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.     

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.     

pH-Sensitive brush polymer-drug conjugates by ring-opening metathesis copolymerization

Representing a new category of polymer-drug conjugates, brush polymer-drug conjugates were prepared by ring-opening metathesis copolymerization. Following judicious structural design, these conjugates exhibited well-shielded drug moieties, significant water solubility, well-defined nanostructures, and acid-triggered drug release.     

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.     

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.     

Biodegradable starburst carbon chain polymer-protein and lysine dendrite conjugates: adjustment of immune properties,DNA bonding and delivery

In the past decade, the development of gene therapy technology has focused on the design of new nonviral carriers for gene delivery. Proteins modified with polyethyleneimine^[1] or polylysine^[2] as well as dendrites^[3] have shown to be perspective carriers for DNA targeted delivery. The usage of protein conjugates as carriers of biologically active compounds will depend on the adjustment of their immune properties. To investigate this we have prepared starburst carbon chain polymer/protein conjugates containing low molecular weight biologically active compounds, salsolinol and bradykinin, in the polymer moieties and studied their immune properties. We have shown that chemical structure of the polymer moiety determines the conjugate biodegradation as well as their immune properties. The starburst poly(N-vinylimidazole) transferring poly(N-vinylimidazole) and polylysine 3G lysine dendrite conjugates have been prepared. The study of their ability to bind DNA and to guarantee its targeted delivery have shown that they are perspective DNA carriers.     

Advances and trends in the design, analysis, and characterization of polymer–protein conjugates for “PEGylaided” bioprocesses

In addition to their use as therapeutics and because of their enhanced properties, PEGylated proteins have potential application in fields such as bioprocessing. However, the use of PEGylated conjugates to improve the performance of bioprocess has not been widely explored. This limited additional industrial use of PEG-protein conjugates can be attributed to the fact that PEGylation reactions, separation of the products, and final characterization of the structure and activity of the resulting species are not trivial tasks. The development of bioprocessing operations based on PEGylated proteins relies heavily in the use of analytical tools that must sometimes be adapted from the strategies used in pharmaceutical conjugate development. For instance, to evaluate conjugate performance in bioprocessing operations, both chromatographic and non-chromatographic steps must be used to separate and quantify the resulting reaction species. Characterization of the conjugates by mass spectrometry, circular dichroism, and specific activity assays, among other adapted techniques, is then required to evaluate the feasibility of using the conjugates in any operation. Correct selection of the technical and analytical methods in each of the steps from design of the PEGylation reaction to its final engineering application will ensure success in implementing a "PEGylaided" process. In this context, the objective of this review is to describe technological and analytical trends in developing successful applications of PEGylated conjugates in bioprocesses and to describe potential fields in which these proteins can be exploited.     

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.     

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.     

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is ¹⁷⁷Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.     

Synthesis of 2,6-Dimethoxyhydroquinone-3-mercaptoacetyl-peptide-chlorambucil Conjugates

In previous paper, we had reported the synthesis of three conjugates of the cytotoxicity agents: 2,6-Dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA)1, which is a derivative of 2,6-dimethoxy-p-benzoquinone (DMQ). DMQ is a naturally fermented product of wheat germ and was found to have a wide spectrum of cytotoxicity against various tumor cell lines under the synergistic activation of L-ascorbic acid2-5 . Owing to the very low aqueous solubility of DMQ, we prepared derivatives of the …     

Multifunctional dendritic polymers in nanomedicine: opportunities and challenges

Nanotechnology has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncological disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromolecular nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clinical targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chemical pathways. In this critical review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 references).     

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.     

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.     

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.      

Molecular Modeling of Steroid–Nucleoside Conjugates: A Preliminary Structural Study

In recent years, molecular modeling has been used to predict structure and chemical behavior of molecules in order to design drugs and enhance the performance of pharmaceuticals. The size and complexity of molecules studied computationally has grown as the computational power available has increased, along with the creation and formulation of new theories and methods. We will apply these methods to a unique set of steroid-nucleoside conjugates in order to interpret their differences in activity. In the set of four studied in this work (three acids bonded to AZT through an ester bond and an additional isomer of the second in the series), only the cholenic acid-conjugated species (Conjugate 1) has exhibited antitumor behavior, while the other two, P-16-acid and P-21-oic acid (prednisolone with an ester linkage to zidovudine, AZT), do not. In this study, we use molecular mechanics and semiempirical techniques to compare structures and to examine rotational barriers and solvation effects on many of the low-lying conformations of these four conjugates, as well as to use electrostatic potential isosurfaces in order to gain insight into the contributions to the activity or inactivity of these potential antitumor drugs.     

Carrier-free supramolecular nanomedicines assembled by small-molecule therapeutics for cancer treatment

Nanomedicines have shown great promise in cancer therapy, but are challenged by limited drug loading, safety concerns of drug carriers, and complexity of function integration. Recently, carrier-free nanomedicines produced by supramolecular assembly of small-molecule therapeutic functionalities and their conjugates were proposed to address these issues. These nanomedicines achieve very high drug loading, enhanced tumor accumulation and improved therapeutic efficiency, and avoid carrier-related sa...     

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.     

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.