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The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained release carriers: in situ-forming implants.

ABSTRACT: Our previous studies revealed that the PLGA-based particulate systems loaded with cucurbitacin showed limited anti-melanoma efficiency in xenograft animal models after intratumoral injection, which was due to the undesirable initial burst release and the leakage of the particulate carriers from the injection site through the pinhole. In this paper, two categories of in situ-forming implants (ISFIs) for intratumoral injection, PLGA ISFIs and SAIB ISFIs, were systemically evaluated for their potentials for on solid tumor treatment via intratumoral injection. The in vitro drug release profiles of these two ISFIs were different due to the different sol-gel transition properties. The pharmacodynamics results revealed that SAIB ISFIs displayed obvious therapeutic efficiencies to melanoma, and multi-points injection of SASIB ISFIs displayed better efficiency than single-point injection. The different sol-gel transition properties and mechanism for PLGA ISFIs and SAIB ISFIs affected both the drug release and strongly impacted the pharmacokinetic parameters and pharmacodynamic effectiveness. Also, the adhesive property of SAIB to the local tissue could extend the retention and inhibit the leakage of the SAIB ISFIs, thus enhanced the anticancer effectiveness. Comparison of the various intratumoral injection systems, appropriate drug release profiles (lower initial burst and steady release) and good retention (minimum leakage from the injection site) would benefit to the antitumor effects of the intratumoral depots.

SUBMITTER: Guo J

PROVIDER: S-EPMC4508284 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained release carriers: in situ-forming implants.

Guo Jianbo J Wang Junwei J Cai Chenchen C Xu Jinghua J Yu Hongdan H Xu Hui H Xing Tang T

AAPS PharmSciTech 20150122 4

Our previous studies revealed that the PLGA-based particulate systems loaded with cucurbitacin showed limited anti-melanoma efficiency in xenograft animal models after intratumoral injection, which was due to the undesirable initial burst release and the leakage of the particulate carriers from the injection site through the pinhole. In this paper, two categories of in situ-forming implants (ISFIs) for intratumoral injection, PLGA ISFIs and SAIB ISFIs, were systemically evaluated for their poten ...[more]

PMID: 25609378

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Project description:The intratumoral injection of therapeutic agents responsive to external stimuli has gained considerable interest in treating accessible tumors due to its biocompatibility and capacity to reduce side effects. For the first time, a novel approach is explored to investigate the feasibility of utilizing low-intensity ultrasound in combination with intratumoral injection of drug-loaded magnetic nanoparticles (MNPs) to thermal necrosis and chemotherapy with the objective of maximizing tumor damage while avoiding harm to surrounding healthy tissue. In this study, a mathematical framework is proposed based on a multi-compartment model to evaluate the effects of ultrasound transducer's specifications, MNPs size and distribution, and drug release in response to the tumor microenvironment characteristics. The results indicate that while a higher injection rate may increase interstitial fluid pressure, it also simultaneously enhances the concentration of the therapeutic agent. Moreover, by increasing the power and frequency of the transducer, the acoustic pressure and intensity can be enhanced. This, in turn, increases the impact on accumulated MNPs, resulting in a rise in temperature and localized heat generation. Results have demonstrated that smaller MNPs have a lower capacity to generate heat compared to larger MNPs, primarily due to the impact of sound waves on them. It is worth noting that smaller MNPs have been observed to have enhanced diffusion, allowing them to effectively spread within the tumor. However, their smaller size also leads to rapid elimination from the extracellular space into the bloodstream. To summarize, this study demonstrated that the local injection of MNPs carrying drugs not only enables localized chemotherapy but also enhances the effectiveness of low-intensity ultrasound in inducing tissue thermal necrosis. The findings of this study can serve as a valuable and reliable resource for future research in this field and contribute to the development of personalized medicine.

Project description: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 (LD50) 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.

Dataset Information

The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained release carriers: in situ-forming implants.

Publications

The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained release carriers: in situ-forming implants.

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