A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer

Vogus, Douglas R.; Evans, Michael A.; Pusuluri, Anusha; Barajas, Alexandra; Zhang, Mengwen; Krishnan, Vinu; Nowak, Maksymilian; Menegatti, Stefano; Helgeson, Matthew E.; Squires, Todd M.; Mitragotri, Samir

doi:10.1016/j.jconrel.2017.08.016

Cited by 77 publications

(65 citation statements)

References 54 publications

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“…Recently, a number of HA-based drug carriers for antitumor drugs have been developed, [43][44][45][46] and they improved antitumor activity of the drugs in vivo. However, antitumor drugs often cause adverse effects, but M-β-CyD is expected to provide slight side effects because it has been widely used as pharmaceutical excipients, compared to common antitumor drugs.…”

Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

et al. 2018

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Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

et al. 2018

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“…Severe toxicity issues have impaired the clinical progress of combination chemotherapy, but several preclinical studies and clinical studies outlining ways to mitigate this toxicity foreshadow its reemergence. By controlling drug molar ratios and schedules of chemotherapeutics, higher efficacies at low doses have been obtained . We propose an optimized combination of DOX and CPT as a low dose therapy option for aggressive breast cancer.…”

Section: Resultsmentioning

confidence: 99%

“…By controlling drug molar ratios and schedules of chemotherapeutics, higher efficacies at low doses have been obtained. 11,53,54 We propose an optimized combination of DOX and CPT as a low dose therapy option for aggressive breast cancer. DOX and CPT were found to be a potent drug pair that exhibited molar ratio-dependent synergy against human triple negative breast cancer cells, MDA-MB-231.…”

Section: Discussionmentioning

confidence: 99%

Role of synergy and immunostimulation in design of chemotherapy combinations: An analysis of doxorubicin and camptothecin

Pusuluri

Krishnan

et al. 2019

Bioengineering & Transla Med

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Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near‐their maximum tolerated doses (MTDs), elevating the risk of dose‐related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low‐dose treatment option for breast cancer. DOX‐CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA‐MB‐231). This combination led to excellent long‐term survival of mice bearing MDA‐MB‐231 tumors at doses roughly five‐fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX‐CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.

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“…In addition, many studies tested the synergy between Dox and Gem in different types of cancer [16][17][18][19][20][21] . The main mechanism of action of Dox is the intercalation with DNA and disruption of topoisomerase-II-mediated DNA repair and generation of free radicals and their damage to cellular membranes 22 .…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Liposomal Drug Loading by Using Supersaturated Drug Solution

Tamam

Abdel-Aleem

Abdel-Rahman

et al. 2019

Bulletin of Pharmaceutical Sciences. Assiut

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Liposomes are used for systemic delivery of chemotherapeutic drugs to reduce their nonspecific side effects. Liposomes can encapsulate hydrophilic and lipophilic drugs in the water compartment and the lipid membrane, respectively. However, typical drug loading capacity of liposomes by passive loading method is less than 1%. The low drug loading efficiency is problematic because it necessitates the use of a large amount of carrier materials that may cause undesirable biological effects. To increase drug loading in liposomes, weusedsupersaturated drug solutionswith gemcitabine (GEM) and doxorubicin (Dox) as examples. The prepared liposomes showed higher drug loading compared with passive loading, maintainedstabilityand provided sustained drug release for 48 hrs.

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A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer

Cited by 77 publications

References 54 publications

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

Role of synergy and immunostimulation in design of chemotherapy combinations: An analysis of doxorubicin and camptothecin

Enhancement of Liposomal Drug Loading by Using Supersaturated Drug Solution

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