The Effect of Additives on the Behavior of Phase Sensitive In Situ Forming Implants

Solorio, Luis; Sundarapandiyan, Divya; Olear, Alex; Exner, Agata A.

doi:10.1002/jps.24558

Cited by 25 publications

(23 citation statements)

References 44 publications

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“…Dox release studies showed that the addition of Val to the implants resulted in a significantly smaller burst release of Dox within 6 hours, which may be due to Val's high lipophilicity altering the solvent/non-solvent exchange kinetics 49 . These reports are consistent with other studies, where the addition of lipophilic molecules www.nature.com/scientificreports www.nature.com/scientificreports/ into ISFIs, such as glycerol monostearate, ethyl heptanoate, stearic acid, ethyl heptanoate, methyl heptanoate, and ethyl nonoate, reduce solvent excretion therefore leading to a reduction in burst release [50][51][52][53] . Dox + P85 ISFIs showed no effect on the burst release, which was equivalent to a previous study 54 .…”

Section: Discussionsupporting

confidence: 91%

“…A limitation to the current work is that the treatment only consisted of a single injection of ISFI at the beginning of the study. As shown with the release curves, approximately 50% of the Dox is released within 10 days and another 10% in the following 10 days 22,31,[57][58][59] . Allowing the study to progress further than 20 days and using multiple injections of the ISFI will likely elicit stronger therapeutic effects.…”

Section: Discussionmentioning

confidence: 66%

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Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Jeganathan

Budziszewski

Hernandez

et al. 2020

Sci Rep

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P-glycoprotein (Pgp), a member of the ATP-binding cassette family, is one of the major causes of multidrug resistance in tumors. Current clinical treatments to overcome MDR involve the co-delivery of a Pgp inhibitor and a chemotherapeutic. A concern for this treatment that has led to varied clinical trial success is the associated systemic toxicities involving endogenous Pgp. Local drug delivery systems, such as in situ forming implants (ISFIs), alleviate this problem by delivering a high concentration of the drug directly to the target site without the associated systemic toxicities. ISFIs are polymeric drug solutions that undergo a phase transition upon injection into an aqueous environment to form a solid drug eluting depot allowing for a high initial intratumoral drug concentration. In this study, we have developed an ISFI capable of overcoming the Pgp resistance by co-delivering a chemotherapeutic, Doxorubicin (Dox), with a Pgp inhibitor, either Pluronic P85 or Valspodar (Val). Studies investigated in vitro cytotoxicity of Dox when combined with either Pgp inhibitor, effect of the inhibitors on release of Dox from implants in PBS, in vivo Dox distribution and retention in a subcutaneous flank colorectal murine tumor, and therapeutic response characterized by tumor growth curves and histopathology. Dox + Val showed a 4-fold reduction in the 50% lethal dose (LD 50) after 48 hours. Concurrent delivery of Dox and Val showed the greatest difference at 16 days post injection for both Dox penetration and retention. This treatment group had a 5-fold maximum Dox penetration compared to Dox alone ISFIs (0.53 ± 0.22 cm vs 0.11 ± 0.11 cm, respectively, from the center of the ISFI). Additionally, there was a 3-fold increase in normalized total intratumoral Dox intensity with the Dox + Val ISFIs compared to Dox alone ISFIs (0.54 ± 0.11 vs 0.18 ± 0.09, respectively). Dox + Val ISFIs showed a 2-fold reduction in tumor growth and a 27.69% increase in necrosis 20 days post-injection compared to Dox alone ISFIs. These findings demonstrate that co-delivery of Dox and Val via ISFI can avoid systemic toxicity issues seen with clinical Pgp inhibitors. Annually, approximately 650,000 cancer patients receive neoadjuvant, standard or adjuvant chemotherapy 1. Systemic chemotherapy is severely hampered by its dose-limiting toxicity, inefficient transport, and limited retention in tumors leading to sub-lethal doses 2. These sub-lethal concentrations of the drug can cause mutations in cancer cells leading to multidrug-resistant (MDR) tumors. MDR is described as the ability of cancer cells to be resistant to a multitude of drugs that are structurally and functionally different 3. Numerous mechanisms are involved in the development of MDR 4. One of the most studied mechanisms of MDR is the upregulation of transmembrane ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp). They function through ATP hydrolysis at the intracellular domain causing a mechanical conformation of the Pgp thus ejecting the drug into the extracellul...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Jeganathan

Budziszewski

Hernandez

et al. 2020

Sci Rep

Self Cite

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“…As one may expect, these differences in implant behavior can be attributed to the ultimate implant shape, size, and microstructure. Implant size and shape are both influenced by the injection procedure and formulation[16], while implant microstructure has been correlated to the rate of phase inversion[12, 17, 18]. ISFIs were originally intended to be injected into the subcutaneous or intramuscular space, which chemically speaking, can be considered to be a mixture of water, organic solvent, proteins and salts.…”

Section: Introductionmentioning

confidence: 99%

Macroporous acrylamide phantoms improve prediction of in vivo performance of in situ forming implants

Hernandez

Gawlik

Goss

et al. 2016

Journal of Controlled Release

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In situ forming implants (ISFIs) have shown promise as a sustained, local drug delivery system for therapeutics in a variety of applications. However, development of ISFIs has been hindered by poor correlation between in vitro study results and in vivo performance. In contrast to oral dosage forms, there is currently no clear consensus on a standard for in vitro drug dissolution studies for parenteral formulations. Recent studies have suggested that the disparity between in vivo and in vitro behavior of phase-inverting ISFIs may be, in part, due to differences in injection site stiffness. Accordingly, this study aimed to create acrylamide-based hydrogel phantoms of various porosities and stiffness, which we hypothesized would better predict in vivo performance. Implant microstructure and shape were found to be dependent on the stiffness of the phantoms, while drug release was found to be dependent on both phantom porosity and stiffness. Specifically, SEM analysis revealed that implant porosity and interconnectivity decreased with increasing phantom stiffness and better mimicked the microstructure seen in vivo. Burst release of drug increased from 31% to 43% when in standard acrylamide phantoms vs macroporous phantoms (10 kPa), improving the correlation to the burst release seen in vivo. Implants in 30 kPa macroporous phantoms had the best correlation with in vivo burst release, significantly improving (p < 0.05) the burst release relative to in vivo from 64%, using a standard PBS dissolution method, to 92%. These findings confirm that implant behavior is affected by injection site stiffness. Importantly, with appropriate optimization and validation, hydrogel phantoms such as the one investigated here could be used to improve the in vitro-in vivo correlation of in situ forming implant formulations and potentially augment their advancement to clinical use.

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“…This process involves water absorption and swelling of the implant that leads to detachment of polymeric chains and subsequently polymeric chains scission. [26,27] In general, weight loss increased significantly in all blends (comparing the first and last time points, p < 0.0001). RG756 implant showed significantly lower weight loss compared with RG752 because of its higher molecular weight ( Fig.…”

Section: Effect Of Plga Typementioning

confidence: 84%

“…The solidification of implant does not occur instantly, but it is a continuous process that depends on the kinetics of the phase inversion. This process involves water absorption and swelling of the implant that leads to detachment of polymeric chains and subsequently polymeric chains scission . In general, weight loss increased significantly in all blends (comparing the first and last time points, p < 0.0001).…”

Section: Resultsmentioning

confidence: 99%

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

Enayati

Mobedi

Hojjati-Emami³

et al. 2017

Polym. Adv. Technol.

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In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic‐co‐glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano‐hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic‐co‐glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first‐order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90‐day period with significant decrease of burst release phase (50%, p < 0.001) compared with the conventional Eligard formulation. The histopathology test showed that the formulated implant had no effects of toxicity or tissue necrosis in organs of the animal model. Copyright © 2017 John Wiley & Sons, Ltd.

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The Effect of Additives on the Behavior of Phase Sensitive In Situ Forming Implants

Cited by 25 publications

References 44 publications

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Macroporous acrylamide phantoms improve prediction of in vivo performance of in situ forming implants

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

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