Boosting the Potential of Chemotherapy in Advanced Breast Cancer Lung Metastasis via Micro-Combinatorial Hydrogel Particles
Breast cancer cell colonization of the lungs is associated with a dismal prognosis as the distributed nature of the disease and poor permeability of the metastatic foci challenge the therapeutic efficacy of small molecules, antibodies, and nanomedicines. Taking advantage of the unique physiology of the pulmonary circulation, here, micro-combinatorial hydrogel particles (µCGP) are realized via soft lithographic techniques to enhance the specific delivery of a cocktail of cytotoxic nanoparticles to metastatic foci. By cross-linking short poly(ethylene glycol) (PEG) chains with erodible linkers within a shape-defining template, a deformable and biodegradable polymeric skeleton is realized and loaded with a variety of therapeutic and imaging agents, including docetaxel-nanoparticles. In a model of advanced breast cancer lung metastasis, µCGP amplified the colocalization of docetaxel-nanoparticles with pulmonary metastatic foci, prolonged the retention of chemotoxic molecules at the diseased site, suppressed lesion growth, and boosted survival beyond 20 weeks post nodule engraftment. The flexible design and modular architecture of µCGP would allow the efficient deployment of complex combination therapies in other vascular districts too, possibly addressing metastatic diseases of different origins.
View details for DOI 10.1002/advs.202205223
View details for Web of Science ID 000919112900001
View details for PubMedID 36683230
A Coarse-Grained Molecular Dynamics Description of Docetaxel-Conjugate Release from PLGA Matrices
Despite the extensive use of poly-lactic-glycolic-acid (PLGA) in biomedical applications, computational research on the mesoscopic characterization of PLGA-based delivery systems is limited. In this study, a computational model for PLGA is proposed, developed, and validated for the reproducibility of transport properties that can influence drug release, the rate of which remains difficult to control. For computational efficiency, coarse-grained (CG) models of the molecular components under consideration were built using the MARTINI force field version 2.2. The translocation free energy barrier ΔGt* across the PLGA matrix in the aqueous phase of docetaxel and derivatives of varying sizes and solubilities was predicted via molecular dynamics (MD) simulations and compared with experimental release data. The thermodynamic quantity ΔGt* anticipates and can help explain the release kinetics of hydrophobic compounds from the PLGA matrix, albeit within the limit of a drug concentration below a critical aggregation concentration. The proposed computational framework would allow one to predict the pharmacological behavior of polymeric implants loaded with a variety of payloads under different conditions, limiting the experimental workload and associated costs.
View details for DOI 10.1021/acs.biomac.2c00903
View details for Web of Science ID 000874668200001
View details for PubMedID 36237166
Boosting the therapeutic efficacy of discoidal nanoconstructs against glioblastoma with rationally designed PEG-Docetaxel conjugates
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
2022; 174: 90-100
Maximizing loading while modulating the release of therapeutic molecules from nanoparticles and implantable drug delivery systems is the key to successfully address deadly diseases like brain cancer. Here, four different conjugates of the potent chemotherapeutic molecule docetaxel (DTXL)were realized to optimize the pharmacological properties of 1,000 × 400 nmDiscoidal PolymericNanoconstructs(DPNs). DTXL was covalently linked to poly-(ethylene) glycol(PEG)chains of different molecular weights, namely 350, 550 and 1,000 Da, and oleic acid (OA). After extensive physico-chemical and pharmacological characterizations, the conjugate PEG550-DTXL showedan optimal compromise between loading and sustained release out of DPNs, as opposed to the insufficient loading of PEG1000-DTXL and PEG350-DTXL and the excessively slow release of OA-DTXL. Not surprisingly, viability tests conducted on U87-MG cells showed a delay in cytotoxic activity for the DTXL conjugates compared to free DTXL within the first 48 h. However, PEG550-DTXL returned an IC50 value of ∼ 10 nMat 72 h, which is comparable to free DTXL.In mice bearing orthotopically implanted U87-MG cells, the intravenous administration of PEG550-DTXL loaded DPNs doubled the overall animal survival (52.5 days) as compared to temozolomide (27 days) and the untreated controls (32 days). Collectively, these results continue to demonstrate that the therapeutic efficacy of nanoparticles can be boosted by rationally designing drug conjugates-particle complexes for optimal loading and release profiles.
View details for DOI 10.1016/j.ejpb.2022.03.011
View details for Web of Science ID 000803850300001
View details for PubMedID 35358697
- Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth NANO RESEARCH 2022; 15 (1): 482-491