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Advanced Drug Delivery Reviews (v.62, #2)

Editorial Board (pp. ii).

HPMA copolymers: 30years of advances by Twan Lammers (Theme Editor); Karel Ulbrich (Theme Editor) (pp. 119-121).

HPMA copolymers: Origins, early developments, present, and future by Kopecek Jindřich Kopeček; Kopeckova Pavla Kopečková (pp. 122-149).

The overview covers the discovery of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, initial studies on their synthesis, evaluation of biological properties, and explorations of their potential as carriers of biologically active compounds in general and anticancer drugs in particular. The focus is on the research in the authors' laboratory — the development of macromolecular therapeutics for the treatment of cancer and musculoskeletal diseases. In addition, the evaluation of HPMA (co)polymers as building blocks of modified and new biomaterials is presented: the utilization of semitelechelic poly(HPMA) and HPMA copolymers for the modification of biomaterial and protein surfaces and the design of hybrid block and graft HPMA copolymers that self-assemble into smart hydrogels. Finally, suggestions for the design of second-generation macromolecular therapeutics are portrayed.

Keywords: N; -(2-hydroxypropyl)methacrylamide; Cancer; Cleavable spacers; Bioconjugates; Hydrogels; Self-assembly

Structural and chemical aspects of HPMA copolymers as drug carriers by Karel Ulbrich; Vladimír Šubr (pp. 150-166).

Synthetic strategies and chemical and structural aspects of the synthesis of HPMA copolymer conjugates with various drugs and other biologically active molecules are described and discussed in this chapter. The discussion is held from the viewpoint of design and structure of the polymer backbone and biodegradable spacer between a polymer and drug, structure and methods of attachment of the employed drugs to the carrier and structure and methods of conjugation with targeting moieties. Physicochemical properties of the water-soluble polymer–drug conjugates and polymer micelles including mechanisms of drug release are also discussed. Detailed description of biological behavior of the polymer–drug conjugates as well as application of the copolymers for surface modification and targeting of gene delivery vectors are not included, they are presented and discussed in separate chapters of this issue.

Keywords: Drug delivery systems; N; -(2-hydroxypropyl)methacrylamide; Polymer drug conjugates; Synthesis of HPMA copolymers; Drug targeting; Anticancer drugs

HPMA copolymer–cyclic RGD conjugates for tumor targeting by Daniel B. Pike; Hamidreza Ghandehari (pp. 167-183).

This review describes the design and development of N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer–cyclic RGD conjugates for targeting tumor angiogenesis. Relative to non-targetable systems, HPMA copolymer–RGD4C and –RGDfK conjugates have shown increased tumor accumulation in a variety of solid tumors including prostate, lung, and breast tumor xenografts. Compared to free peptides, copolymers had increased tumor accumulation and decreased uptake in non-target organs such as the liver and spleen. Clinically relevant imaging agents such as^99mTc,¹¹¹In, and Gd enabled in vivo imaging of the constructs by scintigraphy and magnetic resonance techniques. Targeted delivery of⁹⁰Y, a radiotherapeutic agent by HPMA copolymer–RGD4C conjugates resulted in tumor size reduction in mice bearing prostate tumor xenografts. Delivery of the geldanamycin derivative 17-(6-aminohexylamino)-17-demethoxygeldanamycin by HPMA copolymer–RGDfK conjugates resulted in increased tumor concentration of the free drug in a prostate xenograft model. These constructs show promise for targeted delivery of therapeutics and imaging agents to solid tumors.

Keywords: Abbreviations; %ID/g; percentage injected dose per gram; ¹¹¹; In; indium-111; ¹²⁵; I; iodine-125; 17-AAG; 17-allylamino-17-demethoxygeldanamycin; 17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin; ⁹⁰; Y; yttrium-90; ^99m; Tc; technetium-99; m; AH; 6-aminohexylamino; AH-GDM; 17-(6-aminohexylamino)-17-demethoxygeldanamycin; AIBN; azobisisobutyronitrile; APMA-benzyl-DOTA; N-methacryloylaminopropyl-2-(4-isothiourea-benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; APMA-CHX-A″-DTPA; N-methacryloylaminopropyl-2-amino-3-(isothiourea-phenyl) propyl-cyclohexane-1,2-diamine-; N,N-N′,N′,N″,N″; -pentaacetic acid; Ci; curie; DPK; N-ω-bis(2-pyridylmethyl)-L-lysine; EPR; enhanced permeability and retention; Gd; gadolinium; GDM; geldanamycin; HPLC; high performance liquid chromatography; HPMA; N-(2-hydroxypropyl)methacrylamide; HUVEC; human umbilical vein endothelial cell; i.v.; intravenous; kDa; kilodalton; LLC; Lewis lung carcinoma; MA-GFLG-AH-GDM; N-methacryloylglycylphenylalanylleucylglycyl-17-(6-aminohexylamino)-17-demethoxygeldanamycin; MA-GG-DPK; N-methacryloylglycylglycyl-(N-ω-bis(2-pyridylmethyl)-L-lysine); MA-GG-ONp; N-methacryloylglycylglycyl-p-nitrophenyl ester; MA-Tyr; N-methacryloyl-tyrosinamide; MR; magnetic resonance; MRI; magnetic resonance imaging; M; _w; weight average molecular weight; p.i.; post-injection; RGD4C; Lys-Ala-Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys-Gly; RGDfK; Arg-Gly-Asp-D-Phe-Lys; RGE4C; Lys-Ala-Cys-Asp-Cys-Arg-Gly-Glu-Cys-Phe-Cys-Gly; SCID; severe combined immunodeficientN-(2-hydroxypropyl) methacrylamide (HPMA); RGDfK; RGD4C; Tumor targeting; Angiogenesis

Immunogenicity and immunomodulatory properties of HPMA-based polymers by Řihova Blanka Říhová; Kovař Marek Kovář (pp. 184-191).

HPMA copolymers are one of the most promising drug carriers as their biophysical and biochemical properties, including their immunocompatibility, are very favorable. So far, there is no evidence that HPMA copolymers can interact with the immune system in a way that would lead either to suppression of some of its crucial functions or to inappropriate activation with possible serious side-effects and thus we can conclude that HPMA copolymers are convincingly proved to be “immunologically” safe. Moreover, it was shown both in mice and humans that HPMA copolymer-bound doxorubicin (DOX–HPMA) conjugates possess besides powerful anti-tumor effect also various immunomodulatory properties and exert significantly decreased side-toxicities, minimized bone marrow toxicity and cardiotoxicity being the most important ones. The possibility to induce potent and long-lasting tumor-specific immunity during the treatment with these compounds which is capable to provide protection against minimal residual disease is one of the most important and therapeutically valuable features of these conjugates.

Keywords: HPMA; Immunogenicity; Immunomodulation; Synergized cancer therapy; Immunotherapy

HPMA copolymers for modulating cellular signaling and overcoming multidrug resistance by Tamara Minko (pp. 192-202).

Unique properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer granted its wide use as a carrier for different nanotherapeutics. However, the role of HPMA in a drug delivery system is not limited solely to a carrier for an active payload. Detailed investigations revealed its deep influence on the molecular mechanisms of antitumor action of chemotherapeutic drugs bound to HPMA copolymer. Such influence involves changing the internalization and intracellular trafficking of an entire HPMA-drug complex, modifying the topography of the accumulation of delivered anticancer drug in the tumor and inside tumor cells, overcoming and suppression of existing drug resistance and preventing its de novo development, inhibition of cellular drug detoxification and intracellular repair mechanisms, affecting cell death signaling pathways and mechanisms of apoptosis and necrosis induction. The present review underlines the major mechanisms of the aforementioned effects leading to the substantial enhancement of cell death-inducing ability of conjugated anticancer drugs.

Keywords: Apoptosis; Tumor hypoxia; Signal transduction; Pump and nonpump resistance; EPR effect; Gene and protein expression; Nanotherapeutics; Macromolecules

Improving the efficacy of combined modality anticancer therapy using HPMA copolymer-based nanomedicine formulations by Twan Lammers (pp. 203-230).

Copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer agents. HPMA copolymers circulate for prolonged periods of time, and by means of the Enhanced Permeability and Retention (EPR) effect, they localize to tumors both effectively and selectively. Because of their beneficial biodistribution, and because of the fact that they are able to improve the balance between the efficacy and the toxicity of chemotherapy, it is reasonable to assume that HPMA copolymers combine well with other treatment modalities. In the present review, efforts in this regard are summarized, and HPMA copolymers are shown to be able to beneficially interact with surgery, with radiotherapy, with hyperthermia, with photodynamic therapy, with chemotherapy and with each other. Together, the insights provided and the evidence obtained strongly suggest that HPMA copolymer-based nanomedicine formulations hold significant potential for improving the efficacy of combined modality anticancer therapy.

Keywords: Cancer; Drug targeting; Nanomedicine; HPMA copolymers; Polymer–drug conjugates; Polymer therapeutics; Chemotherapy; Radiotherapy; Surgery; Photodynamic therapy; Hyperthermia; Combined modality anticancer therapy

Micelles based on HPMA copolymers by M. Talelli; C.J.F. Rijcken; C.F. van Nostrum; G. Storm; W.E. Hennink (pp. 231-239).

Polymeric micelles have been under extensive investigation during the past years as drug delivery systems, particularly for anticancer drugs. They are formed by the self-assembly of amphiphilic block copolymers in aqueous solutions and have a spherical shape and a size in the nano-range (<200nm). Tumor accumulation of polymeric micelles upon intravenous administration can occur as a result of the leaky vasculature of tumor tissue (called the enhanced permeation and retention (EPR) effect).To benefit from the EPR effect, polymeric micelles need to have prolonged circulation times as well as high and stable drug loadings. Poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) is a hydrophilic polymer currently under investigation for its use in polymer–drug conjugates. Its biocompatibility, non-immunogenicity and the possibility for functionalization are properties that resulted in broad pharmaceutical and biomedical applications, also in the micelle technology research. Being hydrophilic, it can serve as a micellar stealth corona, while it can also be modified with hydrophobic moieties to serve as a micellar core in which hydrophobic drugs can be solubilized and retained. HPMA-based polymeric micelles have been showing very promising in vitro and in vivo results. This review summarizes the applications of pHPMA in the field of polymeric micelles, either serving as a micellar stealth corona, or, if hydrophobically rendered by derivatization, as a micellar core.

Keywords: Polymeric micelles; N-(2-hydroxylpropyl) methacrylamide; HPMA; HEMAm; Drug delivery; EPR effect; Micelle core; Micelle corona; Drug targeting

HPMA copolymers for masking and retargeting of therapeutic viruses by Kerry D. Fisher; Leonard W. Seymour (pp. 240-245).

Hydrophilic polymers are widely used already for steric stabilisation of bioactive proteins, changing their pharmacokinetics and modifying their interactions with the biological environment. Polymers may also be conjugated to biological surfaces, such as viruses, bacteria and mammalian cells, also to endow steric protection and changed properties. Reactive polymers based on N-[2-hydroxypropyl]methacrylamide have shown particular promise for surface coating of viruses, particularly adenovirus, and here we describe the important observations and innovations arising from this combination of chemical and genetic engineering. Adenovirus is a versatile agent that already finds important experimental applications as a recombinant vaccine, and also for cancer therapy, although its activity in both settings is often limited by a potent antibody-neutralising response in humans that is generally not seen in experimental animals. Coating with HPMA copolymers provides protection against neutralisation by antibodies and complement, and covalent linkage of novel ligands to the surface of the polymer can endow new infectious tropisms, mediated through different receptors, that can expand the potential applications of this versatile technology for a range of settings.

Keywords: Virus; Viral therapeutics; Vaccine; Vector; Virotherapy; Polymer; Neutralization

Molecular imaging of HPMA copolymers: Visualizing drug delivery in cell, mouse and man by Zheng-Rong Lu (pp. 246-257).

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers and their drug conjugates are some of the most intensively investigated drug delivery systems for over 30years. Some of the HPMA copolymer drug conjugates have entered clinical trials. Various molecular imaging technologies have been used to investigate the mechanism of drug delivery with HPMA copolymers. Fluorescence imaging has been used for the study of the process of intracellular drug delivery, including cell binding, subcellular trafficking and intracellular fate, of HPMA copolymers and drug conjugates. Magnetic resonance imaging and nuclear medicine, including γ-scintigraphy, SPECT and PET, have been used for the non-invasive visualization of pharmacokinetics, biodistribution and drug targeting efficiency of HPMA copolymers in animal models. γ-Scintigraphy has been used to study HPMA copolymer drug conjugates in human patients. The application of imaging technologies in the study of HPMA copolymers and properties of the copolymers demonstrated by imaging is summarized in this review.

Keywords: HPMA copolymers; Molecular imaging; Drug delivery; Polymer drug conjugates; Fluorescence imaging; MRI; PET; SPECT

Beyond oncology — Application of HPMA copolymers in non-cancerous diseases by Xin-Ming Liu; Scott C. Miller; Dong Wang (pp. 258-271).

Macromolecular drug conjugates have been developed to improve the efficacy and safety profile of various therapeutic agents for many years. Among them, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–drug conjugates are the most extensively studied delivery platforms for the effective treatment of cancer. In recent years, the applications of HPMA copolymers for the treatment of a broader range of non-cancerous diseases have also been explored. This review highlights the recent developments in the rational design, synthesis, and evaluation of novel HPMA copolymer–drug conjugates for non-cancerous diseases, such as musculoskeletal diseases, infectious diseases and spinal cord injury. The translation potential of these applications is also briefly discussed.

Keywords: HPMA copolymers; Musculoskeletal diseases; Infectious diseases; Arthritis; Bone-targeting; Central nervous system (CNS)

Do HPMA copolymer conjugates have a future as clinically useful nanomedicines? A critical overview of current status and future opportunities by Ruth Duncan; María J. Vicent (pp. 272-282).

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing doxorubicin designed in the late 1970s/early 1980s as anticancer polymer therapeutics were the first synthetic polymer-based anticancer conjugates to enter clinical trial beginning in 1994. Early clinical results were promising, confirming activity in chemotherapy refractory patients and the safety of HPMA copolymers as a new polymer platform in this setting. Subsequent Phase I/II trials have investigated conjugates containing paclitaxel (PNU 166945), camptothecin (PNU 166148) (both failed in clinical trials underlining the importance of rational design), and most recently HPMA-copolymer platinates (AP5280 and then AP5346-ProLindac^TM) entered Phase II clinical development. There are a growing array of second generation HPMA copolymer-based systems involving combination therapy, incorporating putative targeting ligands, having an ever more complex architecture, and both drug and protein conjugates are being proposed as novel treatments for diseases other than cancer. Despite their promise, and the success of polymeric drugs and polymer-protein conjugates, no polymer–drug conjugate (HPMA copolymer-based or otherwise) has yet entered routine clinical use. It is timely to reflect on the progress made over the last 30years, the relative merits of HPMA copolymers as a platform compared to other polymeric carriers, and comment on their future potential as polymer-based nanomedicines into the 21st century in comparison with the many alternative strategies now emerging for creation of nanopharmaceuticals.

Keywords: HPMA copolymers; Polymer therapeutics; Nanomedicines; Cancer; Phase I/II

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Advanced Drug Delivery Reviews (v.62, #2)