Background/Objectives: Basal cell skin cancer (BCSC) develops when skin cells proliferate uncontrollably. Sonidegib (SDB) is a therapeutic option for the treatment of BCSC by inhibiting hedgehog signaling. The problems with SDB’s low solubility, poor bioavailability, resistance, poor targeting, and first-pass action make it less effective when taken orally. This investigation set out to design an intratumoral in situ pH-sensitive hydrogel of SDB-invasomes (IPHS-INV) that can effectively treat BCSC by improving SDB’s bioavailability, sustainability, targeting, and efficacy while also reducing its resistance and undesirable side effects. Methods: Numerous S-INV formulations were developed using Box–Behnken Design Expert and tested before settling on the optimum S-INV formulation. An experimental 7, 12-dimethylbenzanthracene (DMBA) carcinoma rat model was used for in vivo studies of the IPHS-INV formulation after it was combined with chitosan. Results: Phospholipids (1.72% w/w), cholesterol (0.15% w/w), ethanol (1% v/v), and cineole (1.5% v/v) were shown to be the optimal components in the SDB-invasome formulation. The IPHS-INV formulation outperformed the permeation and bioavailability of free SDB by 7.14 and 6 times, respectively, and sustained its release by 57.41%. The IPHS-INV formulation showed a decrease in tumor volume of 99.05% and a reduction of hypercellular tumors, indicating its anti-cancer activity. The intratumoral IPHS-INV formulation maintained a higher concentration of SDB in tumors, indicating its targeting activity. Conclusions: These findings support the use of the intratumoral IPHS-INV formulation as an effective strategy for the treatment of BCSC.

Background/Objectives: Raloxifene (RLF) is a therapeutic option for invasive breast cancer because it blocks estrogen receptors selectively. Low solubility, limited targeting, first-pass action, and poor absorption are some of the challenges that make RLF in oral form less effective. This study aimed to create an intra-tumoral in situ pH-responsive formulation of RLF–invasome (IPHRLI) for breast cancer treatment, with the goals of sustaining RLF release, minimizing adverse effects, and enhancing solubility, bioavailability, targeting, and effectiveness. Methods: Numerous RLF–invasome formulations were optimized using design expert software (version 12.0.6.0, StatEase Inc., Minneapolis, MN, USA). Integrating an optimal formulation with an amalgam of chitosan and glyceryl monooleate resulted in the IPHRLI formulation. In vivo testing of the IPHRLI formulation was conducted utilizing the Ehrlich cancer model. Results: Requirements for an optimum RLF–invasome formulation were met by a mixture of phospholipids (2.46%), ethanol (2.84%), and cineole (0.5%). The IPHRLI formulation substantially sustained its release by 75.41% after 8 h relative to free RLF. The bioavailability of intra-tumoral IPHRLI was substantially raised by 4.07-fold compared to oral free RLF. Histopathological and tumor volume analyses of intra-tumoral IPHRLI confirmed its efficacy and targeting effect. Conclusions: the intra-tumoral administration of the IPHRLI formulation may provide a potential strategy for breast cancer management.