Polymer–drug conjugates for novel molecular targets (original) (raw)
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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.
Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer
Endocrine Related Cancer, 2005
The last decade has seen successful clinical application of polymer-protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer-anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four-to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m 2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80-320 mg/m 2 , consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.
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.
Polymer conjugates for focal and targeted delivery of drugs
Polymers for Advanced Technologies, 2013
Polymer therapeutics is a very promising and rapidly growing area of nanomedicine, which has significantly improved the therapeutic potential of low-molecular-weight drugs and proteins for cancer treatment. Conjugation of toxic drugs to high-molecular-weight carriers can lead to reduction in systemic toxicity, longer retention time in the body, improved biodistribution and therapeutic efficacy, and site-specific passive accumulation thanks to the leaky tumor vasculature. Furthermore, a targeting moiety can be coupled to the polymer-drug conjugate in order to actively and selectively deliver it to the desired tissue and cellular target. This review presents a summary of currently developed polymer therapeutics with detailed focus on their components and supramolecular structure. The use of polymeric nanocarriers for cancer angiogenesis-targeted delivery is illustrated by specific examples.
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...
WIREs Nanomedicine and Nanobiotechnology, 2020
Polymer conjugation can be considered one of the leading approaches within the vast field of nanotechnology-based drug delivery systems. In fact, such technology can be exploited for delivering an active molecule, such as a small drug, a protein, or genetic material, or it can be applied to other drug delivery systems as a strategy to improve their in vivo behavior or pharmacokinetic activities such as prolonging the half-life of a drug, conferring stealth properties, providing external stimuli responsiveness, and so on. If on the one hand, polymer conjugation with biotech drug is considered the linchpin of the protein delivery field boasting several products in clinical use, on the other, despite dedicated research, conjugation with low molecular weight drugs has not yet achieved the milestone of the first clinical approval. Some of the primary reasons for this debacle are the difficulties connected to achieving selective targeting to diseased tissue, organs, or cells, which is the main goal not only of polymer conjugation but of all delivery systems of small drugs. In light of the need to achieve better drug targeting, researchers are striving to identify more sophisticated, biocompatible delivery approaches and to open new horizons for drug targeting methodologies leading to successful clinical applications.
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.
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