Polymer-drug conjugates as inhalable drug delivery systems: A review

Accelerating interest by the pharmaceutical industry in the identification and development of less invasive routes of nanomedicine administration, coupled with defined efforts to improve the treatment of respiratory diseases through inhaled drug administration has fuelled growing interests in inhalable polymer-drug conjugates. Polymer-drug conjugates can alter the pharmacokinetic profile of the loaded drug after inhaled administration and enable the controlled and sustained exposure of the lungs to drugs when compared to the inhaled or oral administration of the drug alone. However, the major concern with the use of inhalable polymer-drug conjugates is their biocompatibility and long-term safety in the lungs, which is closely linked to lung retention times. A detailed understanding about the pharmacokinetics, lung disposition, clearance and safety of inhaled polymer-drug conjugates with significant translational potential is therefore required. This review therefore provides a comprehensive summary of the latest developments for several types of polymer-drug conjugates that are currently being explored as inhalable drug delivery systems. Finally, the current status and future perspective of the polymer-drug conjugates is also discussed with a focus on current knowledge gaps.     

Polymeric conjugates for drug delivery

The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status.     

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

It is almost four decades since N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers arose as drug carriers. Although fundamentals have been established and significant advantages have been proved, the commercialization of this platform technology was hampered due to modest outcome of clinical trial initiated with PK1, the symbol of first generation polymer-drug conjugates. In this review, we illustrate the exciting progress and approaches offered by more effective 2nd generation HPMA-based polymer-drug conjugates in cancer treatment. For example, a new synthetic strategy endorses inert HPMA polymer with biodegradability, which permitted to prepare high molecular weight HPMA-drug conjugates with simple linear architecture while maintaining good biocompatibility. As expected, extended long-circulating pharmacokinetics and enhanced antitumor activities were achieved in several preclinical investigations. In addition, greater inhibition of tumor growth in combination regimes exhibits the remarkable capability and flexibility of HPMA-based macromolecular therapeutics. The review also discusses the main challenges and strategies for further translation development of 2nd generation HPMA-based polymer-drug conjugates.     

Feasibility of polymer-drug conjugates for non-cancer applications

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^®) 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.     

低温辐射聚合制备聚合物药的慢释放研究

本文研究了低温辐射慢释放药的单体配比、药物含量及辐射刺量对药物释放速率的影响。结果表明,增加疏水性单体MMA,可以有效地控制大分子量药物消炎痛的释放速率;增加MMA及EDGMA,可以有效地控制小分子量药物5-Fu的释放速率;增加5-Fu的比例,可以降低5-Fu的释放速率;随辐照剂量的增加,聚合物药中5-Fu的释放量降低,二者之间成正比关系。     

Synthesis of macromolecular prodrugs of procaine, histamine and isoniazid

The attachment of various drugs bearing -NH2 groups to poly-alpha,beta-aspartic acid as a biodegradable carrier afforded in good yields macromolecular prodrugs which were characterized with respect to composition and drug load by spectroscopic and analytical methods. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in an aqueous medium proved to be useful in the attachment reaction. Isoniazid, procaine and histamine were covalently coupled as pendant groups onto poly-alpha,beta-aspartic acid via an amide bond. In principle, controlled release of the aforementioned drugs can be achieved by biodegradation of the polymer or by cleavage of covalently bound polymer-drug conjugates.     

Synthesis of degradable functional poly(ethylene glycol) analogs as versatile drug delivery carriers

Poly(ethylene glycol) (PEG) is widely used as a water soluble carrier for polymer-drug conjugates. Herein, we report degradable linear PEG analogs (DPEGs) carrying multifunctional groups. The DPEGs were synthesized by a Michael addition based condensation polymerization of dithiols and PEG diacrylates (PEGDA) or dimethacrylates (PEGDMA). They were stable at pH 7.4 but quickly degraded at pH 6.0 and 5.0. Thus, DPEGs could be used as drug carriers without concern for their retention in the body. DPEGs could be made to carry such functional groups as terminal thiol or (meth)acrylate and pendant hydroxyl groups. The functional groups were used for conjugation of drugs and targeting groups. This new type of PEG analog will be useful for drug delivery and the PEGylation of biomolecules and colloidal particles.     

Copolymer of N,N-diallyl-N,N-dimethylammonium chloride with sulfur dioxide as carrier of drugs

Immobilization of drugs on macromolecules of copolymer N,N-diallyl-N,N-dimethylammonium chloride with sulfur dioxide using ion exchange technique was investigated. Ways of producing polymer-drug conjugates of preset compositions were developed. Their structure was found by NMR and IR spectroscopy.     

Micelle-like structures of poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide)-methotrexate conjugates

The objective of this research was to prepare and characterize a micelle-like structure composed of a diblock copolymer-methotrexate (MTX) conjugate. MTX was attached on poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide) (PEO-b-PHAA), obtained by aminolysis of PEO-b-poly(β-benzyl- -aspartate) (PBLA) with ethanolamine. It was hypothesized that after attachment of MTX onto PEO-b-PHAA through an ester bond, the amphiphilic conjugate would self-assemble into a micelle-like structure that would gradually release MTX, owing to unfavorable hydrolysis in a nonpolar core. An active ester of MTX was reacted with PEO-b-PHAA, providing a substitution ratio of 20–45% (molar ratio of drug to aspartamide units). At these levels, PEO-b-PHAA-MTX conjugate may self-assemble in an aqueous medium. Transmission electron microscopy revealed small spherical particles that had a mean diameter of 14 nm. There was no evidence of secondary aggregation. An absence of ¹H-NMR peaks of MTX in D₂O indicated that PEO-b-PHAA-MTX conjugates self-assembled into supramolecular structure where MTX resides in a site with highly restricted mobility, likely a core of a micelle-like structure. Accordingly, the loss of MTX by hydrolysis from PEO-b-PHAA-MTX conjugates was slow at neutral pH, with less than 20% released after 10 days. The stabilization of ester bonds in a nonpolar core of a micelle-like structure is novel in the design of soluble polymer-drug conjugates. PEO-b-PHAA-MTX conjugate micelles may help improve the biodistribution of MTX and help overcome drug resistance.     

Polymer conjugates with potential biological activity based on new derivatives of 2-mercaptobenzoxazole-synthesis and characterization

New potentially biologically active compounds derived from 2-mercapto-benzoxazole were synthesized and coupled on polymeric support of poly (maleic anhydride-alt-vinyl acetate) for the preparation of polymer-drug conjugates with controlled drug release. All compounds were characterized by elemental and spectroscopy (FT-IR, ¹H-NMR) analysis. The toxicological tests recommend the products for further laboratory screening.      

Enhanced drug loading on magnetic nanoparticles by layer-by-layer assembly using drug conjugates: blood compatibility evaluation and targeted drug delivery in cancer cells

Drug targeting using magnetic nanoparticles (MNPs) under the action of an external magnetic field constitutes an important mode of drug delivery. Low cargo capacity, particularly in hydrophobic drugs, is one limitation shown by MNPs. This article describes a simple strategy to enhance the drug-loading capacity of MNPs. The approach was to use polymer-drug conjugates to modify MNPs by layer-by-layer assembly (LbL). Curcumin (CUR) has shown remarkably high cytotoxicity toward various cancer cell lines. However, the drug shows low anticancer activity in vivo because of its reduced systemic bioavailability acquired from its poor aqueous solubility and instability. To address this issue, we synthesized cationic and anionic CUR conjugates by anchoring CUR onto poly(vinylpyrroidone) (PVP-Cur) and onto hyaluronic acid (HA-Cur). We used these oppositely charged conjugates to modify MNPs by layer-by-layer (LbL) assembly. Six double layers of curcumin conjugates were constructed on positively charged amino-terminated magnetic nanoparticles, TMSPEDA@MNPs. Finally, HA was coated onto the outer surface to form HA (HA-Cur/PVP-Cur)(6)@MNPs. Cellular viability studies showed the dose-dependent antiproliferative effect of HA (HA-Cur/PVP-Cur)(6)@MNPs in two cancer cell lines (glioma cells and Caco-2 cells). HA (HA-Cur/PVP-Cur)(6)@MNPs exhibited more cytotoxicity than did free curcumin, which was attributed to the enhanced solubility along with better absorption via hyaluronic acid receptor-mediated endocytosis. Flow cytometry showed enhanced intake of the modified MNPs by cells. Confocal microscope images also confirmed the uptake of HA (HA-Cur/PVP-Cur)(6)@MNPs with greater efficacy. Thus, the strategy that we adopted here appears to have substantial potential in carrying enhanced payloads of hydrophobic drugs to specified targets.     

Macromolecular metal compounds in cancer research: Concepts and synthetic approaches

The anticancer activity of metal compounds has been a topic of major interest in drug research for two decades. Platinum compounds, in particular, including cisplatin (cis-diamminedichloroplatinum(II)) and second generation derivatives, have for many years been among the leading drugs administered in clinical cancer therapy, although excessive toxicity, induction of drug resistance, and other formidable, detrimental side effects continue to militate against efficacious utilization and achievement of satisfactory cure rates. Adding to the toxicity problem, most bioactive metal complexes dissolve poorly, if at all, in aqueous media, possess low stability in solution, undergo rapid depletion from central circulation, and often times are prevented from smooth cell entry by molecular charge or polarity. The concept of polymer-drug conjugation, designed to overcome the pharmacokinetic barriers to satisfactory clinical chemotherapy with present-day anticancer drugs, is finding increasing acceptance in biomedical research. The concept has been utilized in our laboratory for the purpose of enhancing the effectiveness of metal-containing carcinostatic agents. In the present communication we demonstrate the practicability of synthesizing platinum-, iron-, and tin-containing polymer conjugates that are biodegradable, dissolve completely in water, and are structurally designed so as to permit release of the active metal compound in the biological environment. Following a brief review of initial results, we discuss selected synthetic approaches and obtained conjugates, in which the metals are bound to polymer-attached ligands as dichloroplatinum(II), di-η⁵-cyclopentadienyliron, and diorganotin(IV) moieties.     

Imparting size, shape, and composition control of materials for nanomedicine

This tutorial review presents an overview of strategies for the synthesis and fabrication of organic nanomaterials, specifically those with potential for use in medical applications. Examples include liposomes, micelles, polymer-drug conjugates and dendrimers. Methods of driving shape via"bottom-up" synthetic approaches and thermodynamics and kinetics are discussed. Furthermore, methods of driving shape via"top-down" physical and engineering techniques are also explored. Finally, a novel method (referred to as PRINT) used to produce nanoparticles that are shape-specific, can contain any cargo, and can be easily modified is examined along with its potential future role in nanomedicine.     

Polymer-Based Therapeutics

Polymeric materials have been applied in therapeutic applications, such as drug delivery and tissue regeneration, for decades owing to their biocompatibility and suitable mechanical properties. In addition, select polymer-drug conjugates have been used as bioactive pharmaceuticals owing to their increased drug efficacy, solubility, and target specificity compared with small-molecule drugs. Increased synthetic control of polymer properties has permitted the production of polymer assemblies for the targeted and controlled delivery of drugs, and polymeric sequestrants take advantage of their lack of solubility for the sequestration of target molecules in vivo. In more recent studies reviewed in greater detail here, the properties of polymers that distinguish them from small-molecule drugs, such as their high molecular weight and their ability to display multiple pendant moieties, have been specifically exploited for activating cellular targets or inhibiting the binding of pathogens. The elucidation of relevant structure-function relationships in investigations of this kind has relied on the combination of living polymerization methods with chemical conjugation methods, and protein engineering methods have shown increasing potential in the manipulation of architectural features of such polymer therapeutics. Garnering a detailed understanding of the various mechanisms by which multivalent polymers engage biological targets is certain to expand the role of polymers as therapeutics, by enabling highly specific activities of designed polymers in the biological environment.     

Radiation curing of intelligent coating for controlled release and permeation

Intelligent membranes for pH and temperature-responsive drug releases were developed by coating and curing of polymer-drug composite film with electrolyte or N-isopropyl acrylamide curable mixture. It was proved that those intelligent membranes showed the stimule-sensitive and responsive release functions and could be produced efficiently by radiation curing prosessing with a conveyer system.     

Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery

Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (～6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (～5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.     

药物的聚乙二醇修饰研究进展

简要介绍了聚乙二醇(polyethylene glycol, PEG)的生理化学特性, 药物的聚乙二醇修饰的优势, 详细介绍了蛋白质药物和小分子药物的聚乙二醇修饰技术及其在药物研究中的应用进展, 认为药物的聚乙二醇修饰技术通过改变药物的分子结构, 可以有效地改善药物动力学和药效等性质, 增加注射药物的临床应用范围. 同时基于药物的聚乙二醇修饰技术的优势和研究现状, 评述了药物的聚乙二醇修饰技术的发展前景.     

Molecularly Precise Dendrimer–Drug Conjugates with Tunable Drug Release for Cancer Therapy

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer–drug conjugates. Current dendrimer–drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer–drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.     

Water-soluble dendritic core-shell-type architectures based on polyglycerol for solubilization of hydrophobic drugs

Since many potential drugs are poorly water soluble, there is a high demand for solubilization agents. Here, we describe the synthesis of dendritic core-shell-type architectures based on hyperbranched polyglycerol for the solubilization of hydrophobic drugs. Amphiphilic macromolecules containing hydrophobic biphenyl groups in the core were synthesized in an efficient three- or four-step procedure by employing Suzuki-coupling reactions. These species were then used to solubilize the commercial drug nimodipine, a calcium antagonist used for the treatment of heart diseases and neurological deficits. Pyrene was also used as a hydrophobic model compound. It turned out that the transport properties of the dendritic polyglycerol derivatives, which are based on hydrophobic host-guest interactions, depend strongly on the degree and type of core functionalization. In the case of the multifunctional nimodipine, additional specific polymer-drug interactions could be tailored by this flexible core design, as detected by UV spectroscopy. The enhancement of solubilization increased 300-fold for nimodipine and 6000-fold for pyrene at a polymer concentration of 10 wt%. The sizes of the polymer-drug complexes were determined by both dynamic light scattering (DLS) experiments and transmission electron microscopy (TEM), and extremely well-defined aggregates with diameters of approximately 10 nm in the presence of a drug were observed. These findings together with a low critical aggregate concentration of 4x10(-6) mol L-1 indicate the controlled self-assembly of the presented amphiphilic dendritic core-shell-type architectures rather than a unimolecular transport behavior.     

Interactions between an anticancer drug and polymeric micelles based on biodegradable polyesters

Interactions between the anticancer drug quercetin and biodegradable polyesters within micelles were investigated by DSC, WAXD, and UV analyses. For micelles based on poly(ethylene glycol) methyl ether-block-poly(epsilon-caprolactone) (MPEG-PCL), DSC analysis indicated that the interactions were between the hydrophobic core and the drug within the micelle. For micelles based on poly(ethylene glycol) methyl ether-block-poly(L-lactide) (MPEG-PLLA), the interactions were between the hydrophobic core and the drug and between hydrophilic segments and the drug. WAXD results indicated that no crystalline phase of the drug was found in either of the micelle types. Based on the DSC and WAXD results, two probable micelle structures were proposed. The UV spectra revealed the presence of hydrogen bonding as the main interaction between the drug and the polyesters. In vitro studies demonstrated that quercetin release from micelles was sustained and was affected by the polymer-drug interaction.