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1.
Nat Rev Clin Oncol ; 21(6): 407-427, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38589512

ABSTRACT

The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours.


Subject(s)
Neoplasms , Nucleic Acids , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/therapy , Nucleic Acids/therapeutic use , Tumor Microenvironment/drug effects , Genetic Therapy/methods , Nanoparticles/therapeutic use , Antineoplastic Agents/therapeutic use , Drug Delivery Systems/methods
2.
Proc Natl Acad Sci U S A ; 121(11): e2307801120, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38437539

ABSTRACT

Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.


Subject(s)
Liver , Stem Cells , Heart , Cations , Cholesterol , RNA, Messenger
3.
Adv Healthc Mater ; : e2304033, 2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38318754

ABSTRACT

Poly(ethylene glycol) (PEG)-lipids are used in Food-and-Drug-Administration-approved lipid nanoparticle (LNP)-RNA drugs, which are safe and effective. However, it is reported that PEG-lipids may also contribute to accelerated blood clearance and rare cases of hypersensitivity; this highlights the utility of exploring PEG-lipid alternatives. Here, it is shown that LNPs containing poly(2-ethyl-2-oxazoline) (PEOZ)-lipids can deliver messenger RNA (mRNA) to multiple cell types in mice inside and outside the liver. In addition, it is reported that LNPs formulated with PEOZ-lipids show reduced clearance from the bloodstream and lower levels of antistealth lipid immunoglobulin Ms than LNPs formulated with PEG-lipids. These data justify further exploration of PEOZ-lipids as alternatives to PEG-lipids in LNP-RNA formulations.

4.
J Control Release ; 357: 394-403, 2023 05.
Article in English | MEDLINE | ID: mdl-37028451

ABSTRACT

Lipid nanoparticles (LNPs) are a clinically relevant way to deliver therapeutic mRNA to hepatocytes in patients. However, LNP-mRNA delivery to end-stage solid tumors such as head and neck squamous cell carcinoma (HNSCC) remains more challenging. While scientists have used in vitro assays to evaluate potential nanoparticles for HNSCC delivery, high-throughput delivery assays performed directly in vivo have not been reported. Here we use a high-throughput LNP assay to evaluate how 94 chemically distinct nanoparticles delivered nucleic acids to HNSCC solid tumors in vivo. DNA barcodes were used to identify LNPHNSCC, a novel LNP for systemic delivery to HNSCC solid tumors. Importantly, LNPHNSCC retains tropism to HNSCC solid tumors while minimizing off-target delivery to the liver.


Subject(s)
Head and Neck Neoplasms , Nanoparticles , Humans , Squamous Cell Carcinoma of Head and Neck , RNA, Messenger/genetics , Lipids , Head and Neck Neoplasms/genetics , RNA, Small Interfering/genetics
5.
Nat Chem ; 15(4): 508-515, 2023 04.
Article in English | MEDLINE | ID: mdl-36864143

ABSTRACT

Stereochemistry can alter small-molecule pharmacokinetics, safety and efficacy. However, it is unclear whether the stereochemistry of a single compound within a multicomponent colloid such as a lipid nanoparticle (LNP) can influence its activity in vivo. Here we report that LNPs containing stereopure 20α-hydroxycholesterol (20α) delivered mRNA to liver cells up to 3-fold more potently than LNPs containing a mixture of both 20α- and 20ß-hydroxycholesterols (20mix). This effect was not driven by LNP physiochemical traits. Instead, in vivo single-cell RNA sequencing and imaging revealed that 20mix LNPs were sorted into phagocytic pathways more than 20α LNPs, resulting in key differences between LNP biodistribution and subsequent LNP functional delivery. These data are consistent with the fact that nanoparticle biodistribution is necessary, but not sufficient, for mRNA delivery, and that stereochemistry-dependent interactions between LNPs and target cells can improve mRNA delivery.


Subject(s)
Lipids , Nanoparticles , Lipids/chemistry , RNA, Messenger/genetics , Tissue Distribution , Nanoparticles/chemistry
6.
Nano Lett ; 23(3): 993-1002, 2023 02 08.
Article in English | MEDLINE | ID: mdl-36701517

ABSTRACT

Lipid nanoparticles (LNPs) have delivered RNA to hepatocytes in patients, underscoring the potential impact of nonliver delivery. Scientists can shift LNP tropism to the lung by adding cationic helper lipids; however, the biological response to these LNPs remains understudied. To evaluate the hypothesis that charged LNPs lead to differential cellular responses, we quantified how 137 LNPs delivered mRNA to 19 cell types in vivo. Consistent with previous studies, we observed helper lipid-dependent tropism. After identifying and individually characterizing three LNPs that targeted different tissues, we studied the in vivo transcriptomic response to these using single-cell RNA sequencing. Out of 835 potential pathways, 27 were upregulated in the lung, and of these 27, 19 were related to either RNA or protein metabolism. These data suggest that endogenous cellular RNA and protein machinery affects mRNA delivery to the lung in vivo.


Subject(s)
Lipids , Nanoparticles , Humans , Liposomes/metabolism , Hepatocytes/metabolism , RNA, Messenger/genetics , RNA, Small Interfering
7.
J Control Release ; 353: 270-277, 2023 01.
Article in English | MEDLINE | ID: mdl-36423872

ABSTRACT

Lipid nanoparticles (LNPs) have delivered siRNA and mRNA drugs in humans, underscoring the potential impact of improving the therapeutic window of next-generation LNPs. To increase the LNP therapeutic window, we applied lessons from small-molecule chemistry to ionizable lipid design. Specifically, given that stereochemistry often influences small-molecule safety and pharmacokinetics, we hypothesized that the stereochemistry of lipids within an LNP would influence mRNA delivery. We tested this hypothesis in vivo using 128 novel LNPs that included stereopure derivatives of C12-200, an ionizable lipid that when formulated into LNPs delivers RNA in mice and non-human primates but is not used clinically due to its poor tolerability. We found that a novel C12-200-S LNP delivered up to 2.8-fold and 6.1-fold more mRNA in vivo than its racemic and C12-200-R controls, respectively. To identify the potential causes leading to increased delivery, we quantified LNP biophysical traits and concluded that these did not change with stereochemistry. Instead, we found that stereopure LNPs were better tolerated than racemic LNPs in vivo. These data suggest that LNP-mediated mRNA delivery can be improved by designing LNPs to include stereopure ionizable lipids.


Subject(s)
Lipids , Nanoparticles , Mice , Animals , Lipids/chemistry , RNA, Messenger/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/chemistry , Nanoparticles/chemistry , RNA, Double-Stranded
8.
Int J Pharm ; 605: 120812, 2021 Aug 10.
Article in English | MEDLINE | ID: mdl-34144136

ABSTRACT

Cancer immunotherapy aims to stimulate immune cells to recognize and attack tumor tissue. The immunostimulatory polyanions polyI:C and CpG induce potent pro-inflammatory immune responses as TLR3 and TLR9 agonists, respectively. Clinical trials of TLR agonists, however, have been fraught with immune-related adverse events, even when injecting intratumorally in an effort to minimize systemic exposure. We identified Glatiramer Acetate (GA), a positively-charged polypeptide approved for multiple sclerosis, as a delivery agent capable of complexing with polyI:C or CpG and reducing the mobility of these actives. Small nanoparticles termed polyplexes form when mixing positively-charged GA and negatively-charged immunostimulant (polyI:C or CpG). The ratio of GA to immunostimulant directly affected the potency of TLR activation and the mobility of these actives in simulated tumor tissue. Polyplexes of GA and CpG were injected intratumorally in a tumor model of head and neck cancer (HNC) and significantly mitigated tumor growth as compared to the vehicle controls. Intratumoral injections of CpG showed the slowest tumor growth but exhibited dramatically higher systemic proinflammatory cytokine levels compared to polyplexes of GA with CpG. Sequencing of RNA from resected tumors revealed a similar pattern of upregulated proinflammatory cytokines for CpG and polyplexes, a finding supported by histological tumor staining showing similar infiltration of immune cells induced by these treatments. Intratumoral administration of polyplexes of GA with immunostimulant represents a translational approach to enhance local immune responses while mitigating systemic immune-related adverse events.


Subject(s)
Nanoparticles , Neoplasms , Adjuvants, Immunologic , Glatiramer Acetate , Humans , Immunotherapy , Neoplasms/drug therapy , Oligodeoxyribonucleotides
9.
ACS Appl Bio Mater ; 4(1): 387-391, 2021 01 18.
Article in English | MEDLINE | ID: mdl-35014289

ABSTRACT

Multiple sclerosis is complex and heterogeneous. Better tools are needed to be able to monitor this disease among individuals, but blood-based biomarkers are often too rare to profile. In this work, we developed antigen-specific biomaterials to replicate the central nervous system niche where multiple sclerosis biomarkers are amplified. We incorporated mouse brain homogenate into a microporous gelatin methacrylate network. Homogenate-containing biomaterials differentially stimulated cells and led to the marked amplification of disease-relevant, antigen-specific B cells. These results demonstrate that biomaterials containing primary tissue homogenate retain antigen specificity and may be a useful tool for decoding human autoimmunity.


Subject(s)
Antigens/metabolism , Biocompatible Materials/chemistry , Brain/metabolism , Animals , Antigens/chemistry , Autoimmunity , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B7-2 Antigen/metabolism , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Gelatin/chemistry , Mice , Myelin Proteolipid Protein/chemistry , Myelin Proteolipid Protein/immunology , Myelin Proteolipid Protein/metabolism , Peptide Fragments/chemistry , Peptide Fragments/immunology , Peptide Fragments/metabolism , Spleen/cytology , Spleen/metabolism
10.
Adv Mater Technol ; 6(6)2021 Jun.
Article in English | MEDLINE | ID: mdl-36304209

ABSTRACT

The capacity for a soft material to combine remote sensing and remote actuation is highly desirable for many applications in soft robotics and wearable technologies. This work presents a silicone elastomer with a suspension of a small weight fraction of ferromagnetic nickel nanorods, which is capable of both sensing deformation and altering stiffness in the presence of an external magnetic field. Cylinders composed of silicone elastomer and 1% by weight nickel nanorods experience large increases in compressive modulus when exposed to an external magnetic field. Incremental compressions totaling 600 g of force applied to the same silicone-nanorod composites increase the magnetic field strength measured by a Hall effect sensor enabling the material to be used as a soft load cell capable of detecting the rate, duration, and magnitude of force applied. In addition, lattice structures are 3D printed using an ink composed of silicone elastomer and 1% by weight nickel nanorods, which possess the same sensing capacity.

11.
Macromol Biosci ; 20(12): e2000251, 2020 12.
Article in English | MEDLINE | ID: mdl-32924274

ABSTRACT

Designing an in vitro model of the tumor extracellular microenvironment to screen intratumoral drugs is an active challenge. As recent clinical successes of human intratumoral therapies stimulate research on intratumoral delivery, a need for a 3D tumor model to screen intratumoral therapies arises. When injecting the drug formulation directly into the tumor, the biophysics affecting intratumoral retention must be considered; especially for biologic therapies, which may be dominated by extracellular transport mechanisms. Fibrotic regions in solid tumors are typically rich in collagen I fibers. Using shear rheology, head and neck tumors with higher collagen density show a higher stiffness. Similarly, the stiffness of the hyaluronic acid (HA) hydrogel models is increased by adding collagen fibers to model the bulk biomechanical properties of solid tumors. HA hydrogels are then used as intratumoral injection site simulators to model in vitro the retention of glatiramer acetate (GA) and polyethylene glycol (PEG) administered intratumorally. Both compounds are also injected in murine tumors and retention is studied ex vivo for comparison. Retention of GA in the hydrogels is significantly longer than PEG, analogous to the solid tumors, suggesting the utility of HA hydrogels with collagen I fibers for screening extracellular drug transport after intratumoral administration.


Subject(s)
Biocompatible Materials/pharmacology , Drug Delivery Systems , Head and Neck Neoplasms/drug therapy , Hydrogels/pharmacology , Animals , Biocompatible Materials/metabolism , Cell Line, Tumor , Drug Carriers/chemistry , Drug Carriers/pharmacology , Drug Compounding , Glatiramer Acetate/chemistry , Head and Neck Neoplasms/metabolism , Humans , Hyaluronic Acid/chemistry , Hydrogels/chemistry , Mice , Polyethylene Glycols/pharmacology , Xenograft Model Antitumor Assays
12.
J Control Release ; 326: 203-221, 2020 10 10.
Article in English | MEDLINE | ID: mdl-32673633

ABSTRACT

Cancer therapies aim to kill tumor cells directly or engage the immune system to fight malignancy. Checkpoint inhibitors, oncolytic viruses, cell-based immunotherapies, cytokines, and adjuvants have been applied to prompt the immune system to recognize and attack cancer cells. However, systemic exposure of cancer therapies can induce unwanted adverse events. Intratumoral administration of potent therapies utilizes small amounts of drugs, in an effort to minimize systemic exposure and off-target toxicities. Here, we discuss the properties of the tumor microenvironment and transport considerations for intratumoral drug delivery. Specifically, we consider various tumor tissue factors and physicochemical factors that can affect tumor retention after intratumoral injection. We also review approved and clinical-stage intratumoral therapies and consider how the molecular and biophysical properties (e.g. size and charge) of these therapies influences intratumoral transport (e.g. tumor retention and cellular uptake). Finally, we offer a critical review and highlight several emerging approaches to promote tumor retention and limit systemic exposure of potent intratumoral therapies.


Subject(s)
Neoplasms , Oncolytic Virotherapy , Oncolytic Viruses , Pharmaceutical Preparations , Humans , Immunotherapy , Neoplasms/drug therapy , Tumor Microenvironment
13.
J Pharm Sci ; 109(9): 2836-2846, 2020 09.
Article in English | MEDLINE | ID: mdl-32565351

ABSTRACT

Activation of the immune system to treat cancer has emerged as a powerful therapy tool, however, treatments must overcome the immunosuppressive microenvironment established by tumors. Toll-like receptor (TLR) agonists like CpG and polyI:C are potent stimulators of non-specific, pro-inflammatory immune responses, targeting TLR9 and TLR3, respectively. While these immunostimulants seem promising, systemic exposure can eventually induce severe side effects. Adverse inflammatory reactions in healthy tissues may be avoided by delivering and retaining immunostimulants in proximity to tumors or to primary sites of tumor metastases. Immunostimulants such as CpG and polyI:C cannot be completely immobilized, however, since the target TLR9 and TLR3 are located intracellularly. Previously, polycations like poly-l-lysine (PLL) have been complexed to the anionic CpG or polyI:C with the purpose of improving intracellular delivery and potency. Here, the relationship between PLL molecular weight and immunostimulant complexation, TLR activation, and transport in a simple, model tumor microenvironment was investigated. The polyplexes could be formulated to dramatically limit immunostimulant transport suggesting the potential for injection site retention and minimized systemic exposure of immunostimulants. The molecular weight of PLL and ratio of PLL to immunostimulant affected the accessibility of the immunostimulant within the polyplex and polyplex interaction strength.


Subject(s)
Adjuvants, Immunologic , Neoplasms , Humans , Neoplasms/drug therapy , Polylysine , Toll-Like Receptors , Tumor Microenvironment
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