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Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: ProLindac™ (AP5346) is DACH (diaminocyclohexane) platinum polymer prodrug currently in phase II clinical development. It uses a 25kDa polymer delivery vehicle based on hydroxypropylmethacrylamide (HPMA) to target the active form of the approved drug oxaliplatin to tumors. The pH-sensitive linker that binds platinum to the polymer releases platinum more rapidly in low pH environments, as found typically in many tumors. This review summarizes the development of ProLindac to date, including preclinical efficacy studies, the phase I monotherapy clinical study in patients with solid tumors, and the phase I/II monotherapy study in patients with recurrent ovarian cancer. Both preclinical and clinical study data indicate that ProLindac exhibits efficacy at least equal to, and likely superior to oxaliplatin, while demonstrating excellent tolerability. Additional clinical studies of ProLindac used in combination with other chemotherapeutic agents are planned. [Copyright &y& Elsevier]

Abstract: This paper reviews an early clinical experience with anthracycline (epirubicin; Epi or doxorubicin; Dox) containing an N-(2-hydroyxypropyl)methacrylamide copolymer carrier targeted with autologous or commercial human immunoglobulin in six patients aged 28–55 suffering from therapy-resistant metastatic cancer. More than 100 biochemical, hematological and immunological parameters, including nine tumor markers, were tested in blood samples taken 24 h after the first and up to 10 months after the last application. The intravenous application proceeded without serious adverse or side effects and did not require hospitalization. Cardiotoxicity was not observed. Four of six monitored patients attained stabilization of disease (liver ultrasound scan and bone computer tomography) with a very good quality of life lasting from seven up to 18 months. Positive response to the treatment was, among others, evaluated as decreased CA 15-3 and CEA tumor markers. In three of five tested patients the serum level of C-reactive protein was temporarily increased 72 h after the treatment. A stable or elevated number of peripheral blood reticulocytes together with activation of natural killer (NK) cells and lymphokine-activated killer (LAK) cells supports the data previously obtained in experimental animals pointing to a dual role, i.e. the cytotoxic and immunomobilizing character of doxorubicin–HPMA conjugates. [Copyright &y& Elsevier]

Abstract: Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway has serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer''s disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed., (© 2013.)

Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum-polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs., (© 2013.)

With the technological development of positron emission tomography (PET) and the advent of novel antibody-directed drug delivery systems, longer-lived positron-emitting radionuclides are moving to the forefront to take important roles in tracking the distribution of biotherapeutics such as antibodies, and for monitoring biological processes and responses. Longer half-life radionuclides possess advantages of convenient on-site preparation procedures for both clinical and non-clinical applications. The suitability of the long half-life radionuclides for imaging intact monoclonal antibodies (mAbs) and their respective fragments, which have inherently long biological half-lives, has attracted increased interest in recent years. In this review, we provide a survey of the recent literature as it applies to the development of nine-selected longer-lived positron emitters with half-lives of 9-140h (e.g., (124)I, (64)Cu, (86)Y and (89)Zr), and describe the biological behaviors of radionuclide-labeled mAbs with respect to distribution and targeting characteristics, potential toxicities, biological applications, and clinical translation potentials., (Published by Elsevier B.V.)