Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer (original) (raw)
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Polymer therapeutics encompasses polymer–drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds.
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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.
Advanced Drug Delivery Reviews, 2009
The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer-drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.
International journal of pharmaceutics, 2018
Utilizing the diverse features of biocompatible polymers to target drugs into the tumor/s has been a research hotspot since last decade. Such polymeric conjugates of anti-cancer drugs have proven their potential in providing sustained release of drugs with reduced systemic toxicity and improved tumor retention. Polymers like polyethylene glycol (PEG), N-(2-Hydroxypropyl) methacrylamide (HPMA), Polylactic-co-glycolic acid (PLGA), Polyamidoamine (PAMAM), and others remain exploited for their specific as well as shared characteristics in the rational delivery of anti-cancer agents. Variable nano size, attachment with tumor-specific proteins, responsiveness to stimuli and ability to deliver a wide range of molecules like drugs, antibodies and peptides are some of the achievements of polymeric nano-conjugates so far. Many such conjugates have shown potential clinically which has attracted the researchers and promoted further advancements of the technique. Apart from achievements the poly...
Polymer–drug conjugates for novel molecular targets
Nanomedicine, 2010
Polymer therapeutics can be already considered as a promising field in the human healthcare context. The discovery of the enhanced permeability and retention effect by Maeda, together with the modular model for the polymer–drug conjugate proposed by Ringsdorf, directed the early steps of polymer therapeutics towards cancer therapy. Orthodox anticancer drugs were preferentially chosen in the development of the first conjugates. The fast evolution of polymer chemistry and bioconjugation techniques, and a deeper understanding of cell biology has opened up exciting new challenges and opportunities. Four main directions have to be considered to develop this ‘platform technology’ further: the control of the synthetic process, the exhaustive characterization of the conjugate architectures, the conquest of combination therapy and the disclosure of new therapeutic targets. We illustrate in this article the exciting approaches offered by polymer–drug conjugates beyond classical cancer therapy...
HPMA-based polymeric conjugates in anticancer therapeutics
Drug Discovery Today, 2020
Polymer therapeutics has gained prominence as an attractive structural polymer chemistry applicable in biomedicals. In this review, we discuss the development and capabilities of N-(2-hydroxypropyl) methacrylamide (HPMA) and HPMA-drug conjugates in cancer therapy. The design, architecture, and structural propert Q3 ies of HPMA make it a versatile system for the synthesis of polymeric conjugations for biomedical applications. Research suggests that HPMA could be a possible alternative for polymers such polyethylene glycol (PEG) in biomedical applications. Although numerous clinical trials of HPMA-drug conjugates are ongoing, no product has been successfully brought to market. Thus, further research is required to develop HPMA-drug conjugates as successful cancer therapeutics. Q5 ver, the effective targeting of drugs and macromolecules to pathogenic cells, specifically the intracellular compartment, remains a significant challenge, particularly against cancers. Research focuses on developing a selective/ targeted delivery vehicle for anticancer effectivity without harming heal Q6 thy cells. At the cellular level, the cell membrane and the inherent compartmentalization of organelles are additional obstacles [1]. To elicit effective therapeutic action, drugs, including macromolecules such as proteins, antibodies, small molecules, and antineoplastic agents, have to be delivered to their specific targets, mainly the cytoplasm or nucleus of cancer cells. However, many chemotherapeutics fail to target tumor cells because of their small size and/or molecular weight, low aqueous solubility, and poor pharmacokinetics (PK). In addition, following intravenous delivery, these agents are rapidly cleared from the circulation. Active and passive targeting are considered to be possible ways to ameliorate this problem to some extent. In active targeting, the polymer is directly conjugated with a ligand moiety, drug, or antibody, whereas in passive targeting, therapeutic carrier enters the tumor vasculature via the enhanced permeation and retention (EPR) effect [2-6]. Targeted delivery by increasing selectivity towards the target and decreasing toxicity can be achieved by carriers including liposomes (e.g., Doxil, Myocet, and Caelyx) [7,8], Reviews KEYNOTE REVIEW
Feasibility of polymer-drug conjugates for non-cancer applications
Current Opinion in Colloid & Interface Science, 2017
Polymer-drug conjugates have been intensely studied in the context of improving cancer chemotherapy and yet the only polymer-drug conjugate on the market (Movantik Ò) has a different therapeutic application (relieving opioid-induced constipation). In parallel, a number of studies have recently been published proposing the use of this approach for treating diseases other than cancer. In this commentary, we analyse the many and very diverse applications that have been proposed for polymer-drug conjugates (ranging from inflammation, to cardiovascular diseases) and the rationales underpinning them. We also highlight key design features to be considered when applying polymer-drug conjugates to these new therapeutic areas.
2015
The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. Th...
Journal of Controlled Release, 2001
There are now at least seven polymer-drug conjugates that have entered phase I / II clinical trial as anticancer agents. These include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1, FCE28068), HPMA copolymer-paclitaxel (PNU 166945), HPMA copolymer-camptothecin, PEG-camptothecin, polyglutamic acid-paclitaxel, an HPMA copolymer-platinate (AP5280) and also an HPMA copolymer-doxorubicin conjugate bearing additionally galactosamine (PK2, FCE28069). The galactosamine is used as a means to target the conjugate to liver for the treatment of primary and secondary liver cancer. Promising early clinical results with lysosomotropic conjugates has stimulated significant interest in this field. Ongoing research is developing (1) conjugates containing drugs that could otherwise not progress due to poor solubility or uncontrollable toxicity; (2) conjugates of agents directed against novel targets; and (3) two-step combinations such as polymer-directed enzyme prodrug therapy (PDEPT) and polymer-enzyme liposome therapy (PELT) that can cause explosive liberation of drug from either polymeric prodrugs or liposomes within the tumour interstitium. Moreover, bioresponsive polymer-based constructs able to promote endosomal escape and thus intracytoplasmic delivery of macromolecular drugs (peptides, proteins and oligonucleotides) are also under study.