Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer immunotherapy.

The crosstalk between breast cancer cells and tumor associated macrophages (TAMs) greatly contributes to tumor progression and immunosuppression. In this work, cat eye syndrome chromosome region candidate 2 (CECR2) is identified to overexpress in breast cancer patients, which can recognize v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and activate nuclear factor κB (NF-κB) to release colony stimulating factor-1 (CSF-1). Pharmacological inhibition of CECR2 by the bromodomain competitor (Bromosporine, Bro) can downregulate CSF-1 to inhibit M2 type TAMs. To amplify the immunotherapeutic effect, a chimeric peptide-based and optical controlled CECR2 competitor (designated as N-PB) is constructed to enhance the nuclear targeted delivery of Bro and initiate an immunogenic cell death (ICD). In vivo results indicate a favorable breast cancer targeting ability and primary tumor suppression effect of N-PB under optical irradiation. Importantly, N-PB downregulates CSF-1 by competitive inhibition of CECR2 and NF-κB(RelA) interactions, thus inhibiting immunosuppressive M2-like TAMs while improving the antitumorigenic M1-like phenotype. Ultimately, the systemic anti-tumor immunity is activated to suppress the metastatic breast cancer in an optical controlled manner. This study provides a promising therapeutic target and reliable strategy for metastatic breast cancer treatment by interrupting immunosuppressive crosstalk between tumor cells and macrophages.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

Chimeric Peptide Engineered Bioregulator for Metastatic Tumor Immunotherapy through Macrophage Polarization and Phagocytosis Restoration.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.

Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors.

As most solid tumors are characterized by a hypoxic microenvironment, enormous efforts have been made to develop strategies to fight hypoxia. This study shows that ivermectin (IVM), an antiparasitic drug, is able to alleviate tumor hypoxia by inhibiting mitochondrial respiration. We explore this to strengthen oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) as a photosensitizer. To synergize their pharmacological behaviors, Ce6 and IVM are encapsulated into stable Pluronic F127 micelles. The micelles are uniform in size and seem well-suited for the co-delivery of Ce6 and IVM. The micelles could passively target the drugs into tumors and enhance their cellular internalization. Most importantly, through mitochondrial dysfunction, the micelles reduce the oxygen consumption (making the tumor less hypoxic). Consequently, the production of reactive oxygen species would be increase which, in turn, improves the efficacy of PDT against hypoxic tumors.

A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.

Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.

Self-delivery nanomedicine for vascular disruption-supplemented chemo-photodynamic tumor therapy.

Tumor vascular blockade is a promising strategy for adjuvant cancer treatment. In this work, a self-delivery nanomedicine is developed based on a vascular disruptor and photosensitizer for tumor synergistic therapy. Specifically, this nanomedicine (designated as CeCA) is comprised of combretastatin A4 (CA4) and chlorine e6 (Ce6) by self-assembly technique. Among which, CA4 could not only induce tubulin inhibition for chemotherapy but also disrupt the vasculature to cause tumor hemorrhage. Moreover, Ce6 is able to generate lots of singlet oxygen (1O2) for synergistic photodynamic therapy (PDT) under light irradiation. It is interesting that the carrier-free CeCA possessed a favorable stability and an improved cellular uptake behavior. After intravenous administration, CeCA prefers to accumulate at tumor site for vascular disruption-supplemented chemo-photodynamic therapy. Notably, CeCA is prepared without additional carriers, which avoids the system toxicity raised by excipients. Consequently, CeCA greatly inhibits the tumor growth and leads to a low side effect in vivo. It might open a window in the development of self-supplementary nanomedicine for synergistic tumor treatment.

Metal-coordinated nanomedicine for combined tumor therapy by inducing paraptosis and apoptosis.

Apoptosis resistance of tumor cells often results in chemoresistance and treatment failure in clinic. In this work, a Cu2+-coordinated morusin/doxorubicin biological organizer (designated as COMBO) is designed to combat cellular resistance to apoptosis for combined tumor therapy. By virtue of the coordination and π-π stacking effects, the self-assembled COMBO possesses nanometer particle size, narrow and homogenous graininess distribution as well as a good dispersion stability. Moreover, COMBO could be disassembled by glutathione (GSH) with an effective drug release and fluorescence recovery. Morusin-mediated paraptosis could induce extensive vacuolization through the dilation of endoplasmic reticulum (ER) and mitochondria, leading to non-apoptotic programmed cell death (PCD) regardless of the cellular resistance to apoptosis. Furthermore, the released doxorubicin prefers to locate in cell nucleus to cause cell apoptosis for combined chemotherapy. By the joint action of paraptosis and apoptosis, COMBO exhibits a great superiority over monotherapy in tumor inhibition with a low system toxicity. This study may open a window in the development of self-delivery nanomedicine for overcoming apoptosis resistance in tumor therapy.

Self-delivery oxidative stress amplifier for chemotherapy sensitized immunotherapy.

Amplifying oxidative stress to break intracellular redox homeostasis could accelerate tumor cell death. In this work, a self-delivery oxidative stress amplifier is developed for chemotherapy sensitized immunotherapy. By virtue of the π-π stacking and coordination effect, copper ions (Cu2+), doxorubicin (DOX) and NLG919 are able to self-assembly into the nanosized oxidative stress amplifier (designated as Cu-DON) with a favorable stability and a biocompatibility. Intravenously administrated Cu-DON could effectively accumulate and penetrate into tumor tissues for cellular uptake. Subsequently, the GSH-responsive DOX release will initiate the immunogenic chemotherapy (IC) for primary tumor inhibition. Moreover, Cu2+-mediated GSH consumption and DOX-triggered oxidative stress could cause the intracellular redox imbalance, contributing to immunogenic cell death (ICD) response. Further, the concomitant release of NLG919 would inhibit indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse immunosuppressive tumor microenvironment (ITM) for enhanced immunotherapy. Consequently, this self-delivery oxidative stress amplifier greatly restrains the growth of primary, distant as well as rechallenged tumors by chemotherapy sensitized immunotherapy, which would shed light on the development of combination therapy to block tumor growth and metastasis in clinic.

Self-delivery nanomedicine to overcome drug resistance for synergistic chemotherapy.

Multidrug resistance (MDR) is one of the prime reasons for the failure of cancer chemotherapy, which continues to be a great challenge to be solved. In this work, α-tocopherol succinate (α-TOS) and doxorubicin (DOX)-based self-delivery nanomedicine (designated as α-TD) is prepared to combat drug resistance for cancer synergistic chemotherapy. Carrier-free α-TD possesses a fairly high drug loading rate and improves the cellular uptake via the endocytosis pathway. More importantly, the apoptotic inducer α-TOS could elevate the reactive oxygen species (ROS) generation, disrupt mitochondrial function and reduce adenosine 5'-triphosphate (ATP) production, which facilitate the intracellular drug retention while decreasing its efflux. As a result, α-TD achieves a considerable synergistic chemotherapeutic effect against drug resistant cancer cells. Moreover, it also exhibits a preferable inhibitory effect on tumor growth with a low system toxicity in vivo. This synergistic drug self-delivery strategy would open a new window for developing carrier-free nanomedicine for overcoming drug resistance in cancer therapy.

A porphysome-based photodynamic O2 economizer for hypoxic tumor treatment by inhibiting mitochondrial respiration.

A porphysome-based photodynamic O2 economizer (P-PAT) is prepared for hypoxic tumor therapy. The self-assembled porphyrin bilayers of P-PAT possess high loading capacity to atovaquone (ATO) (nearly 70%), which could restrain mitochondrial respiration to relieve hypoxia and enhance photodynamic therapy.

Self-Delivery Photo-Immune Stimulators for Photodynamic Sensitized Tumor Immunotherapy.

Self-delivery of photosensitizer and immune modulator to tumor site is highly recommendable to improve the photodynamic immunotherapy yet remains challenging. Herein, self-delivery photoimmune stimulators (designated as iPSs) are developed for photodynamic sensitized tumor immunotherapy. Carrier-free iPSs are constructed by optimizing the noncovalent interactions between the pure drugs of chlorine e6 (Ce6) and NLG919, which avoid the excipients-raised toxicity and immunogenicity. Intravenously administrated iPSs prefer to passively accumulate on tumor tissues for a robust photodynamic therapy (PDT) with the induction of immunogenetic cell death (ICD) cascade to activate cytotoxic T lymphocytes (CTLs) and initiate antitumor immune response. Meanwhile, the concomitant delivery of NLG919 inhibits the activation of indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse the immunosuppressive tumor microenvironment. Ultimately, the photodynamic sensitized immunotherapy with iPSs efficiently inhibit the primary and distant tumor growth with a low system toxicity, which would shed light on the development of self-delivery nanomedicine for clinical transformation in tumor precision therapy.

Experimental research of accurate reduction of zygomatic-orbitomaxillary complex fractures with individual templates.

PURPOSE: To develop a feasible intraoperative guiding device using computer-aided design and computer-aided manufacturing of individual templates to permit anatomic fracture reduction of zygomatic-orbitomaxillary complex (ZOMC) comminuted fractures. The simplicity and accessibility of this method should allow its widespread clinical application. MATERIALS AND METHODS: Under an institutional review board-approved protocol, diverse ZOMC fracture types were created in 6 cadaver heads with a hammer and a saw, and preoperative multislice spiral computerized tomography scan and 3-dimensional reconstruction were performed. Three individual templates were made by computer-aided design and computer-aided manufacturing, and the fractures were repaired under the guidance of individual templates. A clinical case was carried out with this method. After surgery, the outcome evaluation was completed by superimposing the postoperative computed tomographic model onto the planned model. RESULTS: Successful planning and repositioning of the 6 cadavers and a clinical patient were achieved using this method. Computer-aided design and computer-aided manufacturing of individual templates were successfully used in all cases at the time of surgery. Postoperative computed tomographic scans confirmed anatomic repair in all cases. CONCLUSIONS: A feasible intraoperative ZOMC fracture monitoring and reduction guidance device has been developed. This technique is a simple, economical, and readily accessible method of comminuted ZOMC fracture reduction that can be learned and used rapidly.

Accuracy of intraoral vertical ramus osteotomy with a stereolithographic template.

Various modifications have been described to improve the accuracy in intraoral vertical ramus osteotomy (IVRO), but there was not a measurable facility to determine the osteotomy line. The purpose of this study was to evaluate the accuracy of the computer tomography (CT)-based osteotomy template on cadaver mandibles and to assess the outcome after IVRO correcting mandibular prognathism. Four human wet cadaver heads were subjected to a high-resolution multislice spiral CT scan. After the virtual osteotomies in the planning program, the individual osteotomy templates were produced by stereolithography. A stable and secure fit of the stereolithographic templates was achieved via the individual CT-based osteotomy template. The osteotomy lines were performed exactly as planned in the virtual osteotomies planning program. Similar sound outcome was also observed in the clinic. Use of the CT-based osteotomy templates is a safe method for osteotomy. It is rather convenient for vertical osteotomy in IVRO increasing the intraoperative accuracy and efficiency.

Management of high-flow arteriovenous malformation in the maxillofacial region.

Management of high-flow arteriovenous malformation (AVM) in the oral and maxillofacial region, one of the greatest challenges facing oral and maxillofacial surgeons, is patient-specific in almost all cases. The aim of this study was to review our experience with superselective intra-arterial embolization followed by surgical resection and bone wax packing (BWP) of the bone cavity and curettage to manage AVM. Sixteen patients with AVM of the oral and maxillofacial region were included in this study. All patients were evaluated with preoperative angiography, and superselective intra-arterial embolization of the lesions was done in the same session by the same interventional radiologists. Forty-eight to 72 hours later, surgical resection of the soft-tissue vascular lesions and BWP of the bone cavity and curettage were performed. There were no complications related to either the preoperative angiography or the embolization procedure. The pulsation and noise were absent, and the hemorrhage disappeared. Followed up after the surgical treatment for a mean of 38 months (range, 7-63 months), 14 cases were controlled and 2 were improved, and no case was persistent or recurred. Superselective intra-arterial embolization followed by surgical resection and BWP of the bone cavity and curettage was an effective therapy in the oral and maxillofacial region.