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Advanced Drug Delivery Reviews (v.61, #10)

Editorial Board (pp. ii).

The Role of Gene- and Drug Delivery in women's health - Unmet clinical needs and future opportunities by Margit M. Janát-Amsbury (Theme Editor); C.Matthew Peterson (Theme Editor); Sung Wan Kim (Theme Editor) (pp. 767-767).

Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers by Younsoo Bae; Kazunori Kataoka (pp. 768-784).

This review describes our recent efforts on the design and preparation of intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) (PEG-PAA) block copolymers. The polymeric micelles feature a spherical sub-100 nm core–shell structure in which anticancer drugs are loaded avoiding undesirable interactions in vivo. Chemical modification of the core-forming block of PEG-PAA with a hydrazone linkage allows the polymeric micelles to release drugs selectively at acidic pH (4–6). Installation of folic acids on the micelle surface improves cancer cell-specific drug delivery efficiency along with pH-controlled drug release. These intelligent micelles appear to be superior over classical micelles that physically incorporate drugs. Studies showed both controlled drug release and targeted delivery features of the micelles reduced toxicity and improved efficacy significantly. Further developments potentiate combination delivery of multiple drugs using mixed micelles. Therefore clinically relevant performance of the polymeric micelles provides a promising approach for more efficient and patient-friendly cancer therapy.

Keywords: Intelligent polymeric micelles; PEG-poly(amino acid) block copolymers; Controlled drug delivery

OncoGel (ReGel/paclitaxel) — Clinical applications for a novel paclitaxel delivery system by Nancy L. Elstad; Kirk D. Fowers (pp. 785-794).

Cancer treatment regimens often include multiple anticancer agents targeting different cellular mechanisms in delicate balance with associated toxicity. Drug delivery systems offer a unique tool in the treatment of cancer, and applications in the local treatment of cancer have demonstrated utility in providing sustained high local concentrations at the tumor site while minimizing systemic drug levels. Treatment options for local cancer therapy are focused on indications where targeted activity may result in improved patient outcomes such as increased local control and decreased metastatic potential. Targeted therapies may also enhance response to combination anticancer regimens. OncoGel™, a controlled-release depot formulation of paclitaxel in ReGel™, has been evaluated in numerous nonclinical studies. Results from these studies demonstrated OncoGel's ability to physically target paclitaxel to the tumor site with very little reaching the circulation, resulting in an acceptable safety profile with dose-limiting toxicities being local in nature. In addition, OncoGel demonstrated efficacy as a stand-alone treatment and synergistic activity in combination therapies. Clinical studies in superficially-palpable tumors and esophageal carcinoma confirmed local paclitaxel release from OncoGel in patients. OncoGel's ability to improve current treatment options for esophageal and brain cancers is being further evaluated.

Keywords: Drug delivery; ReGel; Paclitaxel; Cancer; Polymers

Novel nanomedicine-based MRI contrast agents for gynecological malignancies by Vicky V. Mody; Mohamed Ismail Nounou; Malavosklish Bikram (pp. 795-807).

Gynecological cancers result in significant morbidity and mortality in women despite advances in treatment and diagnosis. This is due to detection of the disease in the late stages following metastatic spread in which treatment options become limited and may not result in positive outcomes. In addition, traditional contrast agents are not very effective in detecting primary metastatic tumors and cells due to a lack of specificity and sensitivity of the diagnostic tools, which limits their effectiveness. Recently, the field of nanomedicine-based contrast agents offers a great opportunity to develop highly sophisticated devices that can overcome many traditional hurdles of contrast agents including solubility, cell-specific targeting, toxicities, and immunological responses. These nanomedicine-based contrast agents including liposomes, micelles, dendrimers, multifunctional magnetic polymeric nanohybrids, fullerenes, and nanotubes represent improvements over their traditional counterparts, which can significantly advance the field of molecular imaging.

Keywords: Ovarian; Breast; Cervical; Gynecological malignancy; MRI; Dendrimers; Liposomes; Magnetoliposomes; Gadofullerenes

Mirena^® (Levonorgestrel intrauterine system): A successful novel drug delivery option in contraception by Susan Rose; Angela Chaudhari; C. Matthew Peterson (pp. 808-812).

This manuscript serves as a review of Mirena^®, the levonorgestrel intrauterine system (LNG IUS) as a very successful drug delivery system. The LNG IUS has a very high contraceptive efficacy rate, and low rates of patient discontinuation. In addition to its contraceptive benefits, most users experience a decrease in menstrual bleeding over the 5 years of use. LNG IUS has also been used for management of menorrhagia, dysmenorrhea, adenomyosis, and endometrial hyperplasia in some cases. The LNG IUS provides long term efficacy, high rates of compliance, rapid return to fertility, and minimal adverse effects during use.

Keywords: Intrauterine device; Progesterone; Menorrhagia; Endometrial hyperplasia; Copper-T IUD; Contraception

Fetal gene therapy: Opportunities and risks by Anna M. Wagner; Andreina Schoeberlein; Daniel Surbek (pp. 813-821).

Advances in human prenatal medicine and molecular genetics have allowed the diagnosis of many genetic diseases early in gestation. In-utero transplantation of allogeneic hematopoietic stem cells (HSC) has been successfully used as a therapy in different animal models and recently also in human fetuses. Unfortunately, clinical success of this novel treatment is limited by the lack of donor cell engraftment in non-immunocompromised hosts and is thus restricted to diseases where the fetus is affected by severe immunodeficiency. Gene therapy using genetically modified autologous HSC circumvents allogeneic HLA barriers and constitutes one of the most promising new approaches to correct genetic deficits in the fetus. Recent developments of strategies to overcome failure of efficient transduction of quiescent hematopoietic cells include the use of new vector constructs and transduction protocols. These improvements open new perspectives for gene therapy in general and for prenatal gene transfer in particular. The fetus may be especially susceptible for successful gene therapy due to the immunologic naiveté of the immature hematopoietic system during gestation, precluding an immune reaction towards the transgene. Ethical issues, in particular those regarding treatment safety, must be taken into account before clinical trials with fetal gene therapy in human pregnancies can be initiated.

Keywords: Fetal gene therapy; Hemoglobinopathies; Somatic gene delivery; Vector system; In-utero transplantation; Stem cells

Gene therapy of benign gynecological diseases by Memy H. Hassan; Essam E. Othman; Daniela Hornung; Ayman Al-Hendy (pp. 822-835).

Gene therapy is the introduction of genetic material into patient's cells to achieve therapeutic benefit. Advances in molecular biology techniques and better understanding of disease pathogenesis have validated the use of a variety of genes as potential molecular targets for gene therapy based approaches. Gene therapy strategies include: mutation compensation of dysregulated genes; replacement of defective tumor-suppressor genes; inactivation of oncogenes; introduction of suicide genes; immunogenic therapy and antiangiogenesis based approaches. Preclinical studies of gene therapy for various gynecological disorders have not only shown to be feasible, but also showed promising results in diseases such as uterine leiomyomas and endometriosis. In recent years, significant improvement in gene transfer technology has led to the development of targetable vectors, which have fewer side-effects without compromising their efficacy. This review provides an update on developing gene therapy approaches to treat common gynecological diseases such as uterine leiomyoma and endometriosis.

Keywords: Gene therapy; Adenovirus; Uterine leiomyoma; Endometriosis

Advancements in adenoviral based virotherapy for ovarian cancer by Kellie S. Matthews; Ronald D. Alvarez; David T. Curiel (pp. 836-841).

Ovarian cancer is a leading gynecologic malignancy with relatively grim survival statistics. There is a significant need for the development of new treatment options for this malignancy. The development of virotherapy as a treatment option for ovarian cancer has the potential to improve patient survival. Adenoviruses have multiple advantages as vectors for virotherapy including a well-understood structure and the ability to infect cells easily. We will outline the advances in virotherapy in the treatment of ovarian cancer, with particular attention directed toward adenoviral vectors.

Keywords: Ovarian cancer; Adenoviral-based; Chemotherapy

Hypoxia targeting gene expression for breast cancer gene therapy by Minhyung Lee (pp. 842-849).

Gene therapy is a promising strategy to treat various inherited and acquired diseases. However, targeting gene expression to specific tissue is required to minimize side effects of gene therapy. Hypoxia is present in the microenvironment of solid tumors such as breast tumors. A hypoxic tumor targeting gene expression system has been developed for cancer gene therapy. In hypoxic tissues, hypoxia inducible factor (HIF)-1α is accumulated and stimulates transcription of the genes that have hypoxia response elements (HREs) in their promoters. Therefore, transcriptional regulation with a hypoxia inducible promoter is the most widely used strategy for hypoxic tumors targeting gene therapy. In breast cancer gene therapy, breast tumor specific promoters in combination with HREs have been used to induce gene expression in hypoxic breast tumors. Post-transcriptional regulation using an untranslated region (UTR) is also a useful strategy to increase gene expression in hypoxic tumor tissue. In addition, post-translational regulation with the oxygen-dependent degradation (ODD) domain is effective to eliminate therapeutic gene products and reduce side effects in normal tissue. In combination with the breast tumor specific promoters, hypoxic tumor targeting strategies will be useful for the development of a safe breast cancer gene therapy.

Keywords: Breast cancer; Hypoxia; Gene regulation; Targeting

siRNA delivery systems for cancer treatment by Yu-Kyoung Oh; Tae Gwan Park (pp. 850-862).

With increasing knowledge on the molecular mechanisms of endogenous RNA interference, small interfering RNAs (siRNAs) have been emerging as innovative nucleic acid medicines for treatment of incurable diseases such as cancers. Although several siRNA candidates for the treatment of ocular and respiratory diseases are undergoing clinical trials, there are challenges inherent in the further development of siRNAs for anti-cancer therapeutics, because systemic administration will be required in most cases. In addition to nonspecific off-target and immune stimulation problems, appropriate delivery remains a major hurdle. The technologies developed for delivery of nucleic acid medicines such as plasmid DNA and antisense oligonucleotides have paved the way to rapid progress for in vivo delivery of siRNAs. Here, we review various in vivo delivery strategies including chemical modification, conjugation, lipid-based techniques, polymer-based nanosystems, and physical methods. Moreover, the current progress in siRNA delivery systems for gynecologic, liver, lung, and prostate cancers is discussed.

Keywords: RNA interference; Cancer; siRNA delivery; Lipoplex; Polyplex; Targeted delivery

Women and heart disease — Physiologic regulation of gene delivery and expression: Bioreducible polymers and ischemia-inducible gene therapies for the treatment of ischemic heart disease by James W. Yockman; Sung Wan Kim; David A. Bull (pp. 863-870).

Ischemic heart disease (IHD) is the leading cause of death in the United States today. This year over 750,000 women will have a new or recurrent myocardial infarction. Currently, the mainstay of therapy for IHD is revascularization. Increasing evidence, however, suggests that revascularization alone is insufficient for the longer-term management of many patients with IHD. To address these issues, innovative therapies that extend beyond revascularization to protection of the myocyte and preservation of ventricular function are required. The emergence of gene therapy and proteomics offers the potential for innovative prophylactic and treatment strategies for IHD. The goal of our research is to develop therapeutic gene constructs for the treatment of myocardial ischemia that are clinically safe and effective. Toward this end, we describe the development of physiologic regulation of gene delivery and expression using bioreducible polymers and ischemia-inducible gene therapies for the potential treatment of ischemic heart disease in women.

Keywords: Bioreducible; Polymer carriers; Ischemia-inducible; Gene therapy

Drug delivery for in vitro fertilization: Rationale, current strategies and challenges by Margit M. Janát-Amsbury; Kavita M. Gupta; Caroline D. Kablitz; C. Matthew Peterson (pp. 871-882).

In vitro fertilization has experienced phenomenal progress in the last thirty years and awaits the additional refinement and enhancement of medication delivery systems. Opportunity exists for the novel delivery of gonadotropins, progesterone and other adjuvants. This review highlights the rationale for various medications, present delivery methods and introduces the status of novel ideas and possibilities.

Keywords: In vitro; fertilization (IVF); Luteal phase support; Controlled ovarian hyperstimulation; Gonadotropins; Progesterone; GnRH analogues

Current challenges in clinical management of endometrial cancer by Michael Montejo; Theresa L. Werner; David Gaffney (pp. 883-889).

Endometrial cancer remains a management challenge. Improved understanding of the mechanisms of carcinogenesis may enable better understanding of biologic behavior and guide therapy. Improvements in diagnostic imaging, radiation delivery systems, and systemic therapies potentially can improve outcomes while minimizing morbidity. Novel strategies for screening and prevention also hold promise for reducing incidence and mortality of this disease.

Keywords: Clinical management; Endometrial cancer; Mortality

Endometrial Cancer—current state of the art therapies and unmet clinical needs: The role of surgery and preoperative radiographic assessment by Jessica Hunn; Mark K. Dodson; Joel Webb; Andrew P. Soisson (pp. 890-895).

Endometrial carcinoma is the fourth most common cancer among women in the United States. Surgical pathologic staging has been the standard of care since 1988, which consists of analysis of collected peritoneal fluid, hysterectomy/oophorectomy, and pelvic and para-aortic lymphadenectomy. In 2005, it was further recommended that essentially all women with endometrial cancer who choose to undergo surgery have pelvic and para-aortic lymph node analysis. Despite this recommendation, there still remains controversy as to whether all patients with endometrial cancer should undergo full lymph node dissection. In this review, we assess the evidence surrounding this controversy and conclude that women with endometrial cancer should undergo complete lymphadenectomy at the time of surgery. Furthermore, we evaluate the evidence regarding laparoscopic surgical staging as a safe and effective alternative to the more invasive traditional laparotomy. Finally, for those patients who a gynecologic oncologist is not readily available to perform a complete lymph node dissection, we evaluate the various imaging studies and their utility as preoperative triage modalities.

Keywords: Endometrial carcinoma; Lymphadenectomy; Lymph nodes

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Advanced Drug Delivery Reviews (v.61, #10)