Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.
Proceedings of the National Academy of Sciences of the United States of America
2021; 118 (21)
Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.
View details for DOI 10.1073/pnas.2016168118
View details for PubMedID 34021082
Albumin as a "Trojan Horse" for polymeric nanoconjugate transendothelial transport across tumor vasculatures for improved cancer targeting
2018; 6 (5): 1189?1200
Although polymeric nanoconjugates (NCs) hold great promise for the treatment of cancer patients, their clinical utility has been hindered by the lack of efficient delivery of therapeutics to targeted tumor sites. Here, we describe an albumin-functionalized polymeric NC (Alb-NC) capable of crossing the endothelium barrier through a caveolae-mediated transcytosis pathway to better target cancer. The Alb-NC is prepared by nanoprecipitation of doxorubicin (Doxo) conjugates of poly(phenyl O-carboxyanhydrides) bearing aromatic albumin-binding domains followed by subsequent surface decoration of albumin. The administration of Alb-NCs into mice bearing MCF-7 human breast cancer xenografts with limited tumor vascular permeability resulted in markedly increased tumor accumulation and anti-tumor efficacy compared to their conventional counterpart PEGylated NCs (PEG-NCs). The Alb-NC provides a simple, low-cost and broadly applicable strategy to improve the cancer targeting efficiency and therapeutic effectiveness of polymeric nanomedicine.
View details for DOI 10.1039/c8bm00149a
View details for Web of Science ID 000431111600026
View details for PubMedID 29570190
Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (32): E4601?E4609
Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
View details for DOI 10.1073/pnas.1603316113
View details for Web of Science ID 000381293300007
View details for PubMedID 27457945
View details for PubMedCentralID PMC4987772
Targeted Delivery of Immunomodulators to Lymph Nodes
2016; 15 (6): 1202?13
Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.
View details for DOI 10.1016/j.celrep.2016.04.007
View details for Web of Science ID 000376164800007
View details for PubMedID 27134176
View details for PubMedCentralID PMC4973867
Synthesis and Biomedical Applications of Functional Poly(alpha-hydroxy acids) via Ring-Opening Polymerization of O-Carboxyanhydrides
ACCOUNTS OF CHEMICAL RESEARCH
2015; 48 (7): 1777?87
Poly(?-hydroxy acids) (PAHAs) are a class of biodegradable and biocompatible polymers that are widely used in numerous applications. One drawback of these conventional polymers, however, is their lack of side-chain functionalities, which makes it difficult to conjugate active moieties to PAHA or to fine-tune the physical and chemical properties of PAHA-derived materials through side-chain modifications. Thus, extensive efforts have been devoted to the development of methodology that allows facile preparation of PAHAs with controlled molecular weights and a variety of functionalities for widespread utilities. However, it is highly challenging to introduce functional groups into conventional PAHAs derived from ring-opening polymerization (ROP) of lactides and glycolides to yield functional PAHAs with favorable properties, such as tunable hydrophilicity/hydrophobicity, facile postpolymerization modification, and well-defined physicochemical properties. Amino acids are excellent resources for functional polymers because of their low cost, availability, and structural as well as stereochemical diversity. Nevertheless, the synthesis of functional PAHAs using amino acids as building blocks has been rarely reported because of the difficulty of preparing large-scale monomers and poor yields during the synthesis. The synthesis of functionalized PAHAs from O-carboxyanhydrides (OCAs), a class of five-membered cyclic anhydrides derived from amino acids, has proven to be one of the most promising strategies and has thus attracted tremendous interest recently. In this Account, we highlight the recent progress in our group on the synthesis of functional PAHAs via ROP of OCAs and their self-assembly and biomedical applications. New synthetic methodologies that allow the facile preparation of PAHAs with controlled molecular weights and various functionalities through ROP of OCAs are reviewed and evaluated. The in vivo stability, side-chain functionalities, and/or trigger responsiveness of several functional PAHAs are evaluated. Their biomedical applications in drug and gene delivery are also discussed. The ready availability of starting materials from renewable resources and the facile postmodification strategies such as azide-alkyne cycloaddition and the thiol-yne "click" reaction have enabled the production of a multitude of PAHAs with controlled molecular weights, narrow polydispersity, high terminal group fidelities, and structural diversities that are amenable for self-assembly and bioapplications. We anticipate that this new generation of PAHAs and their self-assembled nanosystems as biomaterials will open up exciting new opportunities and have widespread utilities for biological applications.
View details for DOI 10.1021/ar500455z
View details for Web of Science ID 000358556400001
View details for PubMedID 26065588
Bioorthogonal oxime ligation mediated in vivo cancer targeting
2015; 6 (4): 2182?86
Current cancer targeting relying on specific biological interaction between cell surface antigen and respective antibody or its analogue has proven to be effective in the treatment of different cancers; however, this strategy has its own limitations, such as heterogeneity of cancer cells and immunogenicity of the biomacromolecule binding ligands. Bioorthogonal chemical conjugation has emerged as an attractive alternative to biological interaction for in vivo cancer targeting. Here, we report an in vivo cancer targeting strategy mediated by bioorthogonal oxime ligation. Oxyamine group, the artificial target, is introduced onto 4T1 murine breast cancer cells through liposome delivery and fusion. Poly(ethylene glycol) -polylactide (PEG-PLA) nanoparticle (NP) is surface-functionalized with aldehyde groups as targeting ligands. The improved in vivo cancer targeting of PEG-PLA NPs is achieved through specific and efficient chemical reaction between the oxyamine and aldehyde groups.
View details for DOI 10.1039/c5sc00063g
View details for Web of Science ID 000351412800006
View details for PubMedID 26146536
View details for PubMedCentralID PMC4486360
Anticancer camptothecin-N-poly(lactic acid) nanoconjugates with facile hydrolysable linker
2014; 5 (5): 1581?85
We report a strategy of conjugating CPT to the terminal carboxylate group of polylactide (PLA) with a facile hydrolysable amino ester linker via a controlled polymerization method. The obtained CPT-N-PLA conjugates were able to self-assemble into 50-100 nanometer-sized conjugates (NCs) with desired in vitro physicochemical properties and showed enhanced in vivo therapeutic efficacy against Lewis lung carcinoma (LLC) induced in C57BL/6 mice.
View details for DOI 10.1039/c3py01245j
View details for Web of Science ID 000331987700009
View details for PubMedID 26005498
View details for PubMedCentralID PMC4439007
Poly(iohexol) Nanoparticles As Contrast Agents for in Vivo X-ray Computed Tomography Imaging
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2013; 135 (37): 13620?23
Biocompatible poly(iohexol) nanoparticles, prepared through cross-linking of iohexol and hexamethylene diisocyanate followed by coprecipitation of the resulting cross-linked polymer with mPEG-polylactide, were utilized as contrast agents for in vivo X-ray computed tomography (CT) imaging. Compared to conventional small-molecule contrast agents, poly(iohexol) nanoparticles exhibited substantially protracted retention within the tumor bed and a 36-fold increase in CT contrast 4 h post injection, which makes it possible to acquire CT images with improved diagnosis accuracy over a broad time frame without multiple administrations.
View details for DOI 10.1021/ja405196f
View details for Web of Science ID 000330163000003
View details for PubMedID 23987119
View details for PubMedCentralID PMC4232444
Drug-Initiated Ring-Opening Polymerization of O-Carboxyanhydrides for the Preparation of Anticancer Drug-Poly(O-carboxyanhydride) Nanoconjugates
2013; 14 (3): 920?29
We report a novel synthetic strategy of polymer-drug conjugates for nanoparticulate drug delivery: hydroxyl-containing drug (e.g., camptothecin, paclitaxel, doxorubicin and docetaxel) can initiate controlled polymerization of phenyl O-carboxyanhydride (Phe-OCA) to afford drug-poly(Phe-OCA) conjugated nanoparticles, termed drug-PheLA nanoconjugates (NCs). Our new NCs have well-controlled physicochemical properties, including high drug loading, quantitative drug loading efficiency, controlled particle size with narrow particle size distribution, and sustained drug release profile over days without "burst" release effect as observed in conventional polymer/drug encapsulates. Compared with polylactide NCs, the PheLA NCs have increased noncovalent hydrophobic interchain interactions and thereby result in remarkable stability in human serum with negligible particle aggregation. Such distinctive properties can reduce the premature disassembly of NCs upon dilution in the bloodstream and prolong NCs' in vivo circulation with the enhancement of intratumoral accumulation of NCs, which has a bearing on therapeutic effectiveness.
View details for DOI 10.1021/bm301999c
View details for Web of Science ID 000316044700038
View details for PubMedID 23445497
View details for PubMedCentralID PMC3671392
B Cell Response to Vaccination.
As one of the most important weapons against infectious diseases, vaccines have saved countless lives since their first use in the late eighteenth century. Antibodies produced by effector B cells upon vaccination play a critical role in mediating protection. The past several decades of research have led to a revolution in our understanding of B cell response to vaccination. Vaccines against SARS-CoV-2 coronavirus were developed at an unprecedented speed to power our global fight against COVID-19 pandemic. Nevertheless, we still face many challenges in the development of vaccines against many other deadly viruses, such as human immunodeficiency virus (HIV) and influenza virus. In this review, we summarize the latest findings on B cell response to vaccination and pathogen infection. We also discuss the current challenges in the field and the potential strategies targeting B cell response to improve vaccine efficacy.Key abbreviations box: BCR: B cell receptor; bNAb: broadly neutralizing antibody; DC: dendritic cells; DZ: dark zone; EF response: extrafollicular response; FDC: follicular dendritic cell; GC: germinal center; HIV: human immunodeficiency virus; IC: immune complex; LLPC: long-lived plasma cell; LZ: light zone; MBC: memory B cell; SLPB: short-lived plasmablast; TFH: T follicular helper cells; TLR: Toll-like receptor.
View details for DOI 10.1080/08820139.2021.1903033
View details for PubMedID 33779464
Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
Proceedings of the National Academy of Sciences of the United States of America
Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10-mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.
View details for DOI 10.1073/pnas.1921223117
View details for PubMedID 33077598
Immune receptor inhibition through enforced phosphatase recruitment.
Antibodies that antagonize extracellular receptor-ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors1. However, this approach does not directly prevent intracellular signalling, such as through tonic or sustained signalling after ligand engagement. Here we present an alternative approach for attenuating cell-surface receptor signalling, termed receptor inhibition by phosphatase recruitment (RIPR). This approach compels cis-ligation of cell-surface receptors containing ITAM, ITIM or ITSM tyrosine phosphorylation motifs to the promiscuous cell-surface phosphatase CD452,3, which results in the direct intracellular dephosphorylation of tyrosine residues on the receptor target. As an example, we found that tonic signalling by the programmed cell death-1 receptor (PD-1) results in residual suppression of T cell activation, but is not inhibited by ligand-antagonist antibodies. We engineered a PD-1 molecule, which we denote RIPR-PD1, that induces cross-linking of PD-1 to CD45 and inhibits both tonic and ligand-activated signalling. RIPR-PD1 demonstrated enhanced inhibition of checkpoint blockade compared with ligand blocking by anti-PD1 antibodies, and increased therapeutic efficacy over anti-PD1 in mouse tumour models. We also show that the RIPR strategy extends to other immune-receptor targets that contain activating or inhibitory ITIM, ITSM or ITAM motifs; for example, inhibition of the macrophage SIRP? 'don't eat me' signal with a SIRP?-CD45 RIPR molecule potentiates antibody-dependent cellular phagocytosis beyond that of SIRP? blockade alone. RIPR represents a general strategy for direct attenuation of signalling by kinase-activated cell-surface receptors.
View details for DOI 10.1038/s41586-020-2851-2
View details for PubMedID 33087934
Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity.
ACS central science
2020; 6 (10): 1800?1812
Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.
View details for DOI 10.1021/acscentsci.0c00732
View details for PubMedID 33145416
View details for PubMedCentralID PMC7596866
Bifidobacterium can mitigate intestinal immunopathology in the context of immune checkpoint blockade
AMER ASSOC IMMUNOLOGISTS. 2018
View details for Web of Science ID 000459977702091
Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2018; 115 (1): 157?61
Antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe autoimmunity. To investigate this, we combined anti-CTLA-4 treatment with a standard colitis model to give mice a more severe form of the disease. Pretreatment with an antibiotic, vancomycin, provoked an even more severe, largely fatal form, suggesting that a Gram-positive component of the microbiota had a mitigating effect. We then found that a commonly used probiotic, Bifidobacterium, could largely rescue the mice from immunopathology without an apparent effect on antitumor immunity, and this effect may be dependent on regulatory T cells.
View details for PubMedID 29255057
Selective in vivo metabolic cell-labeling-mediated cancer targeting
NATURE CHEMICAL BIOLOGY
2017; 13 (4): 415-+
Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac4ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne-doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice.
View details for Web of Science ID 000397001800017
View details for PubMedID 28192414
View details for PubMedCentralID PMC5458775
Controlled Ring-Opening Polymerization of O-Carboxyanhydrides Using a beta-Diiminate Zinc Catalyst
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2016; 55 (42): 13010?14
Recently O-carboxyanhydrides (OCAs) have emerged as a class of viable monomers which can undergo ring-opening polymerization (ROP) to prepare poly(?-hydroxyalkanoic acid) with functional groups that are typically difficult to achieve by ROP of lactones. Organocatalysts for the ROP of OCAs, such as dimethylaminopyridine (DMAP), may induce undesired epimerization of the ?-carbon atom in polyesters resulting in the loss of isotacticity. Herein, we report the use of (BDI-IE)Zn(OCH(CH3 )COOCH3 ) ((BDI)Zn-1, (BDI-IE)=2-((2,6-diethylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene), for the controlled ROP of various OCAs without epimerization. Both homopolymers and block copolymers with controlled molecular weights, narrow molecular weight distributions, and isotactic backbones can be readily synthesized. (BDI)Zn-1 also enables controlled copolymerization of OCAs and lactide, facilitating the synthesis of block copolymers potentially useful for various biomedical applications. Preliminary mechanistic studies suggest that the monomer/dimer equilibrium of the zinc catalyst influences the ROP of OCAs, with the monomeric (BDI)Zn-1 possessing superior catalytic activity for the initiation of ROP in comparison to the dimeric (BDI)Zn complex.
View details for DOI 10.1002/anie.201605508
View details for Web of Science ID 000385799200008
View details for PubMedID 27634170
The Effects of Spacer Length and Composition on Aptamer-Mediated Cell-Specific Targeting with Nanoscale PEGylated Liposomal Doxorubicin
2016; 17 (12): 1111?17
Aptamer-based targeted drug delivery systems have shown significant promise for clinical applications. Although much progress has been made in this area, it remains unclear how PEG coating would affect the selective binding of DNA aptamers and thus influence the overall targeting efficiency. To answer this question, we herein report a systematic investigation of the interactions between PEG and DNA aptamers on the surface of liposomes by using a series of nanoscale liposomal doxorubicin formulations with different DNA aptamer and PEG modifications. We investigated how the spatial size and composition of the spacer molecules affected the targeting ability of the liposome delivery system. We showed that a spacer of appropriate length was critical to overcome the shielding from surrounding PEG molecules in order to achieve the best targeting effect, regardless of the spacer composition. Our findings provide important guidelines for the design of aptamer-based targeted drug delivery systems.
View details for DOI 10.1002/cbic.201600092
View details for Web of Science ID 000379156400010
View details for PubMedID 27123758
Targeting Tumor Vasculature with Aptamer-Functionalized Doxorubicin - Polylactide Nanoconjugates for Enhanced Cancer Therapy
2015; 9 (5): 5072?81
An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.
View details for DOI 10.1021/acsnano.5b00166
View details for Web of Science ID 000355383000043
View details for PubMedID 25938427
Dimeric Drug Polymeric Nanoparticles with Exceptionally High Drug Loading and Quantitative Loading Efficiency
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2015; 137 (10): 3458?61
Encapsulation of small-molecule drugs in hydrophobic polymers or amphiphilic copolymers has been extensively used for preparing polymeric nanoparticles (NPs). The loadings and loading efficiencies of a wide range of drugs in polymeric NPs, however, tend to be very low. In this Communication, we report a strategy to prepare polymeric NPs with exceptionally high drug loading (>50%) and quantitative loading efficiency. Specifically, a dimeric drug conjugate bearing a trigger-responsive domain was designed and used as the core-constructing unit of the NPs. Upon co-precipitation of the dimeric drug and methoxypoly(ethylene glycol)-block-polylactide (mPEG-PLA), NPs with a dimeric drug core and a polymer shell were formed. The high-drug-loading NPs showed excellent stability in physiological conditions. No premature drug or prodrug release was observed in PBS solution without triggering, while external triggering led to controlled release of drug in its authentic form.
View details for DOI 10.1021/ja513034e
View details for Web of Science ID 000351420800005
View details for PubMedID 25741752
Biodegradable Micelles Capable of Mannose-Mediated Targeted Drug Delivery to Cancer Cells
MACROMOLECULAR RAPID COMMUNICATIONS
2015; 36 (5): 483?89
A targeted micellar drug delivery system is developed from a biocompatible and biodegradable amphiphilic polyester, poly(Lac-OCA)-b-(poly(Tyr(alkynyl)-OCA)-g-mannose) (PLA-b-(PTA-g-mannose), that is synthesized via controlled ring-opening polymerization of O-carboxyanhydride (OCA) and highly efficient "Click" chemistry. Doxorubicin (DOX), a model lipophilic anticancer drug, can be effectively encapsulated into the micelles, and the mannose moiety allows active targeting of the micelles to cancer cells that specifically express mannose receptors, which thereafter enhances the anticancer efficiency of the drug. Comprised entirely of biodegradable and biocompatible polyesters, this micellar system demonstrates promising potentials for targeted drug delivery and cancer therapy.
View details for DOI 10.1002/marc.201400650
View details for Web of Science ID 000350509300010
View details for PubMedID 25619623
View details for PubMedCentralID PMC4486258
Non-invasive, real-time reporting drug release in vitro and in vivo
2015; 51 (32): 6948?51
We developed a real-time drug-reporting conjugate (CPT-SS-CyN) composed of a near-infrared (NIR) fluorescent cyanine-amine dye (CyN), a disulfide linker, and a model therapeutic drug (camptothecin, CPT). Treatment with dithiothreitol (DTT) induces cleavage of the disulfide bond, followed by two simultaneous intramolecular cyclization reactions with identical kinetics, one to cleave the urethane linkage to release the NIR dye and the other to cleave the carbonate linkage to release CPT. The released CyN has an emission wavelength (760 nm) that is significantly different from CPT-SS-CyN (820 nm), enabling easy detection and monitoring of drug release. A linear relationship between the NIR fluorescence intensity at 760 nm and the amount of CPT released was observed, substantiating the use of this drug-reporting conjugate to enable precise, real-time, and non-invasive quantitative monitoring of drug release in live cells and semi-quantitative monitoring in live animals.
View details for DOI 10.1039/c4cc09920f
View details for Web of Science ID 000352630600014
View details for PubMedID 25798457
View details for PubMedCentralID PMC4486253
Redox-responsive self-assembled chain-shattering polymeric therapeutics
2015; 3 (7): 1061?65
We report the design and development of redox-responsive chain-shattering polymeric therapeutics (CSPTs). CSPTs were synthesized by condensation polymerization and further modified with poly(ethylene glycol) (PEG) via "Click" reaction. Size-controlled CSPT nanoparticles (NPs) were formed through nanoprecipitation with high drug loading (up to 18%); the particle size increased in a concentration dependent manner. Drug release from particles was well controlled over 48 h upon redox triggering. The anticancer efficacy of the CSPT NPs was validated both in vitro and in vivo.
View details for DOI 10.1039/c4bm00452c
View details for Web of Science ID 000356309200013
View details for PubMedID 26146551
View details for PubMedCentralID PMC4486357
Investigating the optimal size of anticancer nanomedicine
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2014; 111 (43): 15344?49
Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug-silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo.
View details for DOI 10.1073/pnas.1411499111
View details for Web of Science ID 000343729500035
View details for PubMedID 25316794
View details for PubMedCentralID PMC4217425
Redox-Responsive, Core-Cross-Linked Micelles Capable of On-Demand, Concurrent Drug Release and Structure Disassembly
2013; 14 (10): 3706?12
We developed camptothecin (CPT)-conjugated, core-cross-linked (CCL) micelles that are subject to redox-responsive cleavage of the built-in disulfide bonds, resulting in disruption of the micellar structure and rapid release of CPT. CCL micelles were prepared via coprecipitation of disulfide-containing CPT-poly(tyrosine(alkynyl)-OCA) conjugate and monomethoxy poly(ethylene glycol)-b-poly(tyrosine(alkynyl)-OCA), followed by cross-linking of the micellar core via azide-alkyne click chemistry. CCL micelles exhibited excellent stability under physiological conditions, while they underwent rapid dissociation in reduction circumstance, resulting in burst release of CPT. These redox-responsive CCL micelles showed enhanced cytotoxicity against human breast cancer cells in vitro.
View details for DOI 10.1021/bm401086d
View details for Web of Science ID 000326122800041
View details for PubMedID 24003893
View details for PubMedCentralID PMC4232441
PEG-Polypeptide Dual Brush Block Copolymers: Synthesis and Application in Nanoparticle Surface PEGylation
ACS MACRO LETTERS
2013; 2 (9): 809?13
Amphiphilic polypeptide-containing hybrid dual brush block copolymers with controlled molecular weights and narrow molecular weight distributions were synthesized in one pot via ring-opening metathesis polymerization of sequentially added norbornyl-PEG and N-(2-((trimethylsilyl)amino)ethyl)-5-norbornene-endo-2,3-dicarboximide (M1) followed by ring-opening polymerization of amino acid N-carboxyanhydrides. Polylactide nanoparticles coated with these am phiphilic dual brush block copolymers showed significantly improved stability in PBS solution compared to those coated with amphiphilic linear block copolymers such as PEG-polylactide and PEG-polypeptides.
View details for DOI 10.1021/mz4003672
View details for Web of Science ID 000330017000010
View details for PubMedID 24159425
View details for PubMedCentralID PMC3804265
Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia
2013; 121 (21): 4348?54
We report preclinical proof of principle for effective treatment of B-precursor acute lymphoblastic leukemia (ALL) by targeting the spleen tyrosine kinase (SYK)-dependent antiapoptotic blast cell survival machinery with a unique nanoscale pharmaceutical composition. This nanoscale liposomal formulation (NLF) contains the pentapeptide mimic 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C61) as the first and only selective inhibitor of the substrate binding P-site of SYK. The C61 NLF exhibited a very favorable pharmacokinetic and safety profile in mice, induced apoptosis in primary B-precursor ALL blast cells taken directly from patients as well as in vivo clonogenic ALL xenograft cells, destroyed the in vivo clonogenic fraction of ALL blast cells, and, at nontoxic dose levels, exhibited potent in vivo antileukemic activity against patient-derived ALL cells in xenograft models of aggressive B-precursor ALL. Our findings establish SYK as an attractive molecular target for therapy of B-precursor ALL. Further development of the C61 NLF may provide the foundation for therapeutic innovation against therapy-refractory B-precursor ALL.
View details for DOI 10.1182/blood-2012-11-470633
View details for Web of Science ID 000321873900018
View details for PubMedID 23568490
View details for PubMedCentralID PMC3663427
- Chain-Shattering Polymeric Therapeutics with On-Demand Drug-Release Capability ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 2013; 52 (25): 6435?39
Selective delivery of an anticancer drug with aptamer-functionalized liposomes to breast cancer cells in vitro and in vivo
JOURNAL OF MATERIALS CHEMISTRY B
2013; 1 (39): 5288?97
Selective targeting of cancer cells is a critical step in cancer diagnosis and therapy. To address this need, DNA aptamers have attracted significant attention as possible targeting ligands. However, while their use in targeting cancer cells in vitro has been reported, their effectiveness has rarely been established in vivo. Here we report the development of a liposomal drug delivery system for targeted anticancer chemotherapy. Liposomes were prepared containing doxorubicin as a payload, and functionalized with AS1411, a DNA aptamer with strong binding affinity for nucleolin. AS1411 aptamer-functionalized liposomes increased cellular internalization and cytotoxicity to MCF-7 breast cancer cells as compared to non-targeting liposomes. Furthermore, targeted liposomal doxorubicin improved antitumor efficacy against xenograft MCF-7 breast tumors in athymic nude mice, attributable to their enhanced tumor tissue penetration. This study suggests that AS1411 aptamer-functionalized liposomes can recognize nucleolin overexpressed on MCF-7 cell surface, and therefore enable drug delivery with high specificity and selectivity.
View details for DOI 10.1039/c3tb20412j
View details for Web of Science ID 000324682100014
View details for PubMedID 24159374
View details for PubMedCentralID PMC3800741
Polyvalent Mesoporous Silica Nanoparticle-Aptamer Bioconjugates Target Breast Cancer Cells
ADVANCED HEALTHCARE MATERIALS
2012; 1 (5): 567?72
Spatiotemporal control over the delivery of therapeutic agents is an outstanding challenge to cancer treatment. By taking advantage of recent advances in DNA aptamer biology and mesoporous silica nanotechnology, we report a general approach to design and fabricate controlled release drug delivery systems that are able to effectively target cancer cells. Specifically, polyvalent mesoporous silica nanocarriers-aptamer bioconjugates were constructed; the high-surface-area nanoporous core allowed high drug loading and the surface-conjugated aptamer facilitated the nanoparticle targeting of nucleolin overexpressed MCF-7 cells. The efficient cancer-cell-specific fluorescent imaging and drug delivery of the bioconjugates outline the great potential for therapeutic applications.
View details for DOI 10.1002/adhm.201200116
View details for Web of Science ID 000315114500004
View details for PubMedID 23184791
Targeting Mantle Cell Lymphoma with Anti-SYK Nanoparticles.
Journal of analytical oncology
2012; 1 (1): 1-9
The pentapeptide mimic 1,4-bis(9-O-dihydroquinidinyl)phthalazine / hydroquinidine 1,4-phathalazinediyl diether ("compound 61") (C-61) is the first reported inhibitor targeting the P-site of SYK. Here we report a nanotechnology platform to target C-61 to mantle cell lymphoma (MCL) cells. Liposomal nanoparticles (NP) loaded with C-61 were prepared using the standard thin film evaporation method. The entrapment of C-61 was obtained using the pH gradient procedure with lactobionic acid (LBA) being used as a low pH buffer inside the NP. Formulation F6A was selected as a lead candidate for further biological testing. The average diameter, zeta potential and C-61 content of the F6A NP was 40 nm, 0.1 mV, and 12.6 mg/ml, respectively. F6A induces apoptosis in SYK+ but not SYK- leukemia/lymphoma cells. We also evaluated the cytotoxic activity of F6A in the context of an in vitro artificial bone marrow assay platform based on a 3D scaffold with inverted colloidal crystal geometry mimicking the structural topology of actual bone marrow matrix. The ability of C-61 to induce apoptosis in ALL-1 cells was not adversely affected by the scaffolds. F6A, but not the drug-free NP formulation F6B, caused apoptosis of MCL cell lines MAVER-1 and MINO within 24h. Further development of rationally designed SYK inhibitors and their nanoscale formulations may provide the foundation for therapeutic innovation against a broad spectrum of lymphoid malignancies, including MCL.
View details for PubMedID 23730399
View details for PubMedCentralID PMC3668349
The therapeutic efficacy of camptothecin-encapsulated supramolecular nanoparticles
2012; 33 (4): 1162?69
Nanomaterials have been increasingly employed as drug(s)-incorporated vectors for drug delivery due to their potential of maximizing therapeutic efficacy while minimizing systemic side effects. However, there have been two main challenges for these vectors: (i) the existing synthetic approaches are cumbersome and incapable of achieving precise control of their structural properties, which will affect their biodistribution and therapeutic efficacies, and (ii) lack of an early checkpoint to quickly predict which drug(s)-incorporated vectors exhibit optimal therapeutic outcomes. In this work, we utilized a new rational developmental approach to rapidly screen nanoparticle (NP)-based cancer therapeutic agents containing a built-in companion diagnostic utility for optimal therapeutic efficacy. The approach leverages the advantages of a self-assembly synthetic method for preparation of two different sizes of drug-incorporated supramolecular nanoparticles (SNPs), and a positron emission tomography (PET) imaging-based biodistribution study to quickly evaluate the accumulation of SNPs at a tumor site in vivo and select the favorable SNPs for in vivo therapeutic study. Finally, the enhanced in vivo anti-tumor efficacy of the selected SNPs was validated by tumor reduction/inhibition studies. We foresee our rational developmental approach providing a general strategy in the search of optimal therapeutic agents among the diversity of NP-based therapeutic agents.
View details for DOI 10.1016/j.biomaterials.2011.10.044
View details for Web of Science ID 000298273400017
View details for PubMedID 22074663
View details for PubMedCentralID PMC3786683
- Aptamer-Functionalized, Ultra-Small, Monodisperse Silica Nanoconjugates for Targeted Dual-Modal Imaging of Lymph Nodes with Metastatic Tumors ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 2012; 51 (51): 12721?26
Immunosuppressive Activity of Size-Controlled PEG-PLGA Nanoparticles Containing Encapsulated Cyclosporine A.
Journal of transplantation
2012; 2012: 896141-?
We encapsulated cyclosporine A (CsA) in poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) (PEG-PLGA) nanoparticles (NPs) by nanoprecipitation of CsA and PEG-PLGA. The resulting CsA/PEG-PLGA-NPs were <100?nm in diameter with a narrow particle size distribution. The NP size could be controlled by tuning the polymer concentration, solvent, or water/solvent ratio during formulation. The PEGylated NPs maintained non-aggregated in salt solution. Solid NPs lyoprotected with bovine serum albumin were prepared for the convenience of storage and transportation. The release kinetics of CsA (55.6% released on Day 1) showed potential for maintaining therapeutic CsA concentrations in vivo. In T-cell assays, both free CsA and CsA/PEG-PLGA-NPs suppressed T-cell proliferation and production of inflammatory cytokines dose dependently. In a mixed lymphocyte reaction assay, the IC(50) values for free CsA and CsA/PEG-PLGA-NPs were found to be 30 and 35?ng/mL, respectively. This nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and potentially reduced toxicity.
View details for DOI 10.1155/2012/896141
View details for PubMedID 22545201
View details for PubMedCentralID PMC3321582