Design and Pharmaceutical Evaluation of a Nano-Enabled Crosslinked Multipolymeric Scaffold for Prolonged Intracranial Release of Zidovudine

Abstract

Purpose. Nanomedicine explores and allows for the development of drug delivery devices with superior drug uptake, controlled release and fewer drug side-effects. This study explored the use of nanosystems to formulate an implantable drug delivery device capable of sustained zidovudine release over a prolonged period. Methods. Pectin and alginate nanoparticles were prepared by applying a salting out and controlled gelification approach, respectively. The nanoparticles were characterized by attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS) and were further evaluated for zidovudine (AZT) entrapment efficiency. Multipolymeric scaffolds were prepared by crosslinking carboxymethyl cellulose, polyethylene oxide and epsilon caprolactone for entrapment of zidovudine-loaded alginate nanoparticles to impart enhanced controlled release of zidovudine over the time period. Swelling and textural analysis were conducted on the scaffolds. Prepared scaffolds were treated with hydrochloric acid (HCl) to reduce the swelling of matrix in the hydrated environment thereby further controlling the drug release. Drug release studies in phosphate buffered saline (pH 7.4, 37°C) were undertaken on both zidovudine-loaded nanoparticles and native scaffolds containing alginate nanoparticles. Results. A higher AZT entrapment efficiency was observed in alginate nanoparticles. Biphasic release was observed with both nanoparticle formulations, exhibiting an initial burst release of drug within hours of exposure to PBS, followed by a constant release rate of AZT over the remaining 30 days of nanoparticle analysis. Exposure of the scaffolds to HCl served to reduce the drug release rate from the entrapped alginate nanoparticles and extended the AZT release up to 30 days. Conclusions. The crosslinked multipolymeric scaffold loaded with alginate nanoparticles and treated with 1% HCl showed the potential for prolonged delivery of zidovudine over a period of 30 days and therefore may be a potential candidate for use as an implantable device in treating Aids Dementia Complex.
 
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Research progress on the nucleoside/nucleotide-loaded nanomedicines

“…在提升药物利用度的同时，维持药物在体内的长期药效也是纳米递送系统设计中需要着重考虑的一方面。通过对载体的不同设计，如调整载体pH响应、载体与药物的结合能力、递送系统渗透的速率等，都将改变纳米递送系统在体内的药效。Hamsici等 ［ 23 ］ 将Fmoc结合甘氨酸，并利用两条Fmoc保护的带有相反电荷的激发肽包载吉西他滨前药，其自组装成载吉西他滨前药的一维纳米纤维。当pH值为5.5时，该纳米复合物500 h内稳定释放了37%的前药分子。相比游离吉西他滨或吉西他滨前药，此纳米药物在96 h时对4T1乳腺癌细胞具有更好的杀伤效果，避免药物在血浆中经酶快速代谢，维持了药效。Harilall等 ［ 24 ］ 采用海藻酸-多聚支架纳米载体包封抗病毒核苷药物齐多夫定，可有效稳定齐多夫定的释放，并维持细胞内齐多夫定药效浓度长达30 d。Pattnaik等 ［ 25 ］ 使用二甲基亚砜或PEG400辅助PLGA包封地达诺辛制备纳米药物，其包封率和载药量分别达67.74%和33.87%，在pH 7.4的环境下30 h内释放率约为35%。除了维持细胞内长期浓度外，有些药物也需要在较短的时间内快速响应释放，如Naz等 ［ 20 ］ 制备的纳米药物在pH 5的环境中24 h药物释放率超过90%；Ren等 ［ 26 ］ 利用固体脂质纳米粒作为抗病毒核苷药物更昔洛韦的载体，同时使用硬脂酸甘油酯等辅剂制备纳米药物，并将冰片共包载，更昔洛韦的最高包封率和载药量分别为67.68%和7.80%，在pH 7.4的PBS中12 h释放率约80%。综上，纳米递送系统可通过对药物释放的可控调节来维持血药浓度，其中聚合物载体在药物可控释放方面表现优秀，且能够通过嵌段共聚与基团修饰等途径调整药物的释放率。…”