scholarly journals Bioorthogonal Prodrug–Antibody Conjugates for On-Target and On-Demand Chemotherapy

CCS Chemistry ◽  
2019 ◽  
Vol 1 (2) ◽  
pp. 226-236 ◽  
Author(s):  
Feng Lin ◽  
Long Chen ◽  
Heng Zhang ◽  
William Shu Ching Ngai ◽  
Xiangmei Zeng ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Agent ◽  
Tissue Penetration ◽  
Tumor Penetration ◽  
On Demand ◽  
Drug Conjugates ◽  
Antibody Conjugates ◽  
Antibody Conjugate ◽  
Chemotherapy Agents ◽  
Premature Release

Current antibody–drug conjugates (ADCs) suffer from low tissue penetration and significant side effects, largely due to the permanent linkage and/or premature release of cytotoxic payloads. Herein, we developed a prodrug–antibody conjugate (ProADC) strategy by conjugating a bioorthogonal-activatable prodrug with an antibody that allowed on-target release and on-demand activation of cytotoxic drugs at a tumor site. The bioorthogonal-caged prodrug exhibited an enhanced permeability into and on-demand activation within cancer cells, while the pH-sensitive ADC linker allowed on-target release of the anticancer agent. Together, the ProADCs showed enhanced tumor penetration and alleviated side effects for use as an on-target and on-demand chemotherapy agents.

scholarly journals Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

2021 ◽  
Vol 14 (4) ◽  
pp. 343
Author(s):  
Ahmad Fawzi Hussain ◽  
Armin Grimm ◽  
Wenjie Sheng ◽  
Chaoyu Zhang ◽  
Marwah Al-Rawe ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Amino Acid Residues ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Site Specific ◽  
Drug Conjugates ◽  
Complement Dependent Cytotoxicity ◽  
Antibody Conjugates ◽  
Specific Antigens ◽  
Antibody Conjugate ◽  
Therapeutic Mechanisms

In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific antigens and their therapeutic mechanisms such as blocking specific pathways, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Furthermore, modification techniques have paved the way for improving antibody properties and to develop new classes of antibody-conjugate-based diagnostic and therapeutic agents. These techniques allow arming antibodies with various effector molecules. However, these techniques are utilizing the most frequently used amino acid residues for bioconjugation, such as cysteine and lysine. These bioconjugation approaches generate heterogeneous products with different functional and safety profiles. This is mainly due to the abundance of lysine and cysteine side chains. To overcome these limitations, different site-direct conjugation methods have been applied to arm the antibodies with therapeutic or diagnostics molecules to generate unified antibody conjugates with tailored properties. This review summarizes some of the enzyme-based site-specific conjugation approaches.

scholarly journals Research Progress of Thermosensitive Hydrogel in Tumor Therapeutic

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Nian Ma ◽  
Zhihui Yan
Keyword(s):  
Side Effects ◽  
Tumor Therapy ◽  
Thermal Therapy ◽  
Research Progress ◽  
Therapeutic Effects ◽  
Tumor Treatment ◽  
Tissue Penetration ◽  
Thermosensitive Hydrogel ◽  
Minimal Invasiveness ◽  
On Demand

AbstractCompared with traditional tumor therapy strategies, hydrogel as a drug reservoir system can realize on-demand drug release and deep tissue penetration ability. It also exhibits great tumor-site retention to enhance the permeability and retention effect of tumor treatment. This can significantly overcome the drug's resistance and severe side effects. Inorganic/organic composite hydrogel has attracted wide attention due to its combined effects, enhancing therapeutic effects against various kinds of tumors. In situ injectable hydrogel can securely restrict the drugs in the lesion sites without leakage and guarantee better biosafety. Moreover, hydrogel possesses interconnected macropores which can provide enough space for nutrient transport, cellular activity, and cell–cell interactions. Thermal therapy is an effective strategy for tumor therapy due to its minimal invasiveness and high selectivity. Because the location temperature can be precisely controlled and helps avoid the risks of destroying the body's immune system and ablate normal cells, thermal therapy exhibits significant treatment outcomes. Nonetheless, when the cellular temperature reaches approximately 43 °C, it causes long-term cell inactivation. Based on these merits, thermosensitive hydrogel formulation with adaptive functions shows excellent efficacy, unlimited tissue penetration capacity, and few deleterious side effects. Furthermore, the thermosensitive hydrogel has unique physical properties under the external stimuli, which is the ideal drug delivery system for on-demand release in tumor treatment. This article will review the state of the thermosensitive hydrogel in clinic application for cancer therapy.

scholarly journals Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Guolan Lu ◽  
Naoki Nishio ◽  
Nynke S. van den Berg ◽  
Brock A. Martin ◽  
Shayan Fakurnejad ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Tissue Penetration ◽  
Antibody Drug Conjugates ◽  
Tumor Penetration ◽  
Drug Conjugates ◽  
Phase Clinical Trial ◽  
Dosing Strategy ◽  
Intratumoral Distribution ◽  
Dose Limiting Toxicity ◽  
Antibody Drug

Abstract Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.

Vitamin D as potential therapeutic anticancer agent

2018 ◽  
pp. 1-3
Keyword(s):  
Vitamin D ◽  
Anticancer Activity ◽  
Anticancer Agent ◽  
Antitumor Agents ◽  
Metastatic Potential ◽  
Anticancer Properties ◽  
Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

Beta-Blocker Attenuates Cardiotoxicity Related Anthracycline Usage

2021 ◽  
Vol 104 (8) ◽  
pp. 1389-1392
Keyword(s):  
Side Effects ◽  
Cancer Therapy ◽  
Mortality Rate ◽  
Cancer Patients ◽  
Beta Blocker ◽  
The Other ◽  
Large Numbers ◽  
Therapy Effectiveness ◽  
Chemotherapy Agents

To summarize the recent trials and studies of the role of beta-blocker on the treatment for cancer patients treated with anthracycline to decrease morbidity and mortality rate. Good management of cancer will result in large numbers of cancer survivors. On the other hand, cancer therapy also has side effects, one of which is cardiotoxicity. Cardiotoxicity could reduce therapy effectiveness, hence, increase disease progression and mortality rate. Anthracyclines is one of the chemotherapy agents with cardiotoxicity as a side effect. Beta-blocker has the ability to reduce cardiotoxicity due to anthracyclines usage. Keywords: Beta-blocker; Cardiotoxicity; Anthracyclines

scholarly journals Family’s experience in Caring of Cancer Patient undergoing Oral Chemotherapy : A Study Phenomenology

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Nurul Huda ◽  
Erwin Erwin ◽  
Eka Febriyanti
Keyword(s):  
Health Care ◽  
Side Effects ◽  
Cancer Patient ◽  
Side Effect ◽  
Oral Chemotherapy ◽  
Family Experience ◽  
Home Setting ◽  
Manage Care ◽  
Improve Compliance ◽  
Chemotherapy Agents

ABSTRACTThe use of Oral Chemotherapy is increasing nowadays. Family who directly involve in caring the patient should be aware of the side effect and how to handle this agent safely. Phenomenology approach of qualitative study was conducted to get illustration regarding family experience in managing care of patient receiving oral chemotherapy. Data was collected by semi structured interviewed. Study gathered from 10 participants who meet criteria. The current study showed that three temathic item related to how they manage care to their family’s member. Those are 1) Lack of knolwedge about oral chemotherapy, 2) Confusing in handling safe oral chemotherapy and 3) lack of ability in caring patients when  side effect appeared and following adherence. These three things are considered lacked by the patients.  Therefore, health care professional especially nurses are expected to give more education and attention about administering oral chemotherapy agents, safe handling, adherence and managing side effects  both of in clinical and home setting. Multi-component interventions that include education, equipment, and technology can improve compliance with oral chemotherapy and will help families to secure and provide the appropriate affection to them.ABSTRAKPenggunaan kemoterapi oral semakin meningkat saat ini. Keluarga yang secara langsung terlibat dalam merawat pasien harus menyadari efek samping dan cara menangani terapi ini dengan aman. Penelitian kualitatif dengan pendekatan fenomenologi dilakukan untuk mendapatkan gambaran mengenai pengalaman keluarga dalam mengelola perawatan pasien yang menerima kemoterapi oral. Data dikumpulkan secara semi terstruktur melalui wawancara. Penelitian ini terdiri dari 10 partisipan keluarga yang memenuhi kriteria inklusi. Hasil penelitian menunjukkan  terdapat tiga tema terkait bagaimana keluarga merawat pasien dengan oral chemotherapy di rumah. Ketiga tema tersebut adalah 1) kurangnya pengetahuan keluarga tentang oral kemoterapi, 2) kebingungan keluarga dalam penanganan keamanan oral chemotherapy dan 3) ketidakmampuan keluarga dalam menangani efek samping dan menjaga kepatuhan. Ketiga hal ini dianggap masih belum bisa dilakukan oleh keluarga dan membutuhkan bimbingan serta informasi dari petugas kesehatan. Oleh karena itu, petugas kesehatan professional terutama perawat diharapkan dapat memberikan edukasi dan perhatian yang lebih kepada keluarga  tentang bagaimana pemberian kemoterapi oral yang baik, penanganan yang aman serta peningkatan kepatuhan dalam menjalani perawatan. Memberikan intervensi multikomponen yang mencakup pendidikan, peralatan pendukung, dan teknologi dipercayai dapat meningkatkan kemampuan dalam perawatan dan kepatuhan dalam menjalani kemoterapi oral, sehingga  dapat membantu keluarga untuk memberikan rasa aman dan kasih sayang yang kepada pasien.

scholarly journals Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Chemija ◽  
2018 ◽  
Vol 29 (4) ◽  
Author(s):  
Jonas Šarlauskas ◽  
Aušra Nemeikaitė-Čėnienė ◽  
Audronė Marozienė ◽  
Lina Misevičienė ◽  
Mindaugas Lesanavičius ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Agent ◽  
Redox Cycling ◽  
Nitroaromatic Compounds ◽  
Single Electron ◽  
Reductive Activation ◽  
Cell Nuclei ◽  
Electron Reduction ◽  
Phenylene Diamine

Aerobic cytotoxicity of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ), a bioreductively activated hypoxia-specific anticancer agent, is responsible for TPZ side effects in chemotherapy. In order to clarify its mechanisms, we examined the aerobic cytotoxicity of TPZ and its main metabolites, 3-amino-1,2,4-benzotriazine-1-oxide and 3-amino-1,2,4-benzotriazine in murine hepatoma MH22a cells, and their reduction by NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP+ reductase (FNR). Analogous studies of several quinones and nitroaromatic compounds with similar values of single-electron reduction midpoint potentials (E17) were carried out. In single-electron reduction by P-450R and FNR, the reactivity of TPZ and its monoxide was similar to that of quinones and nitroaromatics, and increased with an increase in their E17. The cytotoxicity of TPZ and its metabolites possessed a prooxidant character, because it was partly prevented by an antioxidant N,N’-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. Importantly, the cytotoxicity of TPZ and, possibly, its 1-N-oxide, was much higher than that of quinones and nitroaromatics with similar values of E17 and redox cycling activities. A possible additional factor in the aerobic cytotoxicity of TPZ is its reductive activation in oxygen-poor cell nuclei, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

scholarly journals Polymer-Drug Conjugate, a Potential Therapeutic to Combat Breast and Lung Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 406 ◽  
Author(s):  
Sibusiso Alven ◽  
Xhamla Nqoro ◽  
Buhle Buyana ◽  
Blessing A. Aderibigbe
Keyword(s):  
Lung Cancer ◽  
Side Effects ◽  
Anticancer Drugs ◽  
Drug Conjugates ◽  
Body Tissues ◽  
Cell Tissue ◽  
High Death Rate ◽  
High Death ◽  
Life Threatening ◽  
Polymer Drug Conjugates

Cancer is a chronic disease that is responsible for the high death rate, globally. The administration of anticancer drugs is one crucial approach that is employed for the treatment of cancer, although its therapeutic status is not presently satisfactory. The anticancer drugs are limited pharmacologically, resulting from the serious side effects, which could be life-threatening. Polymer drug conjugates, nano-based drug delivery systems can be utilized to protect normal body tissues from the adverse side effects of anticancer drugs and also to overcome drug resistance. They transport therapeutic agents to the target cell/tissue. This review article is based on the therapeutic outcomes of polymer-drug conjugates against breast and lung cancer.

Secondary Long-Term Prophylaxis in Severe Patients with von Willebrand’s Disease: An Italian Cohort Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1782-1782 ◽  
Author(s):  
Augusto B. Federici ◽  
Francesca Gianniello ◽  
Maria T. Canciani ◽  
Pier M. Mannucci
Keyword(s):  
Cohort Study ◽  
Side Effects ◽  
Von Willebrand's Disease ◽  
Packed Red Blood Cells ◽  
Von Willebrand’S Disease ◽  
On Demand ◽  
Before And After ◽  
Type 3 ◽  
Design And Methods

Abstract Background and Objectives. Patients with severe forms of von Willebrand’s disease (VWD) may have frequent episodes of mucocutaneous bleeding and also of hemarthrosis or hematomas. However, little retrospective or prospective data on secondary long term prophylaxis in VWD are available. Aim of this study was to evaluate the efficacy and safety of fixed regimens of prophylaxis with factor VIII/VWF concentrates in our cohort of VWD patients with recurrent joint and gastrointestinal (GI) bleeds. Design and Methods. This is a cohort study on 452 VWD patients regularly followed up at our Center for at least three years. 89/452 cases (20%) were treated with FVIII/VWF concentrates during the last two years because of one or more bleedings and 11/89 (12%) were included in a long term prophylaxis program because of frequent recurrence of bleeds at the same sites. All patients were characterized by a bleeding severity score derived from a detailed history of 11 symptoms. Since concentrates available in Italy are still labelled in FVIII IU, patients were given 40 FVIII IU/Kg of high- (Alphanate, Fanhdi) or intermediate-purity (Haemate-P) concentrates, two times a week (joint bleeds) or every other day (GI bleeds) to maintain FVIII/VWF levels higher than baseline during prophylaxis. Effectiveness of prophylaxis was based on resolution/reduction of bleeding as well as on numbers of transfused packed red blood cells (PRBC) and days of hospitalization. Safety was measured by monitoring side effects and FVIII levels before and after every injection during the first three weeks of prophylaxis. Results. All the 11 patients were severe, as shown by high bleeding scores (> 20) and VWF:RCo baseline levels <10 U/dL. Prophylaxis was started because of GI bleeds in 7 patients with VWD type 3 (n=1), 2A (n=4), 2M (n=1) and 1 (n=1) and for joint bleeds only in VWD type 3 (n= 4). Prophylaxis could stop bleeding in 8 patients and largely reduced hospitalization for PRBC transfusions in the remaining 3. When prophylaxis was compared with previous on demand regimen in all 11 cases, the annual total FVIII IU (x 1000) of concentrate (a) as well as number of PRBC used (b) and days of hospitalization (c) were significantly reduced (mean ± SD, with * p < 0.01): a * = 239±207 versus 385±247; b* = 9±11 versus 3±4; c* = 18±13 versus 4±3. As far as safety, FVIII levels were always <180 U/dL in all VWD and no side effects, including thrombosis, were observed. Interpretations and Conclusions. Secondary long-term prophylaxis by high-and intermediate purity FVIII/VWF concentrates is effective and safe in severe forms of VWD. Cost-effectiveness of these prophylaxis regimens versus on demand therapy should be further investigated in large prospective studies.

Immunotherapy releated cardiomyopathy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14601-e14601
Author(s):  
Ozlem Sonmez ◽  
Ozlem Nuray Sever ◽  
Basak Oyan ◽  
Osman Gokhan Demir
Keyword(s):  
Side Effects ◽  
Checkpoint Inhibitors ◽  
Rare Complication ◽  
Single Agent ◽  
Tnf Alpha ◽  
Oncology Practice ◽  
And Control ◽  
Chemotherapy Agents ◽  
As Effects ◽  
Cessation Of Treatment

e14601 Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.

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