Conjugation of two complementary anti-cancer drugs confers molecular hydrogels as a co-delivery system

Mao, Lina; Wang, Huaimin; Tan, Ming; Ou, Lailiang; Kong, Deling; Yang, Zhimou

doi:10.1039/c1cc16250k

Cited by 113 publications

(73 citation statements)

References 29 publications

(7 reference statements)

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“…In another example, Mao et al designed a dexamethasone-FFFK(PTX/HCPT)E-SS-EE system based on two complementary anticancer drugs for chemotherapy. [189] In this design, PTX serves as an anticancer agent, while dexamethasone acts as an anti-inflammatory to reduce side effects associated with cancer chemotherapy. This multiple complementary prodrug represents a smart co-delivery system for the disease treatment.…”

Section: Prodrug Strategiesmentioning

confidence: 99%

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

Wang

Porter

Konstantopoulos

et al. 2017

Journal of Controlled Release

133

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Paclitaxel (PTX) is one of the most successful drugs ever used in cancer chemotherapy, acting against a variety of cancer types. Formulating PTX with Cremophor EL and ethanol (Taxol®) realized its clinical potential, but the formulation falls short of expectations due to side effects such as peripheral neuropathy, hypotension, and hypersensitivity. Abraxane®, the albumin bound PTX, represents a superior replacement of Taxol® that mitigates the side effects associated with Cremophor EL. While Abraxane® is now considered a gold standard in chemotherapy, its 21% response rate leaves much room for further improvement. The quest for safer and more effective cancer treatments has led to the development of a plethora of innovative PTX formulations, many of which are currently undergoing clinical trials. In this context, we review recent development of PTX drug delivery systems and analyze the design principles underpinning each delivery strategy. We chose several representative examples to highlight the opportunities and challenges of polymeric systems, lipid-based formulations, as well as prodrug strategies.

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Section: Prodrug Strategiesmentioning

confidence: 99%

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

Wang

Porter

Konstantopoulos

et al. 2017

Journal of Controlled Release

133

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“…Drug-based molecular hydrogelators have been in development for almost twenty years now and, in contrast to non-gelating amphiphilic prodrugs, have encompassed a broad range of drug molecules, including inhibitory hormones [139,140], antibiotics [141–143], anti-neoplastics [118,144–147], antiinflammatories [148–151], and anti-virals [152]. The majority of these hydrogelators are peptide-based, as their propensity for hydrogen bonding is ideal for the formation of the filamentous structures generally required for gelation to occur.…”

Section: Supramolecular Hydrogels Formed By Amphiphilic Prodrugsmentioning

confidence: 99%

“…For instance, Yang and coworkers synthesized a conjugate that possessed dexamethasone and either of PTX or HCPT (Fig. 8D) [147]. Dexamethasone is a steroidal drug with anti-inflammatory and immunosuppressant properties that is often used in combination with other anticancer drugs to reduce the associated side-effects [162].…”

Section: Supramolecular Hydrogels Formed By Amphiphilic Prodrugsmentioning

confidence: 99%

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Building nanostructures with drugs

2016

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The convergence of nanoscience and drug delivery has prompted the formation of the field of nanomedicine, one that exploits the novel physicochemical and biological properties of nanostructures for improved medical treatments and reduced side effects. Until recently, this nanostructure-mediated strategy considered the drug to be solely a biologically active compound to be delivered, and its potential as a molecular building unit remained largely unexplored. A growing trend within nanomedicine has been the use of drug molecules to build well-defined nanostructures of various sizes and shapes. This strategy allows for the creation of self-delivering supramolecular nanomedicines containing a high and fixed drug content. Through rational design of the number and type of the drug incorporated, the resulting nanostructures can be tailored to assume various morphologies (e.g. nanospheres, rods, nanofibers, or nanotubes) for a particular mode of administration such as systemic, topical, and local delivery. This review covers the recent advances in this rapidly developing field, with the aim of providing an in-depth evaluation of the exciting opportunities that this new field could create to improve the current clinical practice of nanomedicine.

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“…The lactone ring is necessary for topoisomerase inhibition. 22,23 The active lactone form of SN38 is converted into the inactive carboxylate form at alkaline pH ( Figure 1). However, the activity of the lactone form is much greater than the carboxylate form.…”

Section: Introductionmentioning

confidence: 99%

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

Liu¹,

Piao²,

Gao³

et al. 2015

IJN

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7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C 10 -OH)SN38 and chitosan-(C 20 -OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C 10 -OH)SN38 (CS-(10s)SN38) and chitosan-(C 20 -OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC) 0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P <0.01). A larger AUC 0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 ( P <0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg ( P <0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C 20 -OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

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Conjugation of two complementary anti-cancer drugs confers molecular hydrogels as a co-delivery system

Abstract: We reported in this communication on the first example of a molecular hydrogel system based on two complementary anti-cancer drugs for chemotherapy.

Cited by 113 publications

References 29 publications

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

Building nanostructures with drugs

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

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