Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

Duncan, Ruth; Vicent, Marı́a J.; Greco, Francesca; Nicholson, Robert Ian

doi:10.1677/erc.1.01045

Cited by 161 publications

(89 citation statements)

References 55 publications

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“…Many such carrier-bound agents have entered clinical trials with promising results, which has opened a wide field for further challenging exploration. The topic has been amply reviewed over the past two decades [22][23][24][25][26][27][28][29][30][31][32][33].…”

Section: Polymer-drug Conjugation: a Background Discussionmentioning

confidence: 99%

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

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Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist's arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors' laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10-to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs. This article is dedicated to Professor Astruc.

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Section: Polymer-drug Conjugation: a Background Discussionmentioning

confidence: 99%

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

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“…Although the optimum size of the polymer-drug nanoconjugate required for effective accumulation in the tumour by EPR effect is not yet known, direct observation of the tumor vasculature has demonstrated a tumor-dependent cut off size of 200 nm -2 μm (102,103) while nanoparticle-dependent studies indicated cut off size of 200 nm -1.2 μm (104). In the same vein polymer nanoconjugates with molecular diameter 5 -20 nm has been reported to exhibit excellent intratumoural penetration (uptake) comparable to liposomes and nanoparticles (105). It is well documented that polymer-drug nanoconjugates can increase the therapeutic index of anticancer agents through enhanced permeability and retention (EPR) effect (99,100,(106)(107)(108)(109).…”

Section: Passive Targetingmentioning

confidence: 96%

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

Abioye

Chi-Tangyie²,

Kola-Mustapha³

et al. 2016

PNT

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Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design. However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge. Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines. Method: Existing literature was reviewed. Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading (or conjugation) efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) that underpin the safety, quality and efficacy of the nanoconjugates are also presented. Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines.

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“…This increased access to diverse STIs will certainly expand our capacity for rational mono-and combined therapies in cancer. It was also encouraging to hear from Duncan that state-of-the-art drug delivery may allow more efficient and specific therapeutic targeting of the cancer cell, potentially allowing the complex therapeutic targeting strategies proposed in this Workshop to become a reality (Duncan et al 2005).…”

Section: Summary and Challenges For The Future Use Of Stis In Breast mentioning

confidence: 96%

Consensus Statement

Gee¹,

Howell²,

Gullick³

et al. 2005

Endocr Relat Cancer

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Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure antioestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice. Endocrine-Related Cancer (2005) 12 S1-S7Introduction Anti-hormones (notably the selective oestrogen receptor modulator (SERM) tamoxifen), chemotherapy and modern radiotherapeutic approaches have collectively proved invaluable in the management of breast cancer, both as an adjuvant to surgery and in the advanced disease setting. Indeed, they have contributed substantially to the significant improvement in breast cancer survival that we have seen over recent years. Howell (Howell & Wardley 2005) described how we are furthermore on track for continued improvement, with several exciting new anti-hormones reaching the clinic. Of particular note are the aromatase inhibitors (e.g. anastrazole, letrozole and exemestane) and the pure anti-oestrogens (notably fulvestrant (Faslodex)). Both This Consensus Statement reflects views expressed at the 1st Tenovus/AstraZeneca Workshop. AstraZeneca has supported the publication of these proceedings. Endocrine-Related Cancer (2005) 12 S1-S7Endocrine-Related Cancer (2005) 12 S1-S7

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Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

Cited by 161 publications

References 55 publications

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

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