Combined Antitumor Therapy Research Articles

Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B more Efficiently than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors.

TRAIL is considered a promising antitumor agent because it causes apoptosis of transformed cells without affecting normal cells. However, many types of tumors are cytokine resistant, and combination therapy with various chemotherapeutic drugs is being developed to overcome the resistance. We have demonstrated that the combination of TRAIL with doxorubicin, bortezomib, and panobinostat dramatically reduced the viability of TRAIL-resistant A549 and HT-29 cells. Chemotherapy even more efficiently sensitized cells to the DR5-specific mutant variant of TRAIL DR5-B, which does not have an affinity for decoy receptors. Bortezomib and doxorubicin greatly enhanced the surface expression of the death receptors DR5 and DR4, while panobinostat increased expression of DR5 and suppressed expression of DR4 in both cell lines. All drugs increased surface expression of the decoy receptors DcR1 and DcR2. Unlike the combined treatment, if the cells were pretreated with chemotherapy for 24 h, the cytotoxic activity of TRAIL was less pronounced, while sequential treatment of cells enhanced the effectiveness of DR5-B. The same results were obtained with agonistic anti-DR5 antibodies. Thus, the effectiveness of TRAIL was rather limited due to changes in the ratio of death and decoy receptors and DR5-specific agonists may be preferred in combination antitumor therapy regimens.

Total glossectomy in multimodal treatment of oropharyngeal cancer: immediate results

The study objective is to analyze the results of combined antitumor therapy, which included glossectomy, to treat locally advanced and recurrent oropharyngeal squamous cell cancer.Materials and methods. We performed a retrospective analysis of multimodal antitumor therapy of 19 patients, who were treated in the Nizhny Novgorod Regional Clinical Oncologic Dispensary within 2009–2019. All patients underwent segmental resection of the mandible due to massive tumor invasion into the periosteum. After total glossectomy the defect was filled using pectoralis musculocutaneous flap. Due to the wide local tumor spread, a neck dissection (n = 7) or radical cervical lymphadenectomy (n = 12) were performed. During preventive surgery, metastases that were not detected before surgery were revealed in 2 patients in 1 neck lymph node. Results. Eleven patients had local purulent-necrotic postoperative complications. It was noted that after surgery but without radiation therapy complications developed in fewer patients (n = 4) and were less severe: of I degree – in 3 patients, of III degree – in 1 patient. Radiation therapy before surgery resulted in more severe purulent-necrotic complications in 7 patients: of I degree – in 2 patients, of II degree – in 1, of III degree – in 4. Mortality rates: 30-day, 60-day and 90-day – 10.5 %, 21 % and 37 %, respectively. The causes of death were complications of gastrostomy: profuse bleeding from the stomach wall (n = 1), acute psychosis complicated by cerebral edema (n = 1), increased heart failure (n = 1), necrosis of the anterior abdominal wall and cachexia, developed after gastrostomy (n = 1), continued tumor growth between chemotherapy courses (n = 3). Twelve patients survived more than 90 days after surgery, 3 patients – more than 2 years. As most of the patients could not swallow, they were administered a nasogastric tube, since a simultaneous gastrostomy increases the duration of a traumatic operation and aggravates the postoperative period.Conclusion. Multicomponent surgery after radiation therapy results in more often local purulent-necrotic postoperative complications than if the surgery is performed before radiation therapy. High mortality in the first 90 days after surgery (n = 7) due to local cancer spread is generally determined by the severe condition of patients with advanced cancer and the concomitant diseases. However, rejection of gastrostomy in favor of nasogastric tube seems reasonable, since several deaths in the early postoperative period may be occurred due to complications associated with gastrostomy.

Effectiveness of sacubitril-valsartan in cancer patients with heart failure.

AimsCurrent guidelines recommend sacubitril/valsartan for patients with heart failure and reduced left ventricular ejection fraction (LVEF), but there is lack of evidence of its efficacy and safety in cancer therapy‐related cardiac dysfunction (CTRCD). Our aim was to analyse the potential benefit of sacubitril/valsartan in patients with CTRCD.Methods and resultsWe performed a retrospective multicentre registry (HF‐COH) in six Spanish hospitals with cardio‐oncology clinics including all patients treated with sacubitril/valsartan. Demographic and clinical characteristics and laboratory and echocardiographic data were collected. Median follow‐up was 4.6 [1; 11] months. Sixty‐seven patients were included (median age was 63 ± 14 years; 64% were female, 87% had at least one cardiovascular risk factor). Median time from anti‐cancer therapy to CTRD was 41 [10; 141] months. Breast cancer (45%) and lymphoma (39%) were the most frequent neoplasm, 31% had metastatic disease, and all patients were treated with combination antitumor therapy (70% with anthracyclines). Thirty‐nine per cent of patients had received thoracic radiotherapy. Baseline median LVEF was 33 [27; 37], and 21% had atrial fibrillation. Eighty‐five per cent were on beta‐blocker therapy and 76% on mineralocorticoid receptor antagonists; 90% of the patients were symptomatic NYHA functional class ≥II. Maximal sacubitril/valsartan titration dose was achieved in 8% of patients (50 mg b.i.d.: 60%; 100 mg b.i.d.: 32%). Sacubitril/valsartan was discontinued in four patients (6%). Baseline N‐terminal pro‐B‐type natriuretic peptide levels (1552 pg/mL [692; 3624] vs. 776 [339; 1458]), functional class (2.2 ± 0.6 vs. 1.6 ± 0.6), and LVEF (33% [27; 37] vs. 42 [35; 50]) improved at the end of follow‐up (all P values ≤0.01). No significant statistical differences were found in creatinine (0.9 mg/dL [0.7; 1.1] vs. 0.9 [0.7; 1.1]; P = 0.055) or potassium serum levels (4.5 mg/dL [4.1; 4.8] vs. 4.5 [4.2; 4.8]; P = 0.5). Clinical, echocardiographic, and biochemical improvements were found regardless of the achieved sacubitril–valsartan dose (low or medium/high doses).ConclusionsOur experience suggests that sacubitril/valsartan is well tolerated and improves echocardiographic functional and structural parameters, N‐terminal pro‐B‐type natriuretic peptide levels, and symptomatic status in patients with CTRCD.

In situ tumor-triggered subcellular precise delivery of multi-drugs for enhanced chemo-photothermal-starvation combination antitumor therapy.

Rationale: Drug combination therapy for cancer treatment exerts a more potent antitumor effect. The targeted delivery and release of multiple drugs in a patient's body thus presents a more effective treatment approach, warranting further research. Methods: Two antitumor drugs (ICG: indocyanine green and THP: pirarubicin) were successfully screened to sequentially trigger self-assembling peptides (P60) to produce bacteria-sized particles (500-1000 nm, P60-ICG-THP). First, after mixing equal amount of P60 and ICG, trace amount of water (the mass ratio between P60 and water: 100:1) was used to trigger their assembly into P60-ICG. Subsequently, the assembly of P60-ICG and THP was further triggered by ultrasound treatment to produce P60-ICG-THP. Results: P60-ICG-THP constituted a cluster of several nanoparticles (50-100 nm) and possessed a negative charge. Owing to its size and charge characteristics, P60-ICG-THP could remain outside the cell membrane, avoiding the phagocytic clearance of blood and normal tissue cells in vivo. However, after localizing in the tumor, the size and charge switches of P60-ICG-THP, rapidly triggered by the low pH of the tumor microenvironment, caused P60-ICG-THP to segregate into two parts: (i) positively charged nanoparticles with a size of approximately 50 nm, and (ii) negatively charged particles of an uneven size. The former, mainly carrying THP (chemotherapeutic agent), could immediately cross the cell membrane and deliver pirarubicin into the nucleus of tumor cells. The latter, carrying ICG (used for photothermal therapy), could also enter the cell via the endocytosis pathway or accumulate in tumor blood vessels to selectively block the supply of nutrients and oxygen (cancer starvation). Both these particles could avoid the rapid excretion of ICG in the liver and were conducive to accumulation in the tumor tissue for photothermal therapy. Conclusion: Our drug delivery system not only achieves the precise subcellular delivery of two anticancer drugs due to their size and charge switches in the tumor site, but also provides a new strategy to combine chemotherapy, photothermal therapy, and cancer starvation therapy for the development of a highly efficient antitumor therapeutic regimen.

A nanoplatform with tumor-targeted aggregation and drug-specific release characteristics for photodynamic/photothermal combined antitumor therapy under near-infrared laser irradiation.

Due to their high biocompatibility, high spatial resolution, chromatographic capability, and adjustable size and morphology, magnetic nanoparticles have become the most promising nanomaterials for clinical application in noninvasive imaging and drug delivery for the treatment of malignant tumors. Herein, a novel magnetic nanoparticle coated with calcium carbonate was prepared and loaded with near-infrared drugs to be used as a multifunctional theranostic nanoplatform for the diagnosis and treatment of malignant tumors. Then, these drug-loaded nanoparticles were used for combined photodynamic/photothermal therapy by intravenous administration that was simultaneously guided by fluorescence/MR imaging. Due to the targeted induction of the external magnetic field and tumor response degradation of the calcium carbonate layer, the nanoprobe demonstrated excellent tumor targeting and greatly improved drug aggregation at the tumor site. Finally, single wavelength-mediated photothermal/photodynamic therapy was applied to liver cancer model mice, ultimately achieving an exciting antitumor therapeutic effect. This study may promote further exploration of nanoplatforms based on magnetic nanoparticles for clinical application in the treatment of malignant tumors.

A robust hybrid nanozyme@hydrogel platform as a biomimetic cascade bioreactor for combination antitumor therapy.

The development of highly effective and minimally invasive approaches for cancer treatment is the ultimate goal. Herein, an injectable hybrid hydrogel as a biomimetic cascade bioreactor is designed for combination antitumor therapy by providing spatiotemporally-controlled and long-term delivery of therapeutic agents. This hybrid nanozyme@hydrogel (hPB@gellan) is doped with Prussian blue (PB) nanoparticles via the in situ nanoprecipitation method in the polysaccharide gellan matrix. The obtained PB nanoparticles have a small size of 10 nm and play dual roles as a photothermal agent with a photothermal conversion efficiency of 59.6% and as a nanozyme to decompose hydrogen peroxide into oxygen. By incorporating glucose oxidase (GOD) into the hybrid hydrogel, a cascade bioreactor is formed for PB-promoted glucose consumption. Owing to its shear-thinning and self-recovery properties, the hybrid hydrogel is locally administered into tumors, and shows long-term resistance against body clearance and metabolism. The in vivo antitumor results demonstrate that the tumors in the group of combined photothermal and starvation therapy (GOD/hPB@gellan + NIR) are greatly eliminated with a tumor suppression rate of 99.7% 22 days after the treatment. The outstanding antitumor performance is attributed to the main attack by NIR-triggered hyperthermia and the holding attack by GOD-mediated starvation from the catalytic bioreactor of the hybrid hydrogel. Taking into consideration the advantages of biosafety, simple synthetic approaches and facile manipulation in treatment, the hybrid hydrogel has great potential for clinical translation.

Carrier-Free, Dual-Functional Nanorods Via Self-Assembly Of Pure Drug Molecules For Synergistic Chemo-Photodynamic Therapy.

BackgroundThe combination of chemo-photodynamic therapy based on nano-technology has emerged as a preferable and promising measure for synergetic antitumor therapy.PurposeThe aim of this study was expected to overcome most of the safety concerns from nano-carriers and improve the chemo-photodynamic synergistic antitumor efficacy.MethodsHerein, we reported a facile and effective approach based on the self-assembly of chemotherapeutic agent 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6) for preparing stably dual-functional nanorods (NRs).ResultsThe chemical thermodynamic parameters obtained from isothermal titration calorimeter (ITC) and the microcosmic configuration snapshots acquired by molecular dynamics (MD) simulations verified that HCPT and Ce6 molecules tended to assemble with each other through various intermolecular forces. The as-prepared HCPT/Ce6 NRs possessed a relatively uniform size of around 165 nm and zeta potential of about −29 mV, together with good stability in aqueous solution and freeze-dried state. In addition, both the extra- and intracellular reactive oxygen species (ROS) generation capacity of the NRs under laser irradiation was significantly enhanced compared with Ce6 injections. Moreover, the dual-functional HCPT/Ce6 NRs exhibited a substantial in vitro/in vivo synergistic antitumor efficacy under laser irradiation due to the integration of the two therapeutic modalities into one drug delivery system. Besides, no obvious hepatic or renal toxicity was observed in the NRs treatment groups.ConclusionTaken together, HCPT/Ce6 NRs demonstrated a powerful efficacy in chemo-photodynamic therapy for breast cancer. Therefore, the carrier-free dual-functional NRs prepared in a facile and effective strategy might give inspiration for the development of combined antitumor therapy.

Self-assembling Collagen/Alginate hybrid hydrogels for combinatorial photothermal and immuno tumor therapy

Combination therapy, integrating multiple merits of monotherapy into one platform for enhanced antitumor efficacy while eliminating the likelihoods of tumor recurrence and metastasis, is of particular interest in clinical application. Hydrogels self-assembled by biologically-based building blocks can be used as promising platforms for incorporation of one or more therapeutic drugs to gain additive or synergistic therapeutic functions. Herein, antitumor combination therapy based on injectable collagen/alginate hydrogels is achieved by simultaneous encapsulation of the photothermal drug methylene blue (MB) and immunological agent imiquimod (R837). The resulting hybrid hydrogel (Gel-MB-R837) with shear-thinning and self-healing properties is applicable for localized delivery and prolonged release of therapeutic drugs. The antitumor efficacy can be significantly enhanced by combinatorial photothermal therapy (PTT) and immunotherapy treatments through the synergy of MB and R837. Moreover, the initial PTT not only eradicates primary tumors, but also generates tumor-associated antigens (TAA), which combines with R837 to trigger immune response for further inhibiting tumor recurrence and metastasis. Therefore, the biocompatible hybrid hydrogels starting from naturally-occurring biomacromolecules offer promising prospects for combinatorial photothermal and immuno tumor therapy.

Modulation of pericytes by a fusion protein comprising of a PDGFRβ-antagonistic affibody and TNFα induces tumor vessel normalization and improves chemotherapy

The delivery of anticancer drugs is hampered by tumor vessels with abnormal structure and function, which requires that vessel normalization be mediated by pharmaceutics. The current strategies for vessel normalization focus on direct modulation of endothelial cells (ECs), which frequently affect vessels in normal tissues. Modulating EC-supporting cells, such as pericytes (PCs), is a new direction. Here, we produced a fusion protein, Z-TNFα, by fusing the platelet-derived growth factor receptor β (PDGFRβ)- antagonistic affibody ZPDGFRβ to tumor necrosis factor α (TNFα). Owing to the affinity of fused ZPDGFRβ for PDGFRβ, Z-TNFα binds PDGFRβ+ PCs but not PDGFRβ− ECs. Low-dose (1 μg/mouse) Z-TNFα treatment remodeled the tumor vessels, thus reducing vessel permeability and increasing vessel perfusion. As a result, the Z-TNFα treatment improved the delivery of doxorubicin (DOX) and enhanced its antitumor effect, indicating that Z-TNFα induced normalization of tumor vessels. Mechanically, the tumor vessel normalization mediated by Z-TNFα might be attributed to the reduction of vascular endothelial growth factor (VEGF) secretion by PCs and the elevated expression of intercellular cell adhesion molecule-1 (ICAM-1) in PCs, which might suppress the proliferation and migration of ECs and simultaneously trigger interaction between perivascular macrophages and PCs. These results demonstrated that tumor-associated PCs could be considered novel target cells for vessel normalization, and Z-TNFα might be developed as a potential tool for antitumor combination therapy.

Rodlike MSN@Au Nanohybrid-Modified Supermolecular Photosensitizer for NIRF/MSOT/CT/MR Quadmodal Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Recently, rodlike nanomaterials with specific aspect ratio for efficient cellular uptake have received enormous attention. For functional nanomaterials, such as photothermal agents, large surface areas for their rod-shaped exterior that increase the amount of light absorbed would lead to a higher absorption coefficient as well as drug-loading property. In this project, we coated rodlike mesoporous silica with gold nanoshells (MSNR@Au hybrid), modifying them with ultrasmall gadolinium (Gd)-chelated supramolecular photosensitizers, TPPS4 (MSNR@Au-TPPS4(Gd)), which could be applied to near-infrared fluorescence/multispectral optoacoustic tomography/computed tomography/magnetic resonance imaging and imaging-guided remotely controlled photothermal (PTT)/photodynamic (PDT) combined antitumor therapy. Gold nanoshells, as a perfect PTT agent, were used to assemble the rodlike mesoporous silica nanoparticles with larger superficial area and higher drug loading, thus obtaining the MSNR@Au hybrid. HS-β-CD, which was used as the host, was adsorbed on the gold nanoshell (MSNR@Au-β-CD) to link TPPS4(Gd) through the host-guest reaction, thus forming CD-TPPS4 supramolecular photosensitizers (supraPSs). Compared with conventional PSs, supraPSs have host screens, which could reduce the self-aggregation of TPPS4, and consequently generate 1O2 with high efficiency. The in vivo quadmodal imaging of MSNR@Au-TPPS4(Gd) nanoparticles revealed an intensive tumor uptake effect after injection. The in vivo antitumor efficacy further testified that the synergistic therapy, which was more efficient than any other monotherapy, exhibited an excellent tumor inhibition therapeutic effect. As a result, this encourages to further explore multifunctional theranostic nanoparticles based on gold shells for combined cancer therapy.

Polydopamine-coated gold nanostar for combined antitumor and antiangiogenic therapy in multidrug-resistant breast cancer.

Cancer combination therapy can improve treatment efficacy and is widely utilized in the biomedical field. In this paper, we propose a facile strategy to develop a polydopamine (PDA)-coated Au nanostar (NS@PPFA) as a multifunctional nanoplatform for cancer targeting and combination therapy. The Au nanostar demonstrated high photothermal conversion efficiency because of the tip-enhanced plasmonic effect. Modification of PDA and folic acid on the NS surface improved its drug-loading efficiency and targeting capability. In vitro, compared with nontargeted cells, targeted breast cancer MCF-7 cells demonstrated efficient uptake of chemodrug-loaded NS-D@PPFA through the receptor-mediated endocytosis pathway. In combination with the photothermal effect induced by near-infrared laser irradiation, controlled payload release could be activated in response to both internal (acid) and external (photothermal) stimuli, leading to an efficient chemo-photothermal action against MCF-7 cells and drug-resistant MCF-7/ADR cells. By contrast, cellular damage was less obvious in normal HaCaT (human skin keratinocytes) and NIH-3T3 cells (murine fibroblasts). In addition, payload-free NS@PPFA exhibited a high binding affinity (Kd = 2.68 × 10-10 M) toward vascular endothelial growth factor (VEGF-A165), which was at least two orders of magnitude stronger than that of highly abundant plasma proteins, such as human serum albumin. Furthermore, in vitro study showed that NS@PPFA could effectively inhibit VEGF-A165-induced proliferation, migration, and tube formation of human umbilical vein endothelial cells, resulting in additional therapeutic benefits for eradicating tumors through a simultaneous antiangiogenic action in chemo-photothermal treatment. The combined treatment also exhibited the lowest microvessel density, leading to a potent antitumor effect in vivo. Overall, our “all-in-one” nanoplatform is highly promising for tumor therapy, enabling effective treatment against multidrug-resistant cancers.

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics‐Based Combination Antitumor Therapy

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics‐Based Combination Antitumor Therapy

Progress in multimodal imaging-guided photothermal anti-tumor combined therapy

As one of the diseases with high morbidity and low cure rate in the world, cancer has always threatened the health of the public. However, due to the complexity, diversity and heterogeneity of the tumor, it is difficult to inhibit tumor recurrence and metastasis by relying on surgery, radiotherapy or chemotherapy. Photothermal therapy (PTT) is a cancer treatment by laser irradiation, which converts light energy into heat energy mediated by photothermal agents, and induces local tissue hyperthermia to treat cancer. And it has attracted widespread attention because of its non-specificity, high tumor ablation efficiency, and low toxic side effects on normal cells. However, the clinical transformation process of PTT is also severely limited by some disadvantages including the inconvenience of the delivery, distribution and metabolic process of the photothermal agent and the inaccurate and incomplete evaluation of the results of cancer treatment. The researchers have designed a variety of photothermal agents with multimodal imaging capabilities for cancer diagnosis and treatment. These imaging methods include thermal imaging (TI), photoacoustic (PA) imaging, photoluminescence (PL) imaging, magnetic resonance imaging (MRI), X-ray computed tomography (CT) imaging, and positron emission tomography (PET) imaging. And the imaging-guided cancer treatments have improved the accuracy of tumor visual treatments and greatly facilitated the clinical transformation of PTT. At present, the trend of cancer treatment development has gradually changed from monotherapy to combination therapy. Other therapies in combination with PTT include photodynamic therapy (PDT), chemotherapy, immunotherapy, radiotherapy (RT), sonodynamic therapy (SDT), and other PTT-related therapies. These combination therapies overcome tumor heterogeneity and complexity, reversing multidrug resistance, and reduce unnecessary side effects, and can more effectively achieve cancer diagnosis and treatment. This review summarizes the recent advances in multimodal imaging-guided PTT and multitherapies in combination with PTT for cancer diagnosis and treatment. For a single photothermal treatment, it is often difficult for researchers to effectively monitor the delivery, distribution, metabolism, and excretion of photothermal agents, and to accurately and dynamically track and evaluate the real-time therapeutic effects of tumors. Various strategies have been developed to solve the problems of single photothermal therapy. The new nano-platforms based on PTT-based multimodal imaging methods or therapies reviewed in this paper combine cancer diagnosis and treatment, and effectively overcome the shortcomings of single photothermal anti-tumor therapy, which is difficult to visualize tumors and lack of therapeutic efficiency to provide the development of new cancer diagnosis and treatment technologies new opportunities. Whether it is a single photothermal therapy or a combination of photothermal therapy and other methods, there is still a long way to go to study its therapeutic mechanism and further applications. The ultimate goal of these studies is to go to the clinic, cure the tumor, and benefit mankind. It is believed that with the rapid development of nanotechnology and nanomedicine, these problems will be gradually solved, and the photothermal anti-tumor combination therapy based on multimodal imaging will surely make new breakthroughs.

PH-activatable polymeric nanodrugs enhanced tumor chemo/antiangiogenic combination therapy through improving targeting drug release

It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells.

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics-Based Combination Antitumor Therapy.

Different strategies of chemotherapeutics-based combination cancer therapy have presented enhanced antitumor efficiency and are widely used in clinical cancer treatments. However, several drawbacks of the systems for systemic administration, including low drug accumulation at tumor sites and significant systemic side effects limit their efficacy and application in the clinic. Local drug co-delivery systems based on injectable hydrogels may have considerable advantages, such as a facile drug-delivery procedure, targeted delivery of antitumor agents to tumor sites in a sustained manner, and markedly reduced systemic toxicities. Thus, in recent years, these systems have received increasing attention and consequently various injectable hydrogels have been tested as platforms for local chemotherapeutics-based combination antitumor therapy. In this review, the focus is on recent advances in injectable hydrogel-based drug co-delivery systems for local combination antitumor therapy, including multiple chemotherapeutics combination therapy, chemo-immunotherapy, chemo-radiotherapy, and hyperthermia-chemotherapy. Moreover, the rationale and preparation of local co-delivery systems are summarized and discussed.

Nanotherapeutics with suitable properties for advanced anticancer therapy based on HPMA copolymer-bound ritonavir via pH-sensitive spacers

Ritonavir (RIT) is a widely used antiviral drug that acts as an HIV protease inhibitor with emerging potential in anticancer therapies. RIT causes inhibition of P-glycoprotein, which plays an important role in multidrug resistance (MDR) in cancer cells when overexpressed. Moreover, RIT causes mitochondrial dysfunction, leading to decreased ATP production and reduction of caveolin I expression, which can affect cell migration and tumor progression. To increase its direct antitumor activity, decrease severe side effects induced by the use of free RIT and improve its pharmacokinetics, ritonavir 5-methyl-4-oxohexanoate (RTV) was synthesized and conjugated to a tumor-targeted polymer carrier based on a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. Here we demonstrated that polymer-bound RTV enhanced the internalization of polymer-RTV conjugates, differing in RTV content from 4 to 15 wt%, in HeLa cancer cells compared with polymer without RTV. The most efficient influx and internalization properties were determined for the polymer conjugate bearing 11 wt% of RTV. This conjugate was internalized by cells using both caveolin- and clathrin-dependent endocytic pathways in contrast to the RTV-free polymer, which was preferentially internalized only by clathrin-mediated endocytosis. Moreover, we found the co-localization of the RTV-conjugate with mitochondria and a significant decrease of ATP production in treated cells. Thus, the impact on mitochondrial mechanism can influence the function of ATP-dependent P-glycoprotein and also the cell viability of MDR cancer cells. Overall, this study demonstrated that the polymer-RTV conjugate is a promising polymer-based nanotherapeutic, suitable for antitumor combination therapy with other anticancer drugs and a potential mitochondrial drug delivery system.

Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy

Recently, ultrasmall gadolinium oxide (Gd2O3) nanoparticles with high longitudinal relaxation rate have received enormous attention. However, it can't be concentrated in tumor site through intravenous administration due to its ultrasmall size. In this project, we coated ultrasmall Gd2O3 nanoparticles with a near-infrared (NIR) light-absorbing polymer polypyrrole (PPy), modifying with hyaluronic acid (HA) and loaded aluminum phthalocyanine (AlPc), the Gd2O3@PPy/AlPc-HA nanoparticles could be used for fluorescence (FL)/magnetic resonance (MR)/photoacoustic (PA) imaging guided as well as remotely controlled PTT/PDT combined anti-tumor therapy. Polymerized PPy with high photothermal conversion efficiency was introduced to assemble the ultrasmall Gd2O3 nanoparticles which have high longitudinal relaxation rate and signal-to-noise ratio, thus obtaining Gd2O3@PPy nanoparticles which possess a larger particle size and can be more suitable for tumor targeting based on the EPR effect. HA and AlPc were adsorbed on PPy for HA-mediated tumor targeting and photodynamic therapy respectively. The in vivo triple-modal imaging revealed that Gd2O3@PPy/AlPc-HA nanoparticles possess enhanced tumor uptake effect after intravenous injection. More importantly, the nanoparticles exhibited an obvious photothermal effect, which can trigger the release and de-quench of AlPc. The anti-tumor efficiency further corroborated that the combined therapy achieved an excellent tumor inhibition therapeutic effect which was much better than any other mono-therapy. Consequently, our work encouraged further exploration of polymer-based multifunctional theranostic nanoparticles for cancer combination therapy under remote near-infrared (NIR) light controls.

57P - Immunomonitoring of patients treated with personalized dendritic cell-based vaccine

We manufacture fully personalized monocytederived dendritic cell-based vaccines (DC-based vaccines) that are evaluated in investigator- initiated clinical trial “Combined antitumor therapy with ex vivo manipulated dendritic cells producing interleukin-12 in children, adolescents and young adults with progressive, recurrent or primarily metastatic high-risk tumors”. Detailed immunomonitoring of peripheral blood leucocytes subsets at the baseline and during vaccination is performed and includes routine examined peripheral blood parameters, monocyte subsets, MDSC, specific lymphocyte subsets including Tregs, effector Tcells, NKT-like cells.

Pharmacokinetics of carotenoids and carotene containing compounds

Background. Some natural carotenoids have anti-carcinogenic, anti-mutagenic, and immunomodifying activity and may be considered as potential agents for chemoprevention of cancer. Objective: to study pharmacokinetics of beta-carotene, cantaxantene, lycopene, and carotene-containing compounds created on the base of the mentioned substances. Materials and methods. The study used carotene-containing drugs, which we previously created, such as Betask, Kaskatol, Tomatol, natural carotene-tocopherol complex derived from cankerberry. The research was conducted on mice, rats, rabbits, dogs, piglets, monkeys (Javanese macaque); the observations also involved healthy donors and patients with colorectal cancer before surgery. Carotenoid and retinoid detection was made by high performance liquid chromatography in blood plasma and liver tissue. Results. Comparative analysis of pharmacokinetics of the studied carotenoids demonstrates their relatively low absorption in animals. Bioavailability varies significantly among species; and it increases in the following order: dogs, rabbits, mice, rat, piglets, humans. Pharmacokinetics of carotenoids and carotene-containing compounds was studied with single and multiple administration per os. Cantaxantene and lycopene have a better bioavailability as compared to synthetic beta-carotene. Pharmacokinetics of synthetic carotenes and carotenoids of carotene-containing compounds has no significant differences. Beta-carotene in natural carotene-tocopherol complex has higher bioavailability (2-4 fold higher) as compared to synthetic beta-carotene. Regular complex administration into monkeys results in enhanced beta-carotene levels in blood serum of the animals and inhibits chemically induced carcinogenesis. The patients’ intake of beta-carotene in the pre-operational period was associated with the enhanced pro-vitamin levels in blood serum and stimulation of a number of cellular immune parameters. Conclusions. The studied carotenoids and carotene-containing compounds may be used in combined antitumor therapy and as treatment and prophylactics agents in cancer risk groups.

Combined Chemo-photothermal Antitumor Therapy Using Molybdenum Disulfide Modified with Hyperbranched Polyglycidyl

In the treatment of cancers, molybdenum disulfide (MoS2) has shown great potential as a photoabsorbing agent in photothermal therapy and also as an antitumor drug delivery system in chemotherapy. However, the poor dispersibility and stability of MoS2 in aqueous solutions limit its applications in cancer therapy. To overcome the shortcomings, MoS2 was modified mainly by surface adsorption of linear polymers, such as chitosan and poly(ethylene glycol). As reported, the linear polymers could be more rapidly cleared from blood circulation than their branched counterparts. Herein, we developed hyperbranched polyglycidyl (HPG)-modified MoS2 (MoS2-HPG) by absorbing HPG on the MoS2 surface. The MoS2-HPG as a novel photoabsorbing agent was also used as a nanoscaled carrier to load antitumor drug doxorubicin hydrochloride (DOX) (MoS2-HPG-DOX) for combined chemo-photothermal therapy. The physicochemical and photothermal properties of MoS2-HPG were measured, and the results indicate that MoS2-HPG had good dispersion and stability in aqueous solutions and also high photothermal conversion efficiency. MoS2-HPG displayed good biocompatibility in hemocompatibility and cytotoxicity evaluations in vitro. Furthermore, the combined chemo-photothermal therapy using MoS2-HPG-DOX demonstrated better anticancer effect than the individual chemotherapy or photothermal therapy alone. From the results, MoS2-HPG with combined chemo-photothermal therapy could be developed as a promising therapeutic formulation for clinical cancer treatment.