scholarly journals Bioinspired Composite, pH-Responsive Sodium Deoxycholate Hydrogel and Generation 4.5 Poly(amidoamine) Dendrimer Improves Cancer Treatment Efficacy via Doxorubicin and Resveratrol Co-Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1069
Author(s):  
Tefera Worku Mekonnen ◽  
Abegaz Tizazu Andrgie ◽  
Haile Fentahun Darge ◽  
Yihenew Simegniew Birhan ◽  
Endiries Yibru Hanurry ◽  
...  
Keyword(s):  
Sodium Deoxycholate ◽  
Pamam Dendrimer ◽  
Intratumoral Injection ◽  
Biomedical Science ◽  
Antitumor Effects ◽  
Effective Combination ◽  
Release Studies ◽  
Antitumor Chemotherapy ◽  
Extracellular Microenvironment

Maximizing the antitumor efficacy of doxorubicin (DOX) with a new drug delivery strategy is always desired in the field of biomedical science. Because the clinical applications of DOX in the treatment of cancer is limited by the side effects related to the dose. Herein, we report the co-loading of DOX and resveratrol (RESV) using an injectable in situ formed sodium deoxycholate hydrogel (Na-DOC-hyd) at the pH of the tumor extracellular microenvironment. The sequential, controlled, and sustained release of RESV and DOX for synergistic antitumor effects was confirmed by entrapping G4.5-DOX in the RESV-loaded Na-DOC hydrogel (Na-DOC-hyd-RESV). The synergistic antitumor activity of Na-DOC-hyd-RESV+G4.5-DOX was assessed on HeLa cell xenograft tumor in BALB/c nude mice. In the MTT biocompatibility assay, both the G4.5 PAMAM dendrimer and Na-DOC-hyd exhibited negligible cytotoxicity up to the highest dose of 2.0 mg mL−1 in HeLa, MDA-MB-231, and HaCaT cells. The release profiles of DOX and RESV from the Na-DOC-hyd-RESV+G4.5-DOX confirmed the relatively rapid release of RESV (70.43 ± 1.39%), followed by that of DOX (54.58 ± 0.62%) at pH 6.5 in the 7 days of drug release studies. A single intratumoral injection of Na-DOC-hyd-RESV+G4.5-DOX maximally suppressed tumor growth during the 28 days of the treatment period. Na-DOC-hyd-RESV+G4.5-DOX did not cause any histological damage in the major visceral organs. Therefore, this Na-DOC-hydrogel for dual drugs (DOX and RESV) delivery at the pH of the tumor extracellular microenvironment is a promising, safe, and effective combination for antitumor chemotherapy.

scholarly journals Advances in Injectable In Situ-Forming Hydrogels for Intratumoral Treatment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1953
Author(s):  
Gi Ru Shin ◽  
Hee Eun Kim ◽  
Jae Ho Kim ◽  
Sangdun Choi ◽  
Moon Suk Kim
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Intratumoral Injection ◽  
Chemotherapeutic Agents ◽  
Antitumor Effects ◽  
In Situ Forming ◽  
Target Organs ◽  
In Situ Forming Hydrogels ◽  
Delivery Technology

Chemotherapy has been linked to a variety of severe side effects, and the bioavailability of current chemotherapeutic agents is generally low, which decreases their effectiveness. Therefore, there is an ongoing effort to develop drug delivery systems to increase the bioavailability of these agents and minimize their side effects. Among these, intratumoral injections using in situ-forming hydrogels can improve drugs’ bioavailability and minimize drugs’ accumulation in non-target organs or tissues. This review describes different types of injectable in situ-forming hydrogels and their intratumoral injection for cancer treatment, after which we discuss the antitumor effects of intratumoral injection of drug-loaded hydrogels. This review concludes with perspectives on the future applicability of, and challenges for, the adoption of this drug delivery technology.

scholarly journals The Effect of Bile Salts on the Permeability and Ultrastructure of the Perfused, Energy-Depleted, Rat Blood-Brain Barrier

1991 ◽  
Vol 11 (4) ◽  
pp. 644-654 ◽  
Author(s):  
J. Greenwood ◽  
J. Adu ◽  
A. J. Davey ◽  
N. J. Abbott ◽  
M. W. B. Bradbury
Keyword(s):  
Blood Brain Barrier ◽  
Bile Salts ◽  
Structural Changes ◽  
Sodium Deoxycholate ◽  
Ringer Solution ◽  
Brain Barrier ◽  
Rat Blood ◽  
Blood Brain ◽  
Ultrastructural Damage

The action of bile salts upon the rat blood–brain barrier (BBB) was assessed in the absence of energy-yielding metabolism. Brains were perfused in situ with a Ringer solution for 5 min followed by a 1 min perfusion containing either sodium deoxycholate (DOC), taurochenodeoxycholate (TCDC), or Ringer/DNP. The integrity of the BBB was then determined by perfusing with the radiotracer [14C]mannitol for 2.5 min. Alternatively, the brains were perfusion fixed for ultrastructural assessment. At 0.2 m M DOC, the BBB remained intact and the cerebral ultrastructure was similar to the controls. At 1 m M and above, disruption of the BBB became evident. At 2 m M, the cerebral cortex became severely vacuolated, with damaged endothelium and collapsed capillaries. With TCDC, BBB disruption occurred at 0.2 m M without any apparent ultrastructural damage to the micro vasculature. Following 2 m M TCDC, similar, but less widespread, structural changes to the 2 m M DOC-perfused animals was apparent. Opening of the BBB occurred at a concentration lower than that required to cause lysis of either red blood cells or cultured cerebral endothelial cells. It is proposed that the effect of bile salts at concentrations of 1.5 m M and above is largely due to their lytic action as strong detergents on endothelial cell membranes, but that at lower concentrations a more subtle modification of the BBB occurs.

FORMULATION DEVELOPMENT AND EVALUATION OF AN IN SITU OPHTHALMIC GELLING SYSTEM OF BRIMONIDINE TARTRATE AND TIMOLOL MALEATE FOR THE TREATMENT OF GLAUCOMA

INDIAN DRUGS ◽  
2017 ◽  
Vol 54 (02) ◽  
pp. 76-78
Author(s):  
A Shirodker ◽  
◽  
S. Bhangle ◽  
R. Gude
Keyword(s):  
Hydroxypropyl Methylcellulose ◽  
In Vitro Release ◽  
Content Uniformity ◽  
Formulation Development ◽  
Timolol Maleate ◽  
Release Studies ◽  
Brimonidine Tartrate ◽  
In Situ Gelling

The present study involved formulation of an in situ gelling system of brimonidine tartrate and timolol maleate for the treatment of glaucoma. Carbopol® 980 NF, xanthum gum and hydroxypropyl methylcellulose K4 M were used as polymers. The prepared in situ gelling systems were evaluated for clarity, appearance, texture analysis, pH, viscosity, rheological properties, in vitro gelation, isotonicity, drug content uniformity, in vitro release studies, microbiological evaluation, ex vivo release studies and stability testing. The results of the attenuated total reflectance spectroscopy and differential scanning calorimetry studies confirmed that there is no incompatibility between the drugs and the excipients. The formulations exhibited pseudoplastic rheology and formulation 3 showed the highest release of both the drugs from the formulation. The stability studies showed that the formulation was stable over the given period of time. Thus, it is evident that the in situ gelling system is a promising drug delivery system for the treatment of glaucoma.

scholarly journals The Abscopal Effect: Could a Phenomenon Described Decades Ago Become Key to Enhancing the Response to Immune Therapies in Breast Cancer?

Breast Care ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. 443-449
Author(s):  
Hans-Christian Kolberg ◽  
Oliver Hoffmann ◽  
René Baumann
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Antitumor Immune Response ◽  
Abscopal Effect ◽  
Antitumor Effects ◽  
Effective Combination ◽  
Immunological Mechanisms ◽  
Immune Therapies

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

scholarly journals Simple and effective bacterial-based intratumoral cancer immunotherapy

2021 ◽  
Vol 9 (9) ◽  
pp. e002688
Author(s):  
Christina S E Carroll ◽  
Erin R Andrew ◽  
Laeeq Malik ◽  
Kathryn F Elliott ◽  
Moira Brennan ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Human Cancer ◽  
Intratumoral Injection ◽  
Ct Scans ◽  
Antitumor Effects ◽  
Wide Range

BackgroundWe describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.MethodsEfficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.ResultsSignificantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.ConclusionOur data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.

Speedy one-pot electrochemical synthesis of giant octahedrons from in situ generated pyrrolidinyl PAMAM dendrimer

Soft Matter ◽  
2020 ◽  
Vol 16 (39) ◽  
pp. 9140-9146
Author(s):  
Anup Singhania ◽  
Mrinal Dutta ◽  
Supriya Saha ◽  
Pathik Sahoo ◽  
Bharati Bora ◽  
...  
Keyword(s):  
Electrochemical Synthesis ◽  
Pamam Dendrimer ◽  
One Pot ◽  
Radical Generation

A novel electrochemical synthesis via a radical generation pathway is described here for the generation of a quaternary megamer structure from secondary dendrimers.

Local and systemic antitumor effects of activated autologous dendritic cells for intratumoral injection: A phase I/II trial.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. TPS3133-TPS3133
Author(s):  
Vivek Subbiah ◽  
Ravi Murthy ◽  
Omar Kayaleh ◽  
Marnix Leo Bosch
Keyword(s):  
Dendritic Cells ◽  
Phase I ◽  
Intratumoral Injection ◽  
Antitumor Effects

T Cell Modulation Combined with Intratumoral CpG Cures Lymphoma without the Need for Chemotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1581-1581
Author(s):  
Roch Houot ◽  
R. Levy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Folate Receptor ◽  
Costimulatory Molecule ◽  
Therapeutic Vaccine ◽  
Intratumoral Injection ◽  
Cell Immunity ◽  
Cpg Oligodeoxynucleotide

Abstract Introduction: We have previously shown that intratumoral injection of CpG oligodeoxynucleotide plus systemic chemotherapy can induce T cell immunity against lymphoma and serve as a therapeutic vaccine to cure tumors in a murine lymphoma model (Li et al., J Immunol. 2007). CpG is a Toll-like receptor 9 agonist capable of activating tumor-infiltrating dendritic cells and/or tumor B cells to force tumor antigen presentation in situ when injected intratumorally. Here, we demonstrate that antibody-mediated modulation of T cells enhances the efficacy of CpG vaccination, thereby eliminating the need for chemotherapy. Materials and Methods: Mice were inoculated s.c. with A20 lymphoma tumor cells at two sites (right and left abdomen). Only one site was injected with CpG allowing us to evaluate the systemic anti-tumor response at the distant site. Treatment started when tumors became palpable. CpG was administered intratumorally. T cell modulation was accomplished using systemic (i.p.) administration of monoclonal antibodies against T cell targets: - Regulatory T cells were depleted using anti-Folate Receptor 4 (FR4) antibody or functionally blocked using anti-GITR antibody, - Effector T cells were stimulated using anti-OX40 antibody (to trigger their costimulatory molecule) or anti-CTLA4 antibody (to block inhibitory signals). Results: Treatment with intratumoral injection of CpG alone did not cure any mice. Treatment with CpG and a single antibody (anti-OX40, anti-CTLA4, anti-FR4, or anti-GITR) cured 20–30% of mice. Interestingly, some combinations of antibodies (anti-OX40+anti-CTLA4, anti-OX40+anti-FR4, anti-CTLA4+anti-GITR) potentiated T cell modulation and further enhanced the efficacy of CpG vaccination. In particular, the combination of anti-OX40 and anti-CTLA4 appeared to be especially potent when combined with intratumoral CpG. Indeed, this combination (CpG+anti-OX40+anti-CTLA4) induced anti-tumor T cells capable of secreting IFN-γ in response to overnight culture with A20 tumor cells; it cured more than 80% of mice bearing large and systemic lymphoma tumors without the need for chemotherapy (effective therapy required both CD4 and CD8 T cells); finally, this therapy produced high numbers of anti-tumor memory T cells and provided long-lasting immunity against tumor re-challenge. Conclusions: Our results show that antibody-mediated T cell modulation greatly enhances the therapeutic efficacy of intratumoral vaccination with CpG. Importantly, we show that T cell modulation can be potentiated by appropriate combinations of antibodies against T cell targets. As these reagents (CpG, anti-OX40 and anti-CTLA4 notably) are becoming available for human clinical trials, the combination of intratumoral CpG and immunomodulatory T cell antibodies holds promise for therapeutic vaccination against lymphoma.

scholarly journals An Available Strategy for Nasal Brain Transport of Nanocomposite Based on PAMAM Dendrimers via In Situ Gel

Nanomaterials ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 147 ◽  
Author(s):  
Huichao Xie ◽  
Lingjun Li ◽  
Yue Sun ◽  
Yuzhen Wang ◽  
Shuang Gao ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Drug Carriers ◽  
Pamam Dendrimer ◽  
Pamam Dendrimers ◽  
In Situ Gel ◽  
Transport Efficiency ◽  
Plastic Fluid ◽  
The Brain

Polyamidoamine (PAMAM) dendrimers are efficient drug carriers. The presence of a physiological pathway for nasal brain transport provides a potential path for direct brain-targeted delivery of dendrimer nanocomposites. In this study, we synthesized PAMAM dendrimer composites with a nanoscale size; the particle size of PAE (Paeonol)/mPEG (the heterofunctional PEG polymer with a methoxy)-PAMAM G5.NHAc and mPEG-PAMAM G5.NH2-FITC were 72.41 ± 11.58 nm and 96.51 ± 7.77 nm, and the zeta potential of PAE/mPEG-PAMAM G5.NHAc and mPEG-PAMAM G5.NH2-FITC were + 0.57 ± 0.11 mv and + 9.60 ± 0.41 mv, respectively. The EE% and DL% of PAE in PAE/mPEG-PAMAM G5.NHAc were 53.77% and 13.92%, respectively. PAE/mPEG-PAMAM G5.NHAc/DGG ionic-sensitive in situ gel was prepared, the viscosity of solution and gel state were 112 ± 3.2 mPa and 1403 ± 38.5 mPa, respectively. The in vitro goat mucoadhesive strength of the gel was 4763.36 ± 85.39 dyne/cm2. In situ gel system was proven to be a non-Newtonian pseudo-plastic fluid with shear thinning, thixotropy and yield stress. The optimal model of PAE released from PAE/mPEG-PAMAM G5.NHAc and PAE/mPEG-PAMAM G5.NHAc/DGG were the Higuchi equation and the Korsmeyer-Peppas equation, respectively. The cytotoxicity of the nanocomposites showed a concentration-dependence, and the cell viabilities of PAE/mPEG-PAMAM G5.NHAc were both higher than 95% between 0.0001 μM and 10 μM. mPEG-PAMAM G5.NH2-FITC was efficiently taken up by cells and exhibited strong fluorescence in the cytoplasm and nucleus. Significant accumulation of nanocomposites was observed in the brain after administration of the in situ gel group, and maximum accumulation was reached at 12 h. A small amount of accumulation was observed in the nanocomposite solution group only at 2 h. Therefore, the direct nasal brain transport efficiency of PAMAM dendrimer nanocomposites can be significantly improved after combining with in situ gel. PAMAM dendrimer nanocomposite/DGG is a potential drug delivery system for nasal brain transport.

scholarly journals Antitumor Effects of Curcumin and Glycyrrhetinic Acid-Modified Curcumin-Loaded Cationic Liposome by Intratumoral Administration

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Mingxiang Chang ◽  
Meimei Wu ◽  
Hanmin Li
Keyword(s):  
Antitumor Effect ◽  
Curcuma Longa ◽  
Cationic Liposome ◽  
Intratumoral Injection ◽  
Glycyrrhetinic Acid ◽  
Experimental Results ◽  
High Dose ◽  
Antitumor Activities ◽  
Antitumor Effects ◽  
Experimental Conditions

Curcumin is a hydrophobic polyphenolic compound extracted from the rhizome of Curcuma longa and shows a line of active biological functions, but its application has been limited and questioned because of its low solubility, low bioavailability, and rapid metabolism. In terms of antitumor effect, these disadvantages can be overcome by intratumoral injection. In this study, we present the intratumoral injection of curcumin and glycyrrhetinic acid-modified curcumin-loaded cationic liposome (GAMCLCL) in H22 tumor-bearing mice. The experimental results demonstrated that curcumin exhibited positive antitumor activities in vitro and in vivo by intratumoral injection, but its activities were much weaker than GAMCLCL and adriamycin. Compared with free curcumin, GAMCLCL showed much better effects in improving the blood parameters (WBC, RBC, PLT, ALT, CRE, and LDH), inhibiting tumor growth, reducing tumor microvascular density, downregulating the expression of VEGF-protein and mRNA, and upregulating the expression of caspase-3 protein and mRNA in H22 tumor tissues. Under the experimental conditions of this study, the antitumor effect of high-dose GAMCLCL was similar to adriamycin. In conclusion, the experimental results demonstrated that free curcumin possessed definite antitumor efficacy, but its antitumor activities were weaker, and some strategies should be adopted to overcome its disadvantages, improve, and ensure its clinical efficacy.

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