelles encapsulating the MCL-1 siRNA and DEX was successfully developed and observed to be stable. Physicochemical characteristics such as particle size and particle morphology were ideal for the systemic administration. Folate-conjugated DEX/siRNA-loaded polymeric micelles (DS-FPM) significantly lowered the MCL-1 mRNA expression compared to either DEX/siRNA-loaded polymeric micelles (DS-PM) or free siRNA in Raw264.7 cells and macrophage cells suggesting the importance of targeted nanocarriers. Most importantly, DS-FPM exhibited a greatest decrease in the hind paw volume with lowest clinical score compared to any other treated group indicating a superior anti-inflammatory activity. DS-FPM showed significantly lower levels of the TNF-? and IL-1? compared to AIA model and free groups. The folate receptor (FR)-targeting property of DS-FPM has been demonstrated to be a promising delivery platform for the effective delivery of combination therapeutics (siRNA and DEX) toward the treatment of rheumatoid arthritis.
