Honors & Awards
Excerpts of Dissertation, Peking University (2021)
Outstanding Graduate of Beijing, Peking Univerisity (2021)
Doctoral Innovative Talents Scholarship, Peking University (2019)
Ph.D., Peking University, Pharmaceutics (2021)
B.S., Shenyang Pharmaceutical University, Applied Chemistry (2015)
Kyle Loh, Postdoctoral Faculty Sponsor
Molecular Mechanisms Underlying the Development of Neuroendocrine Prostate Cancer.
Seminars in cancer biology
Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.
View details for DOI 10.1016/j.semcancer.2022.05.007
View details for PubMedID 35597438
A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging
2021; 12 (1): 5460
Surgery is an efficient way to treat localized prostate cancer (PCa), however, it is challenging to demarcate rapidly and accurately the tumor boundary intraoperatively, as existing tumor detection methods are seldom performed in real-time. To overcome those limitations, we develop a fluorescent molecular rotor that specifically targets the prostate-specific membrane antigen (PSMA), an established marker for PCa. The probes have picomolar affinity (IC50 = 63-118 pM) for PSMA and generate virtually instantaneous onset of robust fluorescent signal proportional to the concentration of the PSMA-probe complex. In vitro and ex vivo experiments using PCa cell lines and clinical samples, respectively, indicate the utility of the probe for biomedical applications, including real-time monitoring of endocytosis and tumor staging. Experiments performed in a PCa xenograft model reveal suitability of the probe for imaging applications in vivo.
View details for DOI 10.1038/s41467-021-25746-6
View details for Web of Science ID 000697264200005
View details for PubMedID 34526506
View details for PubMedCentralID PMC8443597
Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy
2021; 12 (1): 2385
Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.
View details for DOI 10.1038/s41467-021-22678-z
View details for Web of Science ID 000642744500013
View details for PubMedID 33888701
View details for PubMedCentralID PMC8062465
Dissecting extracellular and intracellular distribution of nanoparticles and their contribution to therapeutic response by monochromatic ratiometric imaging
2022; 13 (1): 2004
Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics.
View details for DOI 10.1038/s41467-022-29679-6
View details for Web of Science ID 000782630700007
View details for PubMedID 35422063
View details for PubMedCentralID PMC9010411
A pH-Responsive Nanoparticle Library with Precise pH Tunability by Co-Polymerization with Non-Ionizable Monomers
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Precise monitoring of the subtle pH fluctuation during biological events remains a big challenge. Previously, we reported an ultra-pH-sensitive (UPS) nanoprobe library with a sharp pH response using co-polymerization of two tertiary amine-containing monomers with distinct pKa . Currently, we have generalized the UPS nanoparticle library with tunable pH transitions (pHt ) by copolymerization of a tertiary amine-containing monomer with a series of non-ionizable monomers. The pHt of nanoparticles is fine-tuned by the non-ionizable monomers with different hydrophobicity. Each non-ionizable monomer presents a constant contribution to pH tunability regardless of tertiary amine-containing monomers. Based on this strategy, we produced two libraries of nanoprobes with continuous pHt covering the entire physiological pH range (5.0-7.4) for fluorescent imaging of endosome maturation and cancers. This generalized strategy provides a powerful toolkit for biological studies and cancer theranostics.
View details for DOI 10.1002/anie.202200152
View details for Web of Science ID 000767056700001
View details for PubMedID 35218123
Cooperative Self-Assembled Nanoparticle Induces Sequential Immunogenic Cell Death and Toll-Like Receptor Activation for Synergistic Chemo-immunotherapy
2021; 21 (10): 4371-4380
Anticancer immunotherapy is hampered by poor immunogenicity and a profoundly immunosuppressive microenvironment in solid tumors and lymph nodes. Herein, sequential pH/redox-responsive nanoparticles (SRNs) are engineered to activate the immune microenvironment of tumor sites and lymph nodes. The two-modular SRNs could sequentially respond to the acidic tumor microenvironment and endosome compartments of dendritic cells (DCs) to precisely deliver doxorubicin (DOX) and imidazoquinolines (IMDQs). In the tumor microenvironment, released DOX triggers immunogenic cell death. In sentinel lymph nodes, the IMDQ nanoparticle module is dissociated in the acidic endosome compartment to specifically stimulate toll-like receptor 7/8 for DC maturation. Thus, the orchestrated nanoparticle system could enhance the infiltration of CD8α+ T cells in tumors and provoke a strong antitumor immune response toward primary and abscopal tumors in B16-OVA and CT26 tumor-bearing mice models. The cooperative self-assembled nanoparticle strategy provides a potential candidate of nanomedicine to advance the synergistic cancer chemo-immunotherapy.
View details for DOI 10.1021/acs.nanolett.1c00977
View details for Web of Science ID 000657242300032
View details for PubMedID 33984236
pH-Amplified CRET Nanoparticles for In Vivo Imaging of Tumor Metastatic Lymph Nodes
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2021; 60 (26): 14512-14520
Noninvasive imaging strategies have been extensively investigated for in vivo mapping of sentinel lymph nodes (SLNs). However, the current imaging strategies fail to accurately assess tumor metastatic status in SLNs with high sensitivity. Here we report pH-amplified self-illuminating near-infrared nanoparticles, which integrate chemiluminescence resonance energy transfer (CRET) and signal amplification strategy, enabling accurate identification of metastatic SLNs. After draining into lymph nodes, the nanoparticles were phagocytosed and dissociated in acidic phagosomes of inflammatory macrophages to emit near-infrared luminescent light. Using these nanoparticles, we successfully differentiated tumor metastatic lymph nodes from benign ones. These nanoparticles also exhibited excellent imaging capability for early detection of metastatic SLNs in diverse animal tumor models with small tumor volume (100-200 mm3 ).
View details for DOI 10.1002/anie.202102044
View details for Web of Science ID 000651915800001
View details for PubMedID 33860575
Precise Monitoring of Singlet Oxygen in Specific Endocytic Organelles by Super-pH-Resolved Nanosensors
ACS APPLIED MATERIALS & INTERFACES
2021; 13 (16): 18533-18544
Singlet oxygen (1O2) plays a vital role in pathophysiological processes and is the dominant executor of photodynamic therapy (PDT). Several small molecular probes have been designed to detect singlet oxygen for the evaluation of PDT efficacy. However, little attention was paid to the precise visualization of the 1O2 signal at the subcellular organelle level in living biological systems. Herein, a super-pH-resolved (SPR) nanosensor was developed to specifically illuminate 1O2 in endocytic organelles through encoding the cell-impermeant singlet oxygen sensor green (SOSG) into pH-sensitive micelles. The acid-activatable SPR-SOSG achieved more than 10-fold amplification of the 1O2 signal, leading to extremely higher sensitivity of singlet oxygen detection in specific endocytic organelles of living cells and animals, as compared with the nonactivatable nanoprobe and the commercially available 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. Hence, the SPR-SOSG nanoplatform provides a promising tool to evaluate the efficacy and mechanism of nanocarrier-based photodynamic therapy.
View details for DOI 10.1021/acsami.1c01730
View details for Web of Science ID 000645520700013
View details for PubMedID 33856773
Sequential Modulations of Tumor Vasculature and Stromal Barriers Augment the Active Targeting Efficacy of Antibody-Modified Nanophotosensitizer in Desmoplastic Ovarian Carcinoma
2021; 8 (3): 2002253
Active-targeted nanoparticles are attractive carriers due to their potentials to facilitate specific delivery of drugs into tumor cells while sparing normal cells. However, the therapeutic outcomes of active-targeted nanomedicines are hampered by the multiple physiological barriers in the tumor microenvironment (TME). Herein, an epidermal growth factor receptor-targeted ultra-pH-sensitive nanophotosensitizer is fabricated, and the regulation of the TME to augment the active targeting ability and therapeutic efficacy is pinpointed. The results reveal that tumor vasculature normalization with thalidomide indiscriminately enhance the tumor accumulation of passive and active targeted nanoparticles, both of which are sequestered in the stromal bed of tumor mass. Whereas, photoablation of stromal cells located in perivascular regions significantly improves the accessibility of antibody-modified nanophotosensitizer to receptor-overexpressed cancer cells. After sequential regulation of TME, the antitumor efficacy of antibody-modified nanophotosensitizer is drastically enhanced through synergistic enhancements of tumor accumulation and cancer cell accessibility of active-targeted nanoparticles. The study offers deep insights about the intratumoral barriers that hinder the active-targeted nanoparticles delivery, and provides a basis for developing more effective strategies to accelerate the clinical translation of active-targeted nanomedicines.
View details for DOI 10.1002/advs.202002253
View details for Web of Science ID 000600922200001
View details for PubMedID 33552856
View details for PubMedCentralID PMC7856881
A magnetism/laser-auxiliary cascaded drug delivery to pulmonary carcinoma
ACTA PHARMACEUTICA SINICA B
2020; 10 (8): 1549-1562
Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on streptavidin-biotin interaction with the help of c(RGDfK), magnetic fields and lasers. The ultrasmall superparamagnetic iron oxide nanoparticles (USIONPs) modified with c(RGDfK) and biotin are delivered at step 1, followed by streptavidin and the doxorubicin (Dox) loaded nanosystems conjugated with biotin at steps 2 and 3, respectively. The delivery systems were proved to be efficient on A549 cells. The co-localization of signal for each step revealed the targeting mechanism. The external magnetic field could further amplify the endocytosis of USPIONs based on c(RGDfK), and magnify the uptake distinctions among different test groups. Based on photoacoustic imaging, laser-heating treatment could enhance the permeability of tumor venous blood vessels and change the insufficient blood flow in cancer. Then, it was noticed in vivo that only three-step delivery with laser-heating and magnetic fields realized the highest tumor distribution of nanosystem. Finally, the magnetism/laser-auxiliary cascaded delivery exhibited the best antitumor efficacy. Generally, this study demonstrated the necessity of combining physical, biological and chemical means of targeting.
View details for DOI 10.1016/j.apsb.2019.12.017
View details for Web of Science ID 000567649600014
View details for PubMedID 32963949
View details for PubMedCentralID PMC7488357
- pH/Cathepsin B Hierarchical-Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo-Immunotherapy ADVANCED FUNCTIONAL MATERIALS 2020; 30 (39)
A pH-Activatable nanoparticle for dual-stage precisely mitochondria-targeted photodynamic anticancer therapy.
2019; 213: 119219
Mitochondria-targeted photodynamic therapy (PDT) has emerged as one of the most efficient antitumor strategies. However, the therapeutic outcome of mitochondria-targeted PDT nanocarriers has been hampered by its poor capability of endosome escape and always-ON mode which induces normal tissue damage. To tackle these limitations, herein a novel pH-activatable nanoparticle is developed with dual-stage targeting capacity of early endosome and mitochondria for exponential activation of fluorescent signals and photodynamic efficacy. This nanoparticle is composed of pH-responsive mPEG-b-PDPA-Cy7.5 fluorescent copolymer and mitochondria-targeted photosensitizer (TPPa). The TPPa-encapsulated nanoparticles (M-TPPa) exhibit 111- and 151-fold enhancement in fluorescent signal and singlet oxygen generation (SOG) on encounting acidic pH environment, respectively. The M-TPPa can be quickly endocytosed by cancer cells and immediately dissociate at acidic early endosome to activate fluorescent signals and photoactivity. Subsequently, the activated TPPa quickly translocates from early endosome to mitochondria. Under laser irradiation, singlet oxygen could be generated in mitochondria, inducing intrinsic apoptosis in human HO8910 ovarian cancer cells. M-TPPa also exhibits high tumor imaging contrast and remarkable inhibition on tumor progression without obvious toxicity in HO8910-tumor bearing mice. Therefore, the rationally designed nanoparticles, with precise dual-targeting of distinct organelles and theranostic signal amplification, provides a promising strategy for efficient cancer treatment.
View details for DOI 10.1016/j.biomaterials.2019.05.030
View details for PubMedID 31132647
Quick-Responsive Polymer-Based Thermosensitive Liposomes for Controlled Doxorubicin Release and Chemotherapy
ACS BIOMATERIALS SCIENCE & ENGINEERING
2019; 5 (5): 2316-2329
Thermosensitive liposomes (TSLs) have been widely investigated for controlled drug release at specific pathophysiological sites. Although excellent thermo-sensitivity under hyperthermia (HT) was already realized for TSLs, their in vivo stability under physiological temperature still remains challenging. To overcome this limitation, optimized polymer-based thermosensitive liposomes (P-TSLs) with good thermo-sensitivity as well as satisfactory in vivo stability were developed in this study for tumor-specific controlled delivery of doxorubicin (DOX). In particular, polymers including p(NIPAM-r-HPMA) and p(HPMA-r-APMA) were successfully synthesized based on a reversible addition-fragmentation chain transfer (RAFT) technique. Next, thermosensitive polymer p(NIPAM-r-HPMA) was first proposed to be inserted into the lipid bilayer of TTSL by a postinsertion method. The resulting P-TTSL had a phase transition temperature (Tm) of around 42 °C and displayed excellent thermo-sensitivity under HT: nearly 70% of DOX was released within 1 min when only 1% p(NIPAM-r-HPMA) was incorporated. Moreover, its stability was maintained at 37 °C. Compared with TTSL, significantly higher cellular uptake of DOX under HT was noticed in P-TTSL, indicating a burst release of DOX at 42 °C. In addition, both in vitro tumor spheroid experiments and in vivo tumor slices demonstrated an enhanced DOX deep penetration when treated by P-TTSL under HT. To achieve in vivo imaging and local HT under NIR, p (HPMA-r-APMA) was labeled by Cy7.5 and coinserted into TTSL, and the best drug efficacy was observed in CY-P-TTSL with HT along with prolonged blood circulation time. We have further investigated the biocompatibility of the developed CY-P-TTSL, and reduced cardiotoxicity was observed even under HT in comparison with free DOX, demonstrating it is a reliable thermosensitive drug carrier for improving drug stability and therapeutic efficacy.
View details for DOI 10.1021/acsbiomaterials.9b00343
View details for Web of Science ID 000468120000024
View details for PubMedID 33405782
Ultra-pH-sensitive indocyanine green-conjugated nanoprobes for fluorescence imaging-guided photothermal cancer therapy
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
2019; 17: 287-296
Photothermal therapy (PTT) has been recognized as a promising approach for cancer treatment due to its minimal invasiveness and low systemic side effects. However, developing a photothermal agent with accurate tumor imaging capability is a prerequisite for the efficient PTT. Here, we developed a series of ultra-pH-sensitive indocyanine green (ICG)-conjugated nanoparticles for fluorescence imaging-guided tumor PTT. These nanoparticles exhibited high fluorescence activation ratio (~100-fold) with sharp pH transition (ΔpHon/off <0.25), and superior temperature response than free ICG. The in vivo imaging experiments demonstrated that the nanoparticles generated excellent tumor-to-normal tissue contrast through pH-triggered fluorescence activation in tumor sites, which provided information on tumor mass location, boundaries, and shape. Moreover, comparing to free ICG, the nanosystem had significantly longer blood circulation time and more accurate tumor targeting, providing efficient photothermal therapeutic effect against A549 tumor in living animals. In conclusion, this nanoplatform offers a potential strategy for imaging-guided cancer PTT.
View details for DOI 10.1016/j.nano.2019.02.001
View details for Web of Science ID 000467581100024
View details for PubMedID 30763723