An injectable nanosuspension based on orthoester and biomimetic carboxymethyl chitosan nanoparticles for chemo/thermo-synergistic tumor therapy.

A metal protoporphyrin-induced nano-self-assembly for potentiating photothermal therapy by depleting antioxidant defense systems

Flash nanoprecipitation (FNP) is an efficient technique for encapsulating drugs in particulate carriers assembled by amphiphilic polymers. In this study, a novel nanoparticular system of a model drug curcumin (CUR) based on FNP technique was developed by using cheap and commercially available amphiphilic poly(vinyl pyrrolidone) (PVP) as stabilizer and natural polymer chitosan (CS) as trapping agent. Using this strategy, high encapsulation efficiency (EE > 95%) and drug loading capacity (DLC > 40%) of CUR were achieved. The resulting CUR-loaded nanoparticles (NPs) showed a long-term stability (at least 2 months) and pH-responsive release behavior. This work offers a new strategy to prepare cost-effective drug-loaded NPs with high drug loading capacity and opens a unique opportunity for industrial scale-up.

Multimodal near-infrared II (NIR-II) theranostics combined with nanotechnology have emerged as promising treatments for cancer due to their noninvasive and high spatiotemporal nature. Traditional NIR-II theranostics typically comprise useless and massive inert carriers, resulting in low drug loading capacity, reduced therapeutic effects, and potential biotoxicity. To overcome these limitations, this work reports carrier-free NIR-II theranostics simultaneously with high drug loading capacity and multimodal NIR-II imaging capabilities for cancer phototheranostics in the NIR-II window. Carrier-free BTA nanoparticles (NPs) are prepared by self-assembling the NIR-II responsive conjugated oligomer BTA without adding coating agents; these NPs exhibited 100% drug loading and high-performance NIR-II theranostic capabilities. Cancer cell membranes are camouflaged on carrier-free BTA NPs to provide homologous targeting ability, enhanced stability, and 77.8% drug loading. Both in vitro and in vivo studies have indicated that biomimetic NPs provide efficient triple-modal guidance for NIR-II fluorescence, photoacoustic, and photothermal imaging and complete tumor elimination via photothermal therapy (PTT). Additionally, theranostics-based treatments with good biosecurity are demonstrated. This study contributes a new strategy for the design of high-drug-loading NIR-II theranostics and further promotes the clinical translation of theranostic agents.

Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular π-π stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self-assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles.

Background: IGFBP2, known to enhance the invasion capacity of ovarian cancer cells, has been suggested that its inhibition could be potentially a treatment strategy of ovarian cancer. AST-201 (pUMVC3-hIGFBP2) is a therapeutic cancer vaccine using a plasmid DNA encoding IGFBP2 N-terminus. In a phase 1 study (NCT01322802) completed, 100 μg AST-201 (intradermal immunization, id) showed not only a significant efficacy by inducing the Th1-cell immunity against IGFBP2 but also safety and tolerability profiles in ovarian cancer patients. The primary objective of this study is to evaluate whether the administration of AST-201 alone and the combination with pembrolizumab could show anti-tumor efficacy and/or synergic effect in the ID8-Luc2 ovarian cancer mouse model. Also, immunological responses were observed as explorative endpoint. Methods: AST-201 (100 μg/animal, id, mixed with mGM-CSF as an immune adjuvant) was immunized to mice (C57BL/6) once a week for a total of 4 times on different days, either alongside pembrolizumab (10 mg/kg, intraperitoneal injection) twice a week for a total of 3 times on different days. Also, AST-201 was immunized was a mono treatment. The efficacy was evaluated by a tumor growth inhibition (TGI) rate at the last day, and immune cell profiling via FACS analysis was conducted with splenocytes and tumor tissues collected at 8 weeks after the first injection. Results: As a primary endpoint, a TGI rate at Day 55 of AST-201 mono treatment was 67%, comparing to a control group (p<0.05). The anti-tumor effect of AST-201 combining with pembrolizumab was better than standard dose pembrolizumab, based on a TGI rate at Day 55 (78% vs 66%, not significant). Immune profiling showed that AST-201 and pembrolizumab combination regimen could inhibit a tumor growth by transforming TME into inflamed-type (‘hot’) form the low immunoreactivity, which was supported by increased CD4+TEM, and CD8+TEM and T helper cells in splenocyte and TIL analysis. Conclusion: A study demonstrated that AST-201 (IGFBP2 cancer vaccine) showed an anti-tumor effect as mono treatment and would be potentially leading to a synergistic effect with a combination regimen of pembrolizumab. Phase 2 randomized-controlled study of AST-201 in ovarian cancer will be initiated under the MRCT strategy (CornerStone-004 study, NCT05794659). Citation Format: Jinback Lim, Jinho Kang, Hyo-Hyun Park, Jin Kyeong Choi, Jee Hyun Choi, Seong-Yong Jang, Min-Ah Kim, Myeong-Kyu Park, Mary L Disis, Eunkyo Joung, Ashley Yongmin Kim, Hun Jung. AST-201 (pUMVC3-hIGFBP2 N-terminus) demonstrates anti-tumor effect in an ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4114.

BackgroundIGFBP2, known to enhance the invasion capacity of ovarian cancer cells,1 has been suggested that its inhibition could be potentially a treatment strategy of ovarian cancer. AST-201 (pUMVC3-hIGFBP2) is a...

Achieving rapid and precisely controllable drug loading via spontaneous imbibition in porous microneedles: mechanistic and optimization strategies.

BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases and 30-40% of U.S. breast cancer deaths. Although current precision treatments improve TNBC patient outcomes, TNBC heterogeneity has led to therapeutic targeting challenges. Also, the resistance of TNBC to conventional treatment remains a significant clinical problem. Therefore, informed evaluation of new targets can improve the treatment of TNBC, representing an unmet need. Dysregulation of the cell cycle is a hallmark of cancer for unlimited proliferation. Abnormal mitosis and cell-cycle checkpoints are crucial in leading to aneuploidy and genetic instability. Aurora kinase A (AURKA), a serine/threonine kinase, regulates mitosis in the early stages (G2/M phase) by regulating centrosome maturation and disjunction, thereby establishing a bipolar mitotic spindle. VIC-1911 (previously known as TAS-119), a novel, orally active, highly selective inhibitor of AURKA with a low toxicity profile, suppresses the growth of various cancer cell lines in vitro and in vivo. As AURKA can modulate DNA damage response, we hypothesized that VIC-1911 combined with sacituzumab govitecan (SG), which has a topoisomerase 1 inhibitor as a payload, has a synergistic antitumor effect on TNBC. MATERIALS AND METHODS: To evaluate the short-term in vitro efficacy of VIC-1911 alone and combination with SG, a sulforhodamine B cell proliferation assay was performed using 10 TNBC cell lines. For long-term treatment conditions, a colony formation assay was conducted. Western blot and immunofluorescent analyses were conducted to confirm treatment-mediated DNA damage and apoptosis. Human TNBC cell line–derived mammary fat pad xenograft models were used to evaluate the antitumor effect of VIC-1911 and SG. RESULTS: In vitro proliferation, data demonstrated that single-agent VIC-1911 had a nanomolar to micromolar range of half-maximal inhibitory concentrations (2.69 nM to 10.6 mM) in the tested TNBC cell lines. The half-maximal inhibitory concentration was correlated with c-Myc expression (R2=0.4876, p=0.0247). Exposure to the combination of VIC-1911 and SG led to significant death of VIC-1911–sensitive TNBC cell lines (p<0.05). Western blot and immunofluorescent analysis revealed that VIC-1911 and SG combination caused TNBC cell death by inducing expression of phosphorylated histone H2AX (DNA damage marker) and cleaved poly (ADP-ribose) polymerase (apoptosis marker). Furthermore, the combination of VIC-1911 and SG had significantly greater antitumor efficacy than did either agent alone in SUM149 TNBC xenograft models (tumor growth inhibition rate (TGI): VIC-1911, 61.4%; SG, 68.3%; combination, 82.9%; p<0.01) and HCC1806 TNBC xenograft models (TGI: VIC-1911, 49.3%; SG, 66.3%; combination, 85.9%; p<0.01). CONCLUSION: The AURKA inhibitor VIC-1911 has a synergistic antitumor effect with SG by inducing DNA damage in TNBC cells. PDX and additional mechanistic studies are planned to further evaluate VIC-1911 and SG as novel combination therapy for TNBC. Citation Format: Jangsoon Lee, YoungJin Gi, Thomas Myers, Linda Paradiso, Debu Tripathy, Naoto T. Ueno. VIC-1911, a selective Aurora kinase A inhibitor, synergizes with sacituzumab govitecan in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C146.

Mesoporous silica nanoparticles (MSNs) have emerged as promising biomaterials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA‐Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in significant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM‐48‐type) are synthesized and functionalized with a straightforward and efficient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus‐treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r2/r1 = 1.47, r1 = 23.97 mM−1 s−1), which confers a remarkable positive contrast enhancement potential to the compound. The particles could serve as efficient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a significant advance in the design of high colloidal stability silica‐based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.

A photoresponsive and rod-shape nanocarrier: Single wavelength of light triggered photothermal and photodynamic therapy based on AuNRs-capped & Ce6-doped mesoporous silica nanorods.

Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and nonspecific side effects; however, it has been difficult to achieve liposomal Gem with high drug loading capacity. Remote loading, which uses a transmembrane pH gradient to induce an influx of drug and locks the drug in the core as a sulfate complex, does not serve Gem as efficiently as doxorubicin (Dox) due to the low p Ka value of Gem. Existing studies have attempted to improve Gem loading capacity in liposomes by employing lipophilic Gem derivatives or creating a high-concentration gradient for active loading into the hydrophilic cores (small volume loading). In this study, we combine the remote loading approach and small volume loading or hypertonic loading, a new approach to induce the influx of Gem into the preformed liposomes by high osmotic pressure, to achieve a Gem loading capacity of 9.4-10.3 wt % in contrast to 0.14-3.8 wt % of the conventional methods. Liposomal Gem showed a good stability during storage, sustained-release over 120 h in vitro, enhanced cellular uptake, and improved cytotoxicity as compared to free Gem. Liposomal Gem showed a synergistic effect with liposomal Dox on Huh7 hepatocellular carcinoma cells. A mixture of liposomal Gem and liposomal Dox delivered both drugs to the tumor more efficiently than a free drug mixture and showed a relatively good anti-tumor effect in a xenograft model of hepatocellular carcinoma. This study shows that bioactive liposomal Gem with high drug loading capacity can be produced by remote loading combined with additional approaches to increase drug influx into the liposomes.

Preparation and characterization of abalone shells derived biological mesoporous hydroxyapatite microspheres for drug delivery.

Imaging-guided precision oncotherapy mediated by nanoprobes: From seeing to curing

Hydroxycamptothecin (HCPT) loaded PLA nanoparticles were prepared by a facile dialysis method. Three main influential factors, PLA concentration, ratio of HCPT to PLA (wt/wt), dialysis bags with different molecule weight cutoff, were evaluated using an orthogonal design, gave the nanoparticles with an average diameter of approximately 226.8 nm and fine drug loading content (5.16%, w/w). The in vitro drug release studies exhibited a slow and prolonged release profile over 30 days. It is concluded that the new method to prepare HCPT-PLA nanoparticles resulted in improved formulation characteristics including small size, high drug loading capacity, and long sustained drug release.

Biodegradation is a crucial issue for silica‐based mesoporous nanoparticles that is related to the biosafety in tumor therapy. Nowadays, mesoporous silica nanoparticles (MSNs) have been intensively developed to construct multifunctional nanosystems for tumor therapy due to their biocompatibility, high drug loading capacity and easy functionalization; however, their biodegradation is relatively slow and still under debate. To improve the biodegradability of silica‐based mesoporous nanoparticles, a simple organic‐inorganic hybridization strategy to synthesize mesoporous organosilica nanoparticles (MONs) has been successfully developed. By hybridizing the silica framework (–Si–O–Si–) with stimuli‐sensitive organic moieties to form organic‐inorganic network (–Si–R–Si–, R: organic moiety), when exposed to the stimuli environment, the breakdown of the organic‐inorganic network could accelerate the degradation of MONs, which is great promising for MONs as a multifunctional therapeutic nanoplatform in tumor therapy. This review aims to summarize the degradation strategies for MONs to improve biodegradability in recent years, and highlight the potential applications of MONs in tumor therapy. Finally, we also discuss the challenges of MONs for tumor therapy in future clinical translation.