Engineered platelet-based immune engager for tumor post-surgery treatment.

Tumor metastasis and recurrence are principal reasons for the high mortality and poor prognosis of cancers. Inefficient engagement between T cell and tumor cell, as well as the universal existence of immune checkpoints, are important factors to the limited immunological surveillance of the immune systems to tumor cells. Herein, an immune engager based on engineered platelets with CD3 antibody modification (P-aCD3) was constructed to facilitate the contact between T cell and tumor cell via providing the anchoring sites of above two cells. Combined with the immune checkpoint blockade strategy, P-aCD3 effectively enhanced T cell mediated cytotoxicity and inhibited tumor recurrence and metastasis in mice melanoma postoperative model and breast cancer model, resulting in significantly prolonged survival of mice.

Immunogenic dead cells engineered by the sequential treatment of ultraviolet irradiation/cryo-shocking for lung-targeting delivery and tumor vaccination.

Chemoimmunotherapy is a promising strategy in tumor treatments. In this study, immunogenic dead cells were engineered by the sequential treatment of live tumor cells with ultraviolet (UV) irradiation and cryo-shocking. The dead cells could serve as a lung-targeting vehicle and tumor vaccine after differential loading of the chemo-drug 10-hydroxycamptothecin (HCPT) and immune adjuvant Quillaja saponin-21 (QS-21) via physical absorption and chemical conjugation, respectively. After intravenous administration, the dead cells could be trapped in pulmonary capillaries and could fast release HCPT to enhance the drug accumulation in local tissues. Further, the immunogenic dead cells elicited antitumor immune responses together with the conjugated adjuvant QS-21 to achieve the elimination and long-term surveillance of tumor cells. In a lung tumor-bearing mice model, this drug-delivery system achieved synergistic antitumor efficacy and prolonged the survival of mice.

Potentiating cancer vaccination by adjuvant-loaded cryo-shocked tumor cells.

Cancer vaccine holds vast promise in potentiating tumor immunotherapy. Here, we developed a simple cancer vaccine based on the liquid nitrogen-treated cells (LNT cells) that engineered by one-shot shocking of the live tumor cells in liquid nitrogen. In this vaccine, the obtained LNT cells served as both tumor antigens and delivery vehicles to load the adjuvant imiquimod (R837). This design could achieve efficient co-uptake of antigen/adjuvant by antigen presenting cells (APCs) and prolong in vivo retention of tumor antigens and adjuvants. This adjuvant-loaded LNT cells augmented in vivo antitumor responses and enhanced survival in melanoma-bearing mouse model compared with conventional whole-cell vaccine of the mixture of tumor lysis and adjuvant.

Immunosuppressive dead cell as lung-targeting vehicle and cytokine absorption material for cytokine storm attenuation of pneumonia.

Effectively controlling cytokine storm is important to reduce the mortality of severe pneumonia. In this work a bio-functional dead cell was engineered by one-time quick shock of live immune cells in liquid nitrogen, and the obtained immunosuppressive dead cell could server as both lung-targeting vehicle and cytokine absorption material. After loading the anti-inflammatory drugs of dexamethasone (DEX) and baicalin (BAI), the drug-loaded dead cell (DEX&BAI/Dead cell) could first passively target to the lung after intravenous administration and quickly release the drugs under high shearing stress of pulmonary capillaries, realizing drug enrichment in the lung. Then, the immunosuppressive dead cell acted as the camouflage of normal immune cells with various cytokine receptors exposing on their surface, to "capture" the cytokines and further reduce the state of inflammation. With above formulation design, a synergic anti-inflammatory effect between drugs and carrier could be achieved. In a lipopolysaccharide-induced pneumonia mice model, this system could calm down the cytokine storm with high efficacy and elongate the survival of mice.

Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor-Associated Macrophages for Cancer Immunotherapy.

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.

Biomimetic doxorubicin/ginsenoside co-loading nanosystem for chemoimmunotherapy of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) showed limited clinical therapeutic efficiency with chemotherapy for its multi-distributed lesions and hard-to-kill leukemia cells deep in the bone marrow. RESULTS: Here, a biomimetic nanosystem (DR@PLip) based on platelet membrane (PM) coating and doxorubicin (DOX)/ginsenoside (Rg3) co-loading was developed to potentiate the local-to-systemic chemoimmunotherapy for AML. The PM was designed for long-term circulation and better leukemia cells targeting. The participation of Rg3 was proved to enhance the tumor sensitivity to DOX, thus initiating the anti-tumor immune activation and effectively combating the leukemia cells hiding in the bone marrow. CONCLUSIONS: In conclusion, the strategy that combining immediate chemotherapy with long-term immunotherapy achieved improved therapeutic efficiency and prolonged survival, which provided a new perspective for the clinical treatment of AML.

Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy.

Chimeric antigen receptor T cell (CAR T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of CAR T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates CAR T cells and allows in situ penetration-mediated seeding of CAR T cells when implanted in the tumor bed or in the post-surgical resection cavity. CAR T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of CAR T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.

Delivery strategies in treatments of leukemia.

Leukemia is a hematological malignancy associated with the uncontrolled proliferation of mutant progenitors, suppressing the production of normal blood cells. Current treatments, including chemotherapy, radiotherapy, and immunotherapy, still lead to unsatisfactory results with a 5 year survival rate of only 30-50%. The poor prognosis is related to both disease relapse and treatment-associated toxicity. Delivery strategies can improve the in vivo pharmacokinetics of drugs, navigating the therapeutics to target cells or the tumor microenvironment and reversing drug resistance, which maximizes tumor elimination and alleviates systematic adverse effects. This review discusses available FDA-approved anti-leukemia drugs and therapies with a focus on the advances in the development of anti-leukemia drug delivery systems. Additionally, challenges in clinical translation of the delivery strategies and future research opportunities in leukemia treatment are also included.

Microneedle-Mediated Biomimetic Cyclodextrin Metal Organic Frameworks for Active Targeting and Treatment of Hypertrophic Scars.

Due to the lack of a delivery system that actively targets hypertrophic scar fibroblasts (HSFs), it is difficult to concentrate the effects of drugs on hypertrophic scars (HSs). We recently discovered that the HSF membrane has a homologous targeting effect and developed an active targeted drug delivery system for the local treatment of HSs. A diphenyl carbonate cross-linked cyclodextrin metal organic framework (CDF) containing more than 26% (w/w) quercetin (QUE) was coated with a HSF membrane (QUE@HSF/CDF) and then dispersed in Bletilla striata polysaccharide (BSP)-fabricated dissolvable microneedles (BSP-MNs-QUE@HSF/CDF) for local administration. This biomimetic nanodrug delivery system improved efficacy on HSs by regulating Wnt/ß-catenin and JAK2/STAT3 pathways and reducing the expression of collagens I and III in HS, and this performance was superior to those of systems without HSF functionalization or the assistance of microneedles. Additionally, we found that BSP has synergistic effects and the microneedles have higher mechanical strength and better physical stability than microneedles made of hyaluronic acid. This currently designed drug delivery strategy integrating biomimetic nanoparticles and dissolvable microneedles is promising for applications in the fields of skin disease treatment and cosmetics.

Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.

Injectable Biodegradable Polymeric Complex for Glucose-Responsive Insulin Delivery.

Insulin therapy is the central component of treatment for type 1 and advanced type 2 diabetes; however, its narrow therapeutic window is associated with a risk of severe hypoglycemia. A glucose-responsive carrier that demonstrates consistent and slow basal insulin release under a normoglycemic condition and accelerated insulin release in response to hyperglycemia in real-time could offer effective blood glucose regulation with reduced risk of hypoglycemia. Here, we describe a poly(l-lysine)-derived biodegradable glucose-responsive cationic polymer for constructing polymer-insulin complexes for glucose-stimulated insulin delivery. The effects of the modification degree of arylboronic acid in the synthesized cationic polymer and polymer-to-insulin ratio on the glucose-dependent equilibrated free insulin level and the associated insulin release kinetics have been studied. In addition, the blood glucose regulation ability of these complexes and the associated glucose challenge-triggered insulin release are evaluated in type 1 diabetic mice.

Self-assembly delivery system based on small-molecule camptothecin prodrug for treatment of colorectal carcinoma.

The aim of this study was to prepare small-molecule camptothecin (CPT) prodrugs and evaluate their effectiveness in colorectal carcinoma therapy. Prodrug nanoparticles (NPs) were physicochemically characterized and evaluated for their cytotoxicity in human colon cancer (HCT116) cell lines. The antitumor efficacy of the NPs was evaluated in HCT116 tumor-bearing mice. The prepared NPs exhibited high drug loading capacity (32% of CPT w/w) and also kept a high active lactone fraction of CPT (>85%) during circulation. The NPs were internalized into tumor cells efficiently compared with free drug and significantly enhanced the drug's therapeutic efficacy. The developed small-molecule CPT prodrug NPs could be a promising strategy in the clinical therapy of colorectal carcinoma.

Heparin modified photosensitizer-loaded liposomes for tumor treatment and alleviating metastasis in phototherapy.

Phototherapy holds promise in cancer treatment for its prominent antitumor efficacy and low systematic toxicity compared with traditional chemotherapy. However, the higher risk of tumor metastasis caused by the severe hypoxic state during phototherapy is a threat in practical use. Here, in order to tackle this challenge, we developed a delivery system via loading the photosensitizer indocyanine green (ICG) into the low molecular weight heparin (LMWH) modified liposomes (LMWH-ICG-Lip) to realize the synergistic effects between photosensitizer and drug vehicle, achieving better phototherapeutic efficacy and meanwhile alleviating the potential risk of tumor metastasis caused by phototherapy. In this system, besides elongating the photosensitizers' circulation time and enhancing their accumulating efficacy to tumor tissues, LMWH itself also exhibited anti-metastasis efficacy via inhibiting adhesion of platelets to tumor cells and decreasing migration and invasion capability of tumor cells. In vivo efficacy evaluation was conducted on orthotopic 4T1 breast cancer model, and the system of LMWH-ICG-Lip could alleviate metastasis potential of residual tumor cells after irradiation, and elicit optimistic antitumor and anti-metastasis efficacy for phototherapy.

Cryo-shocked cancer cells for targeted drug delivery and vaccination.

Live cells have been vastly engineered into drug delivery vehicles to leverage their targeting capability and cargo release behavior. Here, we describe a simple method to obtain therapeutics-containing "dead cells" by shocking live cancer cells in liquid nitrogen to eliminate pathogenicity while preserving their major structure and chemotaxis toward the lesion site. In an acute myeloid leukemia (AML) mouse model, we demonstrated that the liquid nitrogen-treated AML cells (LNT cells) can augment targeted delivery of doxorubicin (DOX) toward the bone marrow. Moreover, LNT cells serve as a cancer vaccine and promote antitumor immune responses that prolong the survival of tumor-bearing mice. Preimmunization with LNT cells along with an adjuvant also protected healthy mice from AML cell challenge.

Application of HPMC HME polymer as hot melt extrusion carrier in carbamazepine solid dispersion.

AIM: This work is to investigate the application characteristics of a new hot melt extrusion (HME) polymer (HME-grade hydroxypropyl methylcellulose, namely HPMC HME 15LV) in solid dispersion by HME. METHODS: Carbamazepine (CBZ) was chosen as the model drug. And two types of solid dispersion system was prepared by HME, that is, single carrier system which was composed of PVP VA64(VA64) or Soluplus (SOL), and binary carrier which was composed of HPMC HME 15LV and SOL. Phase analysis of the extrudates were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution, moisture absorption and thermal stability CBZ solid dispersion (CBZ-SD) were also investigated. In addition, the mechanism that affects the capsule dissolution was evaluated by the viscosity test and infiltration capability test. RESULTS: CBZ-SD was prepared by HME. DSC and PXRD results indicated that CBZ was amorphous in all solid dispersions. Unlike CBZ-SD powder with high dissolution, CBZ-SD capsules showed the variable gelatinization phenomenon during dissolution and different dissolution behaviors, which can be interpreted by the viscosity test and infiltration capacity test. Furthermore, compared with single carrier system, CBZ-SD made by binary carrier exhibited lower moisture absorption and better thermal stability, which is benefit to the long-term stability of CBZ-SD. CONCLUSION: HPMC HME 15LV, as a new HME carrier, has certain advantages in producing well CBZ-SD preparation. Its low viscosity can prevent the gelatinization phenomenon during capsule dissolution, as well as suitable Tg and low hygroscopicity were also benefit to the stability of CBZ-SD.

Low molecular weight heparin modified bone targeting liposomes for orthotopic osteosarcoma and breast cancer bone metastatic tumors.

The standard-of-care chemotherapy is important in the treatment of osteosarcoma and bone metastastic tumors. However, the efficacy is limited by the specific physiological environment of the bone. Thus, developing an efficient antitumor and anti-metastasis chemotherapeutic formulation is desired for treatment of bone tumors. Herein, we utilized the alendronate (ALN) and low molecular weight heparin (LMWH) modified liposomes to deliver the antitumor drug doxorubicin (DOX), where traditionally-believed non-active drug carrier, targeting moiety could also exhibit biological functions and realize anti-tumor and anti-metastasis efficiency synergistically with the antitumor drug. Specifically, ALN could serve as the bone targeting moiety and the therapeutic agents of anti-osteoporosis. LMWH could enhance the blood circulation time of liposomes and exhibit anti-metastasis efficiency. Besides characterization of typical physiochemical properties of the delivery system, both the orthotopic osteosarcoma model and bone metastasis cancer model were adopted to evaluate the in vivo efficacy. The results proved this system could remarkably suppress tumor growth and inhibit tumor metastasis.

Combretastatin A4 Nanodrug-Induced MMP9 Amplification Boosts Tumor-Selective Release of Doxorubicin Prodrug.

Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.

Liquid jet breakup: A new method for the preparation of poly lactic-co-glycolic acid microspheres.

The purpose of this study was to apply the phenomenon of liquid jet breakup to the preparation of sustained-release microspheres. The mechanisms of liquid jet breakup in different jet states were investigated and the single factor method was used to study the effect of each process parameter on the particle size and size distribution of microspheres. Meantime, the prepared microspheres were characterized by morphology, drug loading, encapsulation efficiency and in vitro release. The results indicated that the process of liquid jet breakup could have 5 different states. The laminar flow state dominated when the Reynolds number (Re) was low, and the prepared microspheres had larger particle sizes. When the Re was high, the turbulent state was dominant and the microspheres had smaller particle sizes. And during the transition state from the laminar flow to the turbulence, the microspheres had a wide particle size distribution. Different process parameters could affect the particle size and distribution of microspheres by changing the Re, surface tension coefficient and viscosity. The microspheres prepared by liquid jet breakup were smooth and round with the drug loading of 35% and the encapsulation efficiency of 88%. In addition, when the polymeric carrier materials were different, the microspheres could have various drug release models such as sustained release with a lag phase, sustained release with no lag phase, pulsed release and so on, which could be applied widespread in the future.

Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer.

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.

Sprayable gel for postsurgical immunotherapy.

Background: Surgery remains the first option to treat most solid tumors. However, despite the development of surgical techniques, the elimination of tumor recurrence after surgery remains a challenge. Design: In a recent study published in Nature Nanotechnology, we described an in-situ-sprayed gel for local delivery of bioresponsive and immunotherapeutic calcium carbonate nanoparticles encapsulated with anti-CD47 antibodies (aCD47@CaCO3) to the surgical site after surgery. CaCO3 nanoparticles react with H+ in the surgical wound site, eliciting an immunosupportive tumor microenvironment after surgery. Meanwhile, the subsequently released aCD47 blocks the 'don't eat me' signal expressed on cancer cells to increase the phagocytosis of cancer cells by macrophages and activate T-cell-mediated antitumor immune responses. Conclusion: The engineered immunotherapeutic gel could activate both innate and adaptive immune responses systemically after local treatment, effectively destroying the remaining cancer cells and reducing tumor recurrence.