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Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.

The Effects of Insulin-Like Growth Factors on Tumorigenesis and Neoplastic Growth

Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing l-analogue amino acids with d-amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG2,40 K conjugate of INF-α-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.

Strategies to improve plasma half life time of peptide and protein drugs

RESEARCH into the neuroendocrine control of reproduction by gonadotropin-releasing hormone (GnRH) has witnessed a remarkable two decades. From the isolation and chemical characterization of GnRH in 1971 through the awarding of the Nobel Prize to Drs. Serially and Guillemin for these accomplishments shortly thereafter, the translation from basic discovery to clinical usefulness has been swift. Food and Drug Administration approvals of GnRH-agonist analogues for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as the use of natural GnRH to induce ovulation, are examples of the clinical usefulness of these fundamental observations. Numerous clinical therapies designed to stimulate . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199101103240205?listPDF=true

Gonadotropin-releasing hormone and its analogues.

Microspheres composed of biocompatible, biodegradable poly(DL-lactide-co-glycolide) (DL-PLG) and staphylococcal enterotoxin B (SEB) toxoid were evaluated as a vaccine delivery system when subcutaneously injected into mice. As measured by circulating immunoglobulin G (IgG) antitoxin titers, the delivery of SEB toxoid via DL-PLG microspheres, 1 to 10 microns in diameter, induced an immune response which was approximately 500 times that seen with nonencapsulated toxoid. The kinetics, magnitude, and duration of the antitoxin response induced with microencapsulated toxoid were similar to those obtained when an equal toxoid dose was administered as an emulsion with complete Freund adjuvant. However, the microspheres did not induce the inflammation and granulomata formation seen with complete Freund adjuvant. The adjuvant activity of the microspheres was not dependent on the superantigenicity of SEB toxin and was equally effective at potentiating circulating IgG antitrinitrophenyl levels in response to microencapsulated trinitrophenyl-keyhole limpet hemocyanin. Empty DL-PLG microspheres were not mitogenic, and SEB toxoid injected as a mixture with empty DL-PLG microspheres was no more effective as an immunogen than toxoid alone. Antigen-containing microspheres 1 to 10 microns in diameter exhibited stronger adjuvant activity than those greater than 10 microns, which correlated with the delivery of the 1- to 10-microns, but not the greater than 10-microns, microspheres into the draining lymph nodes within macrophages. The antibody response induced through immunization with microencapsulated SEB toxoid was protective against the weight loss and splenic V beta 8+ T-cell expansion induced by intravenous toxin administration. These results show that DL-PLG microsphere vaccine delivery systems, which are composed of pharmaceutically acceptable components, possess a strong adjuvant activity for their encapsulated antigens.

https://iai.asm.org/content/iai/59/9/2978.full.pdf

Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin-neutralizing antibodies.

Randomised controlled study of orchidectomy vs long-acting d-trp-6-lhrh microcapsules in advanced prostatic carcinoma

Summary— One hundred and four patients were randomised for the study. Fifty-five were entered into the D-Trp-6-LHRH group and 49 into the orchiectomy group. All pre-treatment patient characteristics were similar and testosterone levels at 1 month or later were in the castrate range in both groups.



Forty-six patients (83%) in the D-Trp-6-LHRH group and 40 (82%) in the orchiectomy group had a partial remission or stable disease at 3 months or later. There was no significant difference between the groups for response or survival.



Three patients in the D-Trp-6-LHRH group had a disease “flare” in the first 10 days of treatment. The flare symptoms resolved by the end of 4 to 8 weeks.



The incidence of flushing, decreased libido and impotence was similar in both groups. Although there was less psychological morbidity in the D-Trp-6-LHRH group the difference did not reach statistical significance. Our results indicate that long-acting D-Trp-6-LHRH offers a safe and highly effective alternative to orchiectomy.

Orchiectomy versus Long-acting D-Trp-6-LHRH in Advanced Prostatic Cancer

Metastatic prostate cancer is well known to respond to hormonal manipulations, but once progression occurs new treatment modalities are required. Specific and systemic antitumour therapy is preferable to local treatments such as radiotherapy in such patients. The finding that somatostain analogue, BIM 23014, inhibits prostatic tumour growth in animal models is of great interest. We treated 25 poor risk patients with progressive metastatic prostate cancer. Sixteen had also failed to respond to ‘total androgen blockade’. Two patients have achieved a partial remission, one of which is maintained at over 30 months, and three had stable disease for over 6 months. Side effects have consisted of mild diarrhoea and abdominal cramp in the first few days of treatment in a minority of the patients. These results are encouraging and further randomized studies are in progress.

Therapeutic response to somatostatin analogue, BIM 23014, in metastatic prostatic cancer

One hundred thirteen patients were randomized for the study. There was no significant difference between the groups for response or survival. The incidence of side effects related to the reduction of testosterone was similar in both groups. Disease "flare" was seen in three patients treated with long-acting D-Trp-6 LH-RH. All symptoms resolved by the end of 8 weeks. There was less psychological morbidity in the D-Trp-6 LH-RH group but the difference did not reach statistical significance. Our results indicate that long-acting D-Trp-6 LH-RH offers a safe and effective alternative to surgical orchidectomy.

L. Edwards

Papers

Randomised controlled study of orchidectomy vs long-acting d-trp-6-lhrh microcapsules in advanced prostatic carcinoma

Orchiectomy versus Long-acting D-Trp-6-LHRH in Advanced Prostatic Cancer

Therapeutic response to somatostatin analogue, BIM 23014, in metastatic prostatic cancer

How would you like to have an orchidectomy for advanced prostatic cancer

Orchiectomy Versus Long-Acting D-Trp-6-LHRH in Advanced Prostatic Cancer