Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic (original) (raw)
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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...
Molecular Pharmaceutics, 2006
Carrier-mediated delivery of drugs into the cytosol is often limited by either release from the carrier or release from an internalizing endolysosome. Here, loading, delivery, and cytosolic uptake of drug mixtures from degradable polymersomes are shown to exploit both the thick membrane of these block copolymer vesicles and their aqueous lumen as well as pHtriggered release within endolysosomes. Our initial in vivo studies demonstrate growth arrest and shrinkage of rapidly growing tumors after a single intravenous injection of polymersomes composed of poly(ethylene glycol)-polyester. Vesicles are shown to break down into membranelytic micelles within hours at 37°C and low pH, although storage at 4°C allows retention of drug for over a month. It is then shown that cell entry of the polymersomes into endolysosomes is followed by copolymer-induced endolysosomal rupture with release of cytotoxic drugs. Above a critical poration concentration (C CPC ) that is easily achieved within endolysosomes and that scales with copolymer proportions and molecular weight, the copolymer micelles are seen to disrupt lipid membranes and thereby enhance drug activity. Neutral polymersomes and related macrosurfactant assemblies can thus create novel pathways within cells for controlled release and delivery. (1) Sonawane, N. D.; Szoka, F. C.; Verkman, A. S. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J. Biol. Chem. 2003, 278, 44826-44831. (2) Lim, Y.-B.; Kim, S.-M.; Suh, H.; Park, J.-S. Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier. Bioconjugate Chem. 2002, 13, 952-957. articles 340 MOLECULAR
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
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.
Polymers for Drug Delivery Systems
Annual Review of Chemical and Biomolecular Engineering, 2010
Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations of chemical engineers. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. In this review, we highlight the fundamental drug delivery systems and their mathematical foundations and discuss the physiological barriers to drug delivery. We review the origins and applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-protein and polymer-drug conjugates. The latest developments in polymers capable of molecular recognition or directing intracellular delivery are surv...
Intracellular targeting of polymer-bound drugs for cancer chemotherapy
Advanced drug delivery reviews, 2005
Macromolecules have been traditionally employed as drug carriers due to their ability to selectively accumulate in malignant tissues compared to healthy tissues by either passive or active targeting, thus precluding undesirable side effects generated by free drug. The therapeutic activity proffered by such conjugates requires that the drug concentrate at its specific subcellular target such as the nucleus. Thus, the suitability of macromolecules as carriers also extends to their propensity to deliver the drug to a predetermined intracellular location. As binding a macromolecule to a drug facilitates cellular uptake by endocytosis, various approaches have been employed to either guide the drug to targets different from endosomal/lysosomal compartments by mediating vesicular escape, or to directly accomplish intracellular (cytoplasmic and nuclear) localization. This review discusses the utility of macromolecules in drug delivery and describes the numerous modalities (with a focus on cell-penetrating peptides) currently available for achieving effective intracellular drug delivery.
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.
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...