A novel adjuvant drug-device combination tissue scaffold for radical prostatectomy

Abstract

Prostate cancer is a leading cause of death in men and despite improved surgical procedures that aid tumor resection, the risk of recurrence after surgery as a result of positive resection margins remains significant. Adjuvant chemotherapy is often required but this is associated with toxicity. Improved ways of delivering highly toxic chemotherapeutic drugs in a more controlled and targeted manner after the prostate has been removed during surgery could reduce the risk of recurrence and avoid systemic toxicity. The aim of this study was to develop a novel drug-device combination tissue scaffold that can be used to deliver the chemotherapeutic agent, docetaxel, into the tissue cavity that is created following radical prostatectomy. The device component investigated consisted of highly porous, poly(dl-lactide-co-glycolide) microparticles made using thermally induced phase separation. A facile method was established for loading docetaxel with high efficiency within one hour. Sustained drug release was observed from the microparticles when placed into a dynamic system simulating tissue perfusion. The drug released from the microparticles into perfusates collected at regular time intervals inhibited colony formation and exhibited sustained cytotoxicity against 3D spheroids of PC3 prostate cancer cells over 10 days. In conclusion, this study demonstrates the concept of combining docetaxel with the biodegradable microparticles at the point of care is technically feasible for achieving an effective drug-device combination tissue scaffold. This approach could provide an effective new approach for delivering adjuvant chemotherapy following radical prostatectomy.

Microporous Biodegradable Films Promote Therapeutic Angiogenesis

“…Furthermore, since the TIPS process is highly versatile, the method used to produce films in the current study provides scope to produce polymer films that exhibit different roughness and pore structures via adjustment of parameters including the polymer:solvent ratio, composition of PLGA (ratio of lactide to glycolide), solvent, and rate of quenching. [ 27 ] The ability to control these parameters through further refinement of the porous films provides greater opportunity to fine tune the proangiogenic effect achieved compared with other approaches investigated for therapeutic angiogenesis, such as gene‐based therapy, thus lowering concerns over oncogenic risks. This provides scope for future studies aimed at elucidating optimal properties of the porous polymer films for regulating therapeutic angiogenesis.…”

Functionalised thermally induced phase separation (TIPS) microparticles enabled for “click” chemistry

“…7,10,11 The TIPS method not only permits tailoring of microparticle size (from nano-to microscale in diameter), porosity and pore morphology but also allows inclusion of active ingredients such as small molecules and protein based therapies into the polymer matrix, as well providing a delivery vehicle for advanced therapies. 8,[11][12][13][14] A further beneficial attribute of PLGA polymeric microparticles is their compatibility with a wide range of materials, including synthetic polymers 15 and biological materials such as antibodies, enabling targeting of specific disease biomarkers. 16 To date, most of the loading of active ingredients such as antibodies or small molecules into micro/nanoparticle systems has been achieved by either blending the compounds into the polymer solution during the fabrication process 11,12,16 or using post-fabrication random conjugation methods (electrostatic or covalent) to append the two entities, e.g.…”

“…physisorption or covalently attaching antibodies (via random surface lysine residue modification) to particles via carbodiimide chemistry. 14,17,18 However, in the case of loading microparticles with antibody, the aforementioned procedures greatly limit antigen-binding and overall target avidity, as well making it difficult to control aggregation. We have recently demonstrated the importance of controlled chemical "click" ligation of proteins for successful nanoconjugate performance, particularly in the context of target affinity.…”

“… 7 , 10 , 11 The TIPS method not only permits tailoring of microparticle size (from nano- to micro-scale in diameter), porosity and pore morphology but also allows inclusion of active ingredients such as small molecules and protein based therapies into the polymer matrix, as well providing a delivery vehicle for advanced therapies. 8 , 11 – 14 …”

Peritumoral Delivery of Docetaxel‐TIPS Microparticles for Prostate Cancer Adjuvant Therapy

“…[13] Given the accessibility of residual cancer in the prostate bed or tissue cavity due to positive surgical margins following excision of the prostate, we have previously proposed the use of biodegradable microparticles to enable the targeted delivery of DTX as an adjuvant therapy during surgical removal of the prostate for cancer. [14] Our previous study established an optimized process for loading TIPS microparticles with DTX and demonstrated in vitro their potential utility for tumor growth inhibition over a period of 12 days. The antisolvent precipitation method used for loading TIPS microparticles with DTX differs from other methods used in previous drug-delivery studies with TIPS microparticles and results in drug being predominantly coated onto the microsphere surface.…”