Current Drug Delivery (v.8, #1)
Editorial [Hot topic: Receptor-Targeted Cancer Therapy (Guest Editor: Li-Chun Sun)] by Li-Chun Sun (1-1).
Conventional radiotherapy and chemotherapy have been applied to treatments after surgery or advanced/metastatic cancers. However, the applications have been limited, partly due to non-specificity that results in toxic side effects and to the eventual multi-drug resistance (MDR) that results from prolonged treatments. Considerable interest has been placed on receptor-targeted cancer therapy following the development of monoclonal antibody (mAb) technology by Kohler and Milstein in 1975. Certain receptors, such as somatostatin (SST) receptors (SSTRs) and gastrin releasing peptide (GRP) receptors, are found aberrantly expressed in much higher concentrations in many cancer cells than they are in normal cells. Peptides and mAbs used as drugdelivery systems have been broadly applied in receptor-targeted tumor imaging and radiotherapy/chemotherapy. During recent years, receptor-targeted nanotechnology has been developed as well. Generally, receptor-targeted therapeutics could increase efficacy and specificity, decrease toxic side effects and MDR. A classical example of increasing therapeutic specificity is that the SSTR2-specific AN-238, a conjugate of an octapeptide SST analog and 2-pyrrolino-DOX, displays potent indirect antitumor activity against human SSTR-negative non-SCLC NCI-H157 xenografts by directly targeting SSTR-positive tumor blood vessels of the host mice. However, these approaches display their own advantages and disadvantages, although great progress has been made. Peptides have some extra advantages. For instance, they are easy to synthesize and optimize and can be quickly investigated for their therapeutic potential since many peptides are relatively small molecules with very few amino acids. Many of these peptides undergo rapid internalization, quick circulatory clearance and good tumor tissue-penetrating ability. But peptides have a short half-life and lack both selectivity and high affinity compared to mAbs. mAbs have limited tumor penetration due to their large size and antigen heterogeneity to cancer cells, but have the advantages of high affinity, specificity and stability. Furthermore, antibodies need much more time to be taken up by tumors. Fab fragments of antibodies are quickly taken up by tumors, but rapid and high renal accumulation with low tumor-uptake rates limits their applications. Nanoparticles can be easily taken up by cancer cells and also by normal cells. In this thematic issue, we collect eight papers from different fields including receptor-targeted applications of nanoparticles, peptides and antibodies. Our attempt is to show the most current progression in these fields.
Somatostatin Receptor-Targeted Anti-Cancer Therapy by Li-Chun Sun, David H. Coy (2-10).
Somatostatin receptors (SSTRs), especially SSTR subtype 2, are found expressed at relatively higher levels in many tumor cells and in tumoral blood vessels relative to normal tissues. This creates an opportunity for developing various cytotoxic SST conjugates that selectively target SSTR2-specific sites. Accordingly, some potent chemotherapeutic agents such as camptothecin (CPT), methotrexate (MTX), paclitaxel (PTX) and doxorubicin (DOX) have been coupled to SSTR2-preferential somatostatin (SST) analogs. These new cytotoxic SST conjugates display significant SSTR-selective anti-tumor abilities in many different types of tumors. For instance, the CPT-SST conjugate JF-10-81, in which CPT is coupled to the N-terminus of a SSTR2-specific SST analog (JF-07-69), had wide ranging anti-tumor and anti-angiogenic ability. This conjugate also showed an ability to overcome multi-drug resistance (MDR) in SSTR-over-expressing and CPT-insensitive human pancreatic carcinoid BON cells. Notably, another DOX-SST conjugate, AN-238, made by coupling pyrrolino-DOX to the SST analog RC-121, displayed indirect anti-tumor activity against SSTR-negative, non-small cell lung cancer H-157 tumor growth by directly targeting SSTR-positive tumoral vessels of host mice. These cytotoxic SST conjugates should deliver chemotherapeutic agents to receptor-specific sites, enhance anti-tumor efficacy, reduce toxic side effects to normal tissues, and to some extent, overcome MDR. These and other peptide conjugates may possibly represent a newer generation of receptor-targeted cancer therapeutics. This review discusses the progress with reference to SST-based and SSTR-selective cytotoxic cancer therapy.
Use of Analogs of Peptide Hormones Conjugated to Cytotoxic Radicals for Chemotherapy Targeted to Receptors on Tumors by Andrew V. Schally, Jorg B. Engel, Gunter Emons, Norman L. Block, Jacek Pinski (11-25).
Specific receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, bombesin, and other peptides are found on various cancers. We review the development of cytotoxic analogs of LH-RH, somatostatin, and bombesin/gastrin releasing peptide (GRP) designed for targeting chemotherapy to peptide receptors on various cancers. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and may be used for the treatment of prostatic and urinary bladder (urothelial), breast, ovarian and endometrial cancers, non-Hodgkin's lymphomas, melanomas, and renal cell carcinomas. DOX and AN-201 have also been incorporated into the cytotoxic analogs of somatostatin, AN-162 and AN-238, respectively, which are targeted to receptors for somatostatin in prostatic, mammary, ovarian, gastric, renal, colorectal and pancreatic cancers, non- Hodgkin's lymphomas, as well as glioblastomas and lung cancers. They are found to suppress the growth of these tumors and their metastases. A cytotoxic analog of bombesin/GRP, AN-215, containing 2-pyrrolino-Dox, has also been synthesized and shown to inhibit growth of various human cancer lines expressing receptors for bombesin/GRP. The toxicity, pharmacokinetics and maximum tolerated doses of AN-152 were assessed in a phase I clinical trial in women with ovarian or endometrial cancer. Disease stabilization and objective responses were found. Analog AN-152 is now in phase II clinical trials. Phase I/II studies with AN-152 in men with hormone-independent relapsed prostate cancer and patients with pancreatic and bladder cancers are pending. Targeted cytotoxic peptide analogs could provide a more efficacious and less toxic therapy for various cancers.
Radioimmunotherapy of Solid Tumors: Searching for the Right Target by Hong Song, George Sgouros (26-44).
Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of 90Y ibritumomab tiuxetan (Zevalin) and 131I Tositumomab (Bexxar) in treating non-Hodgkin's lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under preclinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor.
Receptor Mediated Tumor Targeting: An Emerging Approach for Cancer Therapy by Chandana Mohanty, Manasi Das, Jagat R. Kanwar, Sanjeeb K. Sahoo (45-58).
Receptor-mediated tumor targeting has received major attention in the field of cancer drug delivery in the past few years. Receptors, as molecular target has opened new opportunities for cellular or intracellular targeting of drug loaded delivery systems conjugated with targeting moieties i.e. ligand. This receptor mediated targeting of cancer drug through nano carrier systems to cancerous tissue offer protection and improves the pharmacokinetics of various drugs and help to overcome the systemic toxicity and adverse effects that result from the non-selective nature of most current cancer therapeutic agents. The article reviews the scope of receptor mediated targeting of anticancer drug loaded in various nanocarriers and also summarize recent perspective and challenges in the field of nanocarrier-aided drug delivery and drug targeting for cancer therapy.
Multifunctional Nanomedicine Platform for Cancer Specific Delivery of siRNA by Superparamagnetic Iron Oxide Nanoparticles-Dendrimer Complexes by Oleh Taratula, Olga Garbuzenko, Ronak Savla, Y. Andrew Wang, Huixin He, Tamara Minko (59-69).
The ability of Superparamagnetic Iron Oxide (SPIO) nanoparticles and Poly(Propyleneimine) generation 5 dendrimers (PPI G5) to cooperatively provoke siRNA complexation was investigated in order to develop a targeted, multifunctional siRNA delivery system for cancer therapy. Poly(ethylene glycol) (PEG) coating and cancer specific targeting moiety (LHRH peptide) have been incorporated into SPIO-PPI G5-siRNA complexes to enhance serum stability and selective internalization by cancer cells. Such a modification of siRNA nanoparticles enhanced its internalization into cancer cells and increased the efficiency of targeted gene suppression in vitro. Moreover, the developed siRNA delivery system was capable of sufficiently enhancing in vivo antitumor activity of an anticancer drug (Cisplatin). The proposed approach demonstrates potential for the creation of targeted multifunctional nanomedicine platforms with the ability to deliver therapeutic siRNA specifically to cancer cells in order to prevent severe adverse side effects on healthy tissues and in situ monitoring of the therapeutic outcome using clinically relevant imaging techniques.
Emerging Role of ImmunoPET in Receptor Targeted Cancer Therapy by Jan Marik, Jagath R. Junutula (70-78).
ImmunoPET is a non-invasive imaging technology based on tracking and quantification of radiolabeled monoclonal antibodies, antibody fragments and peptides in vivo. The knowledge of distribution and expression levels of a given receptor is a key for successful receptor targeted cancer therapy. ImmunoPET performed with probes with high affinity and specificity to a given receptor aspires to be a method for obtaining comprehensive information about current in vivo status of the targeted receptor. This review describes methods for radiolabeling of peptides, monoclonal antibodies, and antibody fragments for immunoPET and highlights the recently reported pre-clinical and clinical applications of immunoPET in receptor targeted therapy.
Bombesin Receptor-Mediated Imaging and Cytotoxicity: Review and Current Status by Veronica Sancho, Alessia Di Florio, Terry W. Moody, Robert T. Jensen (79-134).
The three mammalian bombesin (Bn) receptors (gastrin-releasing peptide [GRP] receptor, neuromedin B [NMB] receptor, BRS-3) are one of the classes of G protein-coupled receptors that are most frequently overexpress/ ectopically expressed by common, important malignancies. Because of the clinical success of somatostatin receptor- mediated imaging and cytotoxicity with neuroendocrine tumors, there is now increasing interest in pursuing a similar approach with Bn receptors. In the last few years then have been more than 200 studies in this area. In the present paper, the in vitro and in vivo results, as well as results of human studies from many of these studies are reviewed and the current state of Bn receptor-mediated imaging or cytotoxicity is discussed. Both Bn receptor-mediated imaging studies as well as Bn receptor-mediated tumoral cytotoxic studies using radioactive and non-radioactive Bn-based ligands are covered.
Endoglin-Targeted Cancer Therapy by Ben K. Seon, Akinao Haba, Fumihiko Matsuno, Norihiko Takahashi, Masanori Tsujie, Xinwei She, Naoko Harada, Shima Uneda, Tomoko Tsujie, Hirofumi Toi, Hilda Tsai, Yuro Haruta (135-143).
Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-and#946;. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).