Surface-Modified
Lyotropic Crystalline Nanoconstructs
Bearing Doxorubicin and Buparvaquone Target Sigma Receptors through
pH-Sensitive Charge Conversion to Improve Breast Cancer Therapy
In the current study, we aimed to
develop lyotropic crystalline
nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG)
with a two-tier strategy. The first objective was to confer pH-responsive
charge conversion properties to facilitate the delivery of both doxorubicin
(DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness
their synergistic effects. The second goal was to achieve targeted
delivery to sigma receptors within the tumor tissues. To achieve this,
we designed a pH-responsive charge conversion system using a polymer
consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with
methoxybenzamide (MBA) for potential sigma receptor targeting. The
resulting B + D@LCNs were further modified by surface functionalization
with PLG–MBA to confer both sigma receptor targeting and pH-responsive
charge conversion properties. Our observations indicated that at physiological
pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under
acidic conditions (pH 5.5, characteristic of the tumor microenvironment),
they acquired a positive charge. The particle size of P/B + D-MBA@LCNs
was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ±
1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed
through small-angle X-ray scattering (SAXS) diffraction patterns.
Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was
confirmed using confocal laser scanning microscopy and flow cytometry.
The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M
phase arrest (55.20%) compared to free B + D (37.50%) and induced
mitochondrial depolarization (59.39%) to a greater extent than P/B
+ D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly
improved area under the curve (AUC) values for both DOX and BPQ when
administered as P/B + D-MBA@LCNs, along with enhanced tumor localization.
Tumor regression studies exhibited a substantial reduction in tumor
size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions
compared to B + D and nontargeted P/B + D@LCNs groups, respectively.
In summary, this two-tier strategy demonstrates substantial promise
for the delivery of a drug combination through the prototype formulation.
It offers a potential chemotherapeutic option by minimizing toxic
effects on healthy cells while maximizing therapeutic efficacy.